Is Schizophrenia as ontologically defined as the Flu is? There have been plenty of cases of it being misused as a political diagnosis, in the Soviet Union for instance, and even if there's a known ontology it would still be equivocation if it's never clinically tested for and the diagnosis is still only based on symptoms.
It's necessarily not as ontologically defined, because schizophrenia is a syndrome and the flu is a cause. I think an apples-to-apples comparison would be if it's as well defined as "flulike symptoms", to which the answer is that nobody bothers to define flulike symptoms and they just say "you'll know it when you see it".
Sounds fake. How do I know that syndromes are even a real class of things, vs a word used to pretend there is a class of things that is conveniently shaped to plug that specific hole in human ignorance.
Possibly you could break down a bunch of syndromes into component symptoms, put them in a list, add in other symptoms, collect a huge amount of data from a lot of people as objectively as possible, and see where the clusters are. If infection with the influenza virus is associated with a particular cluster of symptoms, it might make sense to call that cluster "flu-like symptoms" (which may be somewhat different than the cluster we currently call that). If other root causes correlate with that cluster, then it might make sense to take the most common one and use that for the name; it might be "flu", but might theoretically be something else.
Not that we've done that, but it seems like it might be possible?
I'm sure it's possible. It's just been kind of frustrating to see even celebrated rationalists backslide (or remain?) at the level of showing how a math problem can be solved, not doing the math, then championing a result.
The mathematician's problem of enjoying the interesting work of proving that a solution exists, but refusing to do the tedious work of coming up with the actual solution? :-)
Practically speaking, I'd worry about falling afoul of HIPAA or an IRB or something, to get that much data.
Definitely, it's conveniently shaped to plug a specific hole in human ignorance. I think most psychiatrists would probably agree that schizophrenia is a messy concept and it would be great to have less messy concepts, but we're not there yet.
I would encourage you to think of schizophrenia differently, though. I think of syndromes as a way to know who's going to benefit from specific treatments. We have studies showing that, for people who've been diagnosed with schizophrenia, they seem to be less likely to die if they take antipsychotics [1] (modulo a U-shaped dose-response curve, though I suspect reverse causation on the high end, since people with worse schizophrenia tend to end up on higher doses). Obviously, you can disagree with the studies here, but you can disagree with studies about anything; these seem relatively robust compared to a lot of other treatments in medicine.
There are also other benefits to taking antipsychotics in schizophrenia, as well as risks; much ink has been spilled over balancing them, and it's certainly an interesting topic to read about. The same can be said about other treatments for schizophrenia, like psychotherapy or neuromodulation. I will caution that, when interpreting literature in psychiatry, it's important to look at a lot of studies, and look at overall patterns; you will come to incorrect conclusions if you pay too much attention to a single study. But this is a digression.
In other words, schizophrenia is a concept that, among other things, lets doctors find people who will live longer if they give them antipsychotics, and living longer is kind of hard to argue with.
When diagnosing a patient, what criteria do you use to decide when to say "this person has schizophrenia", vs "this person has <some different type of brain problem>"?
According to DSM-5, the person has to be experiencing at least two of the following -- either delusions, hallucinations, or disorganized speech -- over much of the time of a period of at least one month.
There's a bit more to it as well, in terms of ruling out other conditions: for example, autoimmune encephalitis can cause symptoms resembling schizophrenia.
We speak of schizophrenia as if it is a single, well defined pathology (ie. essential nature) when we really still have no basis for such an assertion. The 'diagnosis' being a catch all for a constellation of diverse signs and symptoms with a wide and variable range of expression of largely indeterminate causation(s). (The plurality there - alone- being obvious reason for pause and reconsideration.)
All of which is why we -properly- speak of people having met "criteria consistent with" a diagnosis of schizophrenia. Because, as a matter of fact, we have no warrant to say that they even have the exact same thing. At best we recognize that their particular brain AND mental dysfunctions are being expressed in a recognized and patterned manner.
Dementia is another term often used to describe a clinical presentation with an equally vague and diverse set of conditions yet viewed as somehow being of specific and 'well defined' nature my dint of having been given a name.
Also, autism is vague in the same way. Or better named "autism spectrum disorder". My daughter is on the spectrum, supposedly, but it took years to get the diagnosis, because she was atypical (as are many girls). I'm still not convinced that that is exactly what is going on with her, but it was a helpful diagnosis for us, since we were then able to get her appropriate therapies, and we could point to her dx to convince people to be more understanding of her differences. Our family participated in the SPARK (genetic) project, but we've never heard from them about any particular gene that they identified in our case. More and more, I am suspecting that the environmental factors that I worried may have caused her disorder, might actually have.
I'm also interested in schizophrenia, since a branch of my family also has several members with that. Scott, have they actually identified the relevant gene/s? How many are there? I'd be interested in getting tested just for curiosity's sake. Are there multiple genes, for example? Could different branches of the family show one or some, and not display the symptoms?
Im in a similar situation to yours. I have two daughters both w ASD dx, one profoundly so, one much more typically presenting. We did genetic testing on our more effected child revealing no "de novo" or single cause of the ASD. This doesn't mean her condition isn't mostly genetic. It just means the state of genetic counseling is in the practice of finding and communicating very noticeable obvious differences between an effected individual and the general population. Per Wendy Chung (on The Drive with Peter Attia, who was a lead researched in SPARK I believe) says the current guess is there are 1,000 implicated genes in ASD and researchers are maybe 1/3 the way in mapping them all. Interestingly these genes seem to be generalist, which I take to mean if you have an adequate collection of these genes, you're at risk for developing some kind of neurodevelopmental disorder (ASD, ADHD, schizophrenia, depression). The current state of genetic understanding cant yet tell us exactly which condition/s is most likely to develop per se. But I have very little scientific training or understanding so take all that with a grain of salt. Some links that may be of interest:
I’m surprised that despite a dozen arguments on this list, not one of them is the arguably-correct one: that heritability might be a bad match for human intuitions of what “mostly caused by” means. (e.g. the low concordance probability of schizophrenia in twins, which is counterintuitive. We can respond to this either by saying concordance probabilities are a bad operationalization of “caused by genes,” or by saying the biggest cause of schizophrenia is “shitty luck” or “nonlinear responses to inputs that don’t add up to 1.” Of course, this buys you a whole heck of a lot of other paradoxes instead.)
The concordance is (theoretically) even lower for unrelated people raised in identical environments, so by this logic it makes even less sense to say that it's mostly environmental.
It's possible for two children in the same environment to have (at least somewhat) different childhoods and traumas, and for one of the children to be more traumatized/abused/neglected than the other(s).
Polygenic screening doesn't prevent schizophrenia in a meaningful way, though. It just prevents those embryos with high risk from developing into people (modulo your beliefs about when personhood begins).
That seems at odds with how most people would resolve other moral choices.
For instance, in triage situations, it's normally considered good for doctors to treat the person with the best survival chance rather than picking randomly.
Conversely, it's normally considered obligatory for them to treat as many people as they can--it would be pretty weird to have a situation where it's morally obligatory to give an EQUAL survival chance to everyone, but NOT morally obligatory to make that survival chance be as high as you reasonably can. By analogy, it would be weird if you had a free choice about HOW MANY embryos to incubate, but not a choice of WHICH embryos to incubate.
And I have difficulty imagining anyone arguing that you ought to choose the other parent of your child at random, to give all possible potential children an equal chance, instead of having a baby with your spouse. (You could argue that the difference here is that the embryos aren't fertilized yet, and your obligations only start when they are--but that seems to make the objection from the previous paragraph even more acute.)
If you believe personhood occurs early in embryonic development you shouldn't create superfluous embryos, yes. However, supposing you have already made that error, I don't think assigning equal or near-equal survival chances to each are all that unreasonable. The reductio ad absurdum of your own position would be that if there's some small number of gene combinations that maximize life, all other things being equal ONLY those gene combinations should ever exist. I think most people value hetereogeneity in life to an extent that allows you to leave a large number of QALY's on the table, at which point it's not clear to me that there's an airtight argument for favoring non-schizophrenics over schizophrenics anymore.
I wasn't trying to promote any specific position, but I notice that the position you have chosen to argue against is "it is OBLIGATORY (not merely permissible) to choose the embryo with more QALYs", and there is plenty of room for that position to be wrong without the "it is obligatory to choose by RNG" position being correct. (Also I'm not sure I buy that your reductio really is absurd, but I don't feel strongly enough to want to defend it right now.)
Re "supposing you have already made that error," imagine a story where, due to some SF/F premise, it is possible to suddenly accidentally create several obviously-fully-developed people, where you meant to create one. In all the stories like this that I can recall, the characters take it as morally obvious that you are now obligated to preserve ALL of the people you created (if possible). I cannot recall a single one where it was suggested that you are morally obligated to choose randomly which one to keep, but are free to discard the rest. I predict that a story where all the characters agreed on that standard would evoke moral disgust in most readers.
It's possible that RNG selection actually ends up with less heterogeneity in the end! The only acceptable way to choose embryos is to invent metrics of uncertain value or real-world relevance and then laboriously search for the embryo that maximizes all of them (weighted, of course, with the results of your preliminary work to determine how to choose weights without immorally privileging things like general health, QALYs, intelligence, etc).
I'll take a stab at it then: Embryos aren't "entitled" to anything and you can use absolutely any metric you please for determining which ones get to develop and be born.
I'll agree with that. But it is categorically different from preventing lung cancer by banning cigarettes, or preventing car accident deaths by requiring car seats.
But... why would we care? You can carve reality in an infinity of ways - several infinities, most likely. "it is categorically different" has value only so far as this category pays dividends.
I'm sorry if I'm over-reaching here, but a common argumentation technique is to carve reality at an arbitrary point, they use this categorization as a supporting argument for something else.
In this particular case polygenic testing prevents schizophrenia in future children in all ways that count - pretty much functionally identical with how folic acid or abstaining from smoking and alcohol prevent a bunch of other conditions. We don't use a magnifying glass on how exactly alcohol is bad for you. So why mention that it's categorically different at all?
> You can carve reality in an infinity of ways - several infinities, most likely.
What would this distinction mean? Usually, you'd come up with a category, like "ways in which it is possible to carve reality", and then consider whether the number of things in the category was finite or not. Clearly it isn't, but since there's only one category, there's only one quantity involved.
>I'm sorry if I'm over-reaching here, but a common argumentation technique is to carve reality at an arbitrary point, they use this categorization as a supporting argument for something else.
It’s not as arbitrary as you think. You can prevent schizophrenia “at the societal level” by killing everyone who might get schizophrenia. Who could possibly be against this? You will never have to deal with a schizophrenic again! We can create a schizophrenia-free society!
More seriously, I’m not one of those people who believes in objective morality, but if I was, I would be very concerned that IVF clinics are literally Auschwitz.
I’m not necessarily opposed to IVF, but I think it’s a relevant consideration to bring up if one is arguing that the objections are stupid. It didn’t even click for me reading the post that we were talking about murdering embryos until we get the right one until I saw the top comment in this chain.
I thought one of Scott's recent posts shows that not to be true (or at least not as easy as it seems). Nazi Germany tried to kill all schizophrenics, and they have the same rate as countries that did not. IIRC the rate returned to normal extremely fast as well, like the 50s or 60s.
He's not saying "kill everyone who might get schizophrenia so they won't have kids with schizophrenia" he's saying "kill everyone who might get schizophrenia, then there will be no schizophrenics left in society." Because you killed them all. When more pop up you'll kill them too.
Yes, but in your example the categorization pays dividends immediately and obviously.
My beef isn't with support or condemnation of abortion (for what's worth, I'm European and I find the whole debate strange and exotic, and rather strongly disagree with both extremes). My beef is with sneaking the categorization as an argument for the belief instead of the consequence of the belief.
If OP said "I think we should make a distinction because in one case we're killing embryos and this is bad", this would be owning your position and, agree or not, it's a valid point to make.
Instead, OP suggested in a public forum that it's a categorical difference, with the possible intention of supporting his belief with this categorization. That's circular logic, and it's also use of a Dark Art. Which is ok on Facebook or X, but I thought here should be gently censured.
I'll write a post sometime in the next few weeks about why I don't think it's categorically different from those things at all. If I forget until March, please remind me!
Please do write on this. Ive been internally grappling with the above thread for some time. My entryway has been Michael Sandel and the ethics chapter from the Walter Isaacson biography of Jennifer Doudna
In a counterfactual where people did IVF without screening, they'd still be choosing some embryos over others. Some embryos wouldn't develop into people either way. This just affects which embryos are which. But, in a eugenic sense, these embryos-turned-people could in turn reproduce and spread their genes with different risks for schizophrenia, and in different counterfactuals different embryos in the next generation won't exist at all.
...Who the hell has been saying epilepsy isn't genetic? It's pretty damn obviously genetic. Barring the ones from people getting whacked on the head really hard.
I had never heard that argument either. I have heard there is a drug (lamotrigine) which treats both epilepsy and bipolar, with the latter being closely linked to schizophrenia.
Most drugs used as mood stabilizers, like lamotrigine, were originally developed as anticonvulsants. (The big exception is lithium, which for decades was the only available mood stabilizer.) Bipolar and schizophrenia are both responsive to treatment with antipsychotics, but I don't know that I'd otherwise describe the disorders as "closely linked."
There was a major study in the Lancet 'Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis Cross-Disorder Group of the Psychiatric Genomics Consortium'. This identified shared risk loci with cross-effects on 5 disorders including Bipolar and schizophrenia.
Quoting from Wikipedia's quote of William T. Carpenter:
"Genetic studies do not support the view that schizophrenia, psychotic mood disorders and schizoaffective disorder are distinct etiological entities, but rather the evidence suggests the existence of common inherited vulnerability that increases the risks for all these syndromes. Some susceptibility pathways may be specific for schizophrenia, others for bipolar disorder, and yet other mechanisms and genes may confer risk for mixed schizophrenic and affective [or mood disorder] psychoses, but there is no support from genetics for the view that these are distinct disorders with distinct etiologies and pathogenesis."
> Take the case of epilepsy. Epilepsy is a recurrent abnormal, excessive, and synchronized electrical discharge in the brain. It has a heritability of 70-88%, at par with schizophrenia. However, epilepsy is not broadly characterized as a genetic disorder. The 2017 ILAE Classification of Epilepsies recognizes six etiologic categories: genetic, structural, metabolic, immune, infectious, and unknown.
I guess his idea was that since most epilepsies don't have a ILAE classification of "genetic", schizophrenia shouldn't be called genetic (but Scott's classification of schizophrenia is not simply "genetic", it's "probably mostly genetic").
> By comparison, you can very clearly halve your children’s risk of schizophrenia through polygenic selection, which costs only a few hundred dollars if you’re already doing IVF.
Last time I looked into it, polygenic risk scores for schizophrenia were only able explain ~2% of variance of schizophrenia. It’s really hard to recruit enough schizophrenics for variants in a GWAS to reach genome wide significance. And even with GWAS, you can’t measure things like copy number variants or rare variants. I think it’s at least another few decades until we can screen out schizophrenic embryos.
You can get 40-50% risk reduction with 5 embryos given the current state of PRS models [1][2] (Disclosure: I work at Orchid). I don't have a reference handy but Genomic Prediction has estimated similarly for their models.
> And even with GWAS, you can’t measure things like copy number variants or rare variants.
I should also mention, we do WGS so CNV and rare variants get sequenced (with the usual sequencing caveats). That said, the science behind linking rare variants to disease is very much a work in progress so I don't want to claim that has a big impact on Schizophrenia prevention right now.
Let's assume you are the kind of high-performing family that delays childbearing until after it is normally physically possible and spends multiple tens of thousands of dollars to try to make up for that.
What is the baseline rate of schizophrenia? According to the WHO, the rate of schizophrenia among adults is 0.45%. But it seems likely to me that the rate of eventual schizophrenia among _your_ children would be markedly less. Say it's 0.3%.
Does a 50% risk reduction matter? That would mean that for every 667 children you have, you prevented schizophrenia in one of them. And since it cost a few hundred dollars each time, you spent maybe $170,000 to do it. (Assuming you actually managed to have 667 children, which is an assumption I'm not sure we should overlook.)
It doesn't take a lot to conclude that this is not a cost-effective intervention.
According to this study [1], schizophrenia is associated with about 10-20 years lower life expectancy. So that would be $8500-$17000 per life year, running with your number of $170,000 to prevent a case of schizophrenia, which most people in North America or Europe would consider to be cost effective - and this is ignoring quality-of-life, which would make that cost-effectiveness look more attractive.
1. .45% is a global lower bound that's pretty sensitive to classification and the ability of the medical system to diagnose cases. In the US it's 1.2%. So you can use this, but it's pessimistic.
2. I have no particular reason to think a downgrade of the risk to .3% is accurate, but sure.
3. Like a sibling comment mentioned, $170,000 is incredibly cheap for a lifetime of severe disease prevention. Financially, that dwarfs the QALY ROI of most medical interventions from the past 50 years.
And this is harder to quantify, and you are going to just have to take my word from personal experience on this — Schizophrenia has an *incredibly* hard toll on the family of the affected individual. We need to not just count the QALYs of the individual. We need to count the parents, siblings, the entire support network.
4. Either way, (1) and (2) are irrelevant from the perspective of the families that are actively seeking out Schizophrenia PRS; they are seeking it out *because* of a family history. Having an affected brother or sister will tripe your child's risk. Having 2+ affected 1st degree relatives can get the risk up to 9-10%.
Do you think it's an unreasonable intervention if you can spend $17,000 to prevent Schizophrenia? I feel like even you would grant this one.
> Schizophrenia has an *incredibly* hard toll on the family of the affected individual. We need to not just count the QALYs of the individual. We need to count the parents, siblings, the entire support network.
I don't actually believe that, in the case where one couple has 80 kids (assuming odds a bit worse than 1.2%), the schizophrenia of one of those kids is going to take a major toll on the family. They just won't do the things that you expect of a more typical couple with one child who is schizophrenic.
A similar argument scales down; a 0.6% chance that your one child will develop schizophrenia is essentially impossible to distinguish from a 0.006% chance of the same. You can never have enough children for the odds to make an observable difference. Making changes that are not even theoretically detectible is generally a waste of whatever effort you went to to make the change.
Now, the 0.6% difference is perceptible if you are the government. But then your cost-benefit analysis would want to measure different effects; the fact that parents whose existing child develops schizophrenia sink a lot of resources into that child, if they have them, isn't really relevant. What is the benefit of cutting the number of schizophrenics in half on an ongoing basis? Does it exceed an ongoing cost of $250 per birth in the country? (Or... much much more than that, since applying this policy to everyone would mean replacing all natural conception with IVF implantation?)
At the society level, we will see diminishing returns; cutting the population of schizophrenics in half will probably not also cut the problems caused by schizophrenia in half.
I have a very minor amount of personal experience with schizophrenia in that a homeless woman who appeared to be pretty severely detached from reality once visited my home (staying outside and making no attempt to enter) and we had to call the police to have her removed. If there were 50% fewer schizophrenics, we might estimate that that would have had a 50% chance of happening. But it was a one-off event. I will estimate the value of preventing it at $5. She was known to the police and probably had bothered, and still bothers, other people. But I don't believe that the total amount of bother so generated exceeds $170,000, or $42,000 (close to the relevant figure at $250 per birth and a 1.2% pre-filtering rate). The general value of preventing some cases of schizophrenia isn't very high. Most of the value of prevention is specific, captured by the patient and their close relatives.
> Like a sibling comment mentioned, $170,000 is incredibly cheap for a lifetime of severe disease prevention. Financially, that dwarfs the QALY ROI of most medical interventions from the past 50 years.
I will stipulate this, but I don't think it's a good argument that the benefits exceed the costs. I think it's an example of luxury beliefs making society generally worse off. There was an econlog post a while back making the observation that (1) we have a standard for the value of lives saved by medical interventions, and (2) that standard straightforwardly implies that (under some popular assumptions) the benefit of a full halt to all production, if it stopped the spread of covid, exceeded the cost (which is easy to calculate; a loss of all production in some country is equal to that country's GDP), and then (3) that if we actually did halt all production, many more people would die than were believed to be at risk from the fully unimpeded spread of covid.
One obviously correct lesson to draw from that would be that the value of many lives is not a linear multiple of the value of one life; you can't just scale a number of lives saved by a standard "value of saving one life". But another lesson, less popular than the first one, is that our standard VSL is too large. This is unsurprising; the VSL is derived mainly by a process of first choosing how much we want to spend and then seeing how many lives we can attribute to our spending. When the goal is to spend money, prices are likely to be systematically too high.
So, I tend not to agree with the elements of your point (3). Point (4) is perfectly valid. But point (4) is also something of an argument that families without a family history of schizophrenia are *correctly* not filtering their embryos for schizophrenia; it's not an argument that everyone should start doing it.
> A similar argument scales down; a 0.6% chance that your one child will develop schizophrenia is essentially impossible to distinguish from a 0.006% chance of the same. You can never have enough children for the odds to make an observable difference. Making changes that are not even theoretically detectible is generally a waste of whatever effort you went to to make the change.
Sure, but you're not just selecting against Schizophrenia risk when you do these sorts of selections, you're selecting for/against a hundred different things like it. And on that level if you have a 0.6% chance of *bad thing* for each bad thing for each unselected individual but only a 0.006% chance for each selected individual there's a close to 50% chance of at least one *bad thing* with your child if unselected while you only have a risk of 0.6% of at least one bad thing if you select your embryo.
Now in reality there are tradeoffs because you are limited in the amount of embryos you have to choose from so you can't just independently select on all traits, and therefore you almost certainly won't be able to get the risk of "at least one bad thing" down to 0.6%, but it's perfectly plausible to get the risk down to say 20% instead of 50%, which is most definitely noticably on the individual level.
I don't think people with low risk should be prioritizing schizophrenia risk when doing their embryo selection. But if you *do* have high genetic predisposition to schizophrenia, as can be easily determined, it makes sense to do some embryo selection to lower that risk. Or at least, it makes more sense than any other preventative measures you might take to prevent schizophrenia.
Heritability/Variance explained and PGS (polygenic scores) are two different (but not unrelated) things. For embryo selection/gene modification it's the second you care about, not the first. My understanding is for Schizophrenia we have very good PGS score estimates so we can do embryo selection.
One extreme example to see they are not the same is: consider a gene variant at a locus which is 99.99999999% protective against Schizophrenia, in other words if you carry a copy of this variant you have 99.99999999% reduced risk of Schizophrenia. Such a variant is going to have a very high PGS score. Suppose however this variant is only present in 10 people on the planet, so the total amount of variation in Schizophrenia it explains will be very close to 0.
Now because this variant is so rare you can't use it for embryo slection (with probability very close to 1 no embryo will carry it), but you can use it for e.g. in vivo gene modification. In reality you have lots of loci which are a lot more attuned version of this, so in many cases (including Schizophrenia) you can get pretty good control on the child's risk of developing the disease even if the heritability is low by itslef.
> One extreme example to see they are not the same is: consider a gene variant at a locus which is 99.99999999% protective against Schizophrenia, in other words if you carry a copy of this variant you have 99.99999999% reduced risk of Schizophrenia. Such a variant is going to have a very high PGS score. Suppose however this variant is only present in 10 people on the planet, so the total amount of variation in Schizophrenia it explains will be very close to 0.
This is a good theoretical example, but in reality won't the PGS score be zero because nobody has ever identified the variant?
My late father was epileptic. Today I am the family-tree geek in our extended clan and, with three decades' worth of researching/compiling under my belt, am confident in identifying exactly one person from whom my father may have inherited it: his maternal grandfather. That guy died in 1909 in his late 30s, and from various family lore and old letters and newspaper articles (he'd been a local celebrity) the retroactive diagnosis of epilepsy has decent odds of being correct. Maybe in the range of 75-25.
If that retroactive diagnosis is correct then we have a strong possibility for when/how my great-grandfather became epileptic: in a swimming accident when he was about 20. He was on a group outing at a local swimming hole which was actually an old quarry, a friend started struggling in the water, great-grandpa dove in to help him but had badly misjudged the water depth at the point that he dove in. He slammed his head on a quarry shelf, was knocked unconscious, took days to recover, and was subject to random "episodes" (in the language of the day) for the rest of his life. (All of which is, again, documented both from family lore and a local newspaper article about the incident which occurred in upstate New York.)
I have not found any hints of any epilepsy-type issues among any of that great-grandfather's forebears. Of course that can't conclusively prove a negative but, I do have those folks well-documented in general and going back a good ways.
All of the above leaves me with a question: if we do stipulate that my great-grandfather was epileptic, and that it was caused by that incident rather than a genetic disposition -- then does that enable, or refute, the possibility that my father inherited it from him?
I'm curious how the part about "schizophrenia is so famously hard to define that we’re not even sure it exists" squares with "studies from 1970s China find exactly the same heritability as Western studies". If it's that hard to define, isn't it likely they're using different definitions in different studies, making direct comparisons pretty hard?
I haven't read the 1970s China study, but I would guess they were using the DSM (given how old it is, probably DSM-1) or some other definition comparable to what Westerners use.
More fundamentally, I don't think that difficulty getting an intensional definition necessarily correlates with trouble picking it out when you see it. Porn is the classic example of "impossible to define but I know it when I see it", and I think there would be very high inter-rater reliability on which art is vs. isn't porn (I'm not saying there aren't ambiguous cases, I'm saying most art is either the Mona Lisa which definitely isn't porn, or Hot Vixens In Your Area which definitely is). Likewise, there's huge debate over what definition we should use for "a woman" and some people can't come up with any definition that really satisfies them, but people basically agree on 99% of cases of who's a woman and who isn't.
I don't know if this is a good comparison, considering the distinctions for those examples aren't particularly meaningful. What's art and what's porn is ultimately just subjective, and I personally consider a lot of stuff to be both. I also think gender is stupid and shouldn't exist, and we really should just be referring to chromosomes when it's relevant for medical and scientific contexts.
But schizophrenia is a consistent condition with a consistent mechanism of action, as far as we're aware, anyways. If completely different brain dysfunctions do cause indistinguishable symptoms, that does complicate things a bit. If that is the case, said conditions should be given different names, and then we can meaningfully judge if each of them is caused by genetics.
Disagree. In the ontology of https://slatestarcodex.com/2019/12/04/symptom-condition-cause/ , schizophrenia is a condition, like lung cancer. We don't give lung cancer caused by smoking a different name from lung cancer caused by radiation or lung cancer caused by random bad luck. I think we'll find that schizophrenia is a specific cluster of symptoms caused by a specific kind of damage to a specific abstract system, but that many things can be the upstream cause of that damage.
I don't think the distinction you draw between "symptom", something that a patient reports, and "condition", [definition unclear], is useful. Or rather, it's useful to you as a practicing doctor, because you're mostly working off of patient reports. But you definitely can say that "pulmonary edema is a symptom of X", and people do it all the time. They say that because it's caused by X, and that's what "symptom" means. That gives us a simple and useful distinction between symptoms and causes: if you remove a cause, the symptom will go away, but if you remove a symptom, the cause will remain in place and the symptom will come back.
But what's the distinction between a symptom and a condition? A symptom is a state of being that's easy to perceive, and a condition is a state of being that might be hard to perceive? What happens when you can clearly see a symptom visibly present on the surface of the patient, but the patient doesn't report it to you?
The pulmonary edema example looks to me more like a causal chain than a set of three different kinds of things. The pulmonary edema is a cause of breathing difficulty and a symptom of heroin overdose. The breathing difficulty is a symptom of pulmonary edema. The heroin overdose is a cause of pulmonary edema. Where did the concept of a "condition" come into the analysis?
Regarding argument number 3 specifically, neuroscientist Kevin Mitchell wrote a great book called Innate in which he explains how many mental disorders seem to be caused by non-specific genetic mutations that increase developmental noise. His book is full of insights.
Highly recommend Kevin Mitchell’s work in general. I’ve been reading his blog for 10+ years and his intuitions as a behavioral geneticists have always made a lot of sense to me.
Schizophrenia serves an important social function by generating people who assert and act according to blatantly false ideas for non-predatory reasons:
* Based function: This allows sociopaths to prototype new con games while scapegoating non allied persons who act similarly enough to be confused for them
* Woke function (theoretical): This allows neurotypicals to discern deeply entrenched con games and the people who play them
You don't test them on schizophrenics. You watch the schizophrenics do crazy things and you see which ones have unanticipated effects while taking notes from a distance. Then you make a hypothesis about why it had those effects, and try to deploy those same behaviors to selective intentional effect. Schizophrenics will consistently find and exceed the boundaries of human social life even at personal cost, and more prudent people have the opportunity to observe and selectively learn from these tests, which are unlikely to occur otherwise.
So if society thinks that if you insult Zeus, then he'll strike you with lightning, but a schizophrenic insults Zeus all the time and remains un-electrified, then we might start to suspect that we can get away with the same behavior?
That sounds plausible as a useful side-effect, but I'm dubious that evolution would select for it? There's also a bunch of sayings about how God protects fools and madmen, which I'd guess would be a memetic immune response, basically "don't try this at home, kids".
More likely the first person to tell someone not to insult a metaphor or concrete bad things would happen, and have people believe them, had something wrong with them, but it worked, and leaders noticed it worked, and that's how you ended up with that particular religious tradition at all.
It does seem evolutionarily implausible because it would probably only operate on a group selection basis. I don't really have an answer to that. I just have a theory that fits my observations at the moment. I guess this should make me happy because it is weak evidence group selection is possible which gets me further away from nightmare world interpretations and closer to Kropotkin mutual aid as fitness stuff.
I'm generally fine with group selection as an abstract mechanism; my main problem with it is that it's very easy for people to come up with Just-So stories about how something is adaptive, in ways that it's hard to investigate scientifically. But it's not on the same level as perpetual motion machines.
I think historically we see the opposite. Schizophrenic delusions are often religious and it's more likely people see schizophrenics worried about how Zeus is going to strike them with lightning at anytime and end up believing the same than the opposite.
The only schizophrenic I knew claimed to have experiences of this general type, but was not the sort of person who would inspire anyone to believe what she said. Maybe that's just my WEIRD mindset, though. Perhaps in a pre-rational ancestral habitat, she'd have had higher status and a better life, and have been treated as something of an oracle.
That's not plausible as a useful side effect of schizophrenia just because people curse the gods all the time. By definition, it is their fault when something bad happens to you!
There is always a distinction drawn between offending the gods and doing something that sure sounds like it falls into the same category as what offends the gods.
Here's a classic scene from the Iliad (Perseus's edited version of Samuel Butler's prose translation):
> When they had thus armed, each amid his own people, they strode fierce of aspect into the open space, and both Trojans and Achaeans were struck with awe as they beheld them. They stood near one another on the measured ground, brandishing their spears, and each furious against the other. Alexander aimed first, and struck the round shield of the son of Atreus, but the spear did not pierce it, for the shield turned its point. Menelaos next took aim, praying to Father Zeus as he did so. "King Zeus," he said, "grant me revenge on Alexander who has wronged me; subdue him under my hand that in ages yet to come a man may shrink from doing ill deeds in the house of his host."
> He poised his spear as he spoke, and hurled it at the shield of Alexander. Through shield and cuirass it went, and tore the shirt by his flank, but Alexander swerved aside, and thus saved his life. Then the son of Atreus drew his sword, and drove at the projecting part of his helmet, but the sword fell shivered in three or four pieces from his hand, and he cried, looking towards Heaven, "Father Zeus, of all gods you are the most spiteful; I made sure of my revenge, but the sword has broken in my hand, my spear has been hurled in vain, and I have not killed him."
> With this he flew at Alexander, caught him by the horsehair plume of his helmet, and began dragging him towards the Achaeans. The strap of the helmet that went under his chin was choking him, and Menelaos would have dragged him off to his own great glory had not Zeus' daughter Aphrodite been quick to mark and to break the strap of oxhide, so that the empty helmet came away in his hand.
Alephwyr's premise is flawed; every boundary is going to be tested by a non-schizophrenic whose personality happens to lean in that direction before it gets tested by a schizophrenic. Schizophrenics are too rare for it to be otherwise.
Honestly the much more plausible theory would seem to be just be that some of the genes for schizophrenia are evolutionarily useful *in moderation* , but not when they manifest as full schizophrenia. Since schizoaffective disorder is much easier to explain evolutionarily. I know there was a slatestarcodex article on the idea before. IIRC the article also mentioned how both autism and schizophrenia have a component of both de novo harmful mutations and genes that run in families (which must have some trade off to stick around)
I'm assuming you're trying to say that schizophrenia was naturally selected for? In which case, you're probably wrong, because the genetic conditions responsible for schizophrenia seem to be heritable. If it was a product of natural selection, the genes responsible would be endemic among humanity, with the condition activating due to epigenetic factors instead. This is how homosexuality seems to work, as far as I'm aware.
If you think "how are the most common forms of neurodivergence as common as they are" is a mess, boy, you'll find "how is primary or exclusive homosexuality as common as it is" an even worse one.
(This is because gay people know full well that when we identify clear-enough genetic causes for any form of being weird, society starts to salivate about eradicating it and damn the knock-on effects, don't you want to prevent the worst-case scenario, how heartless are you for not wanting that?, and gay people have more class consciousness and access to social power than autistic or schizotypal people, so prevent doom by bringing this up any time people research the causes of homosexuality hard enough.)
The frequency of schizophrenia seems to be around 1%, which is near the limit of where you can expect something caused by de novo mutations. Homosexuality is closer to 3%, which is indeed harder to explain. My understanding is that it's among the least heritable behavioral traits though.
A beautiful example of the classic "hot take" format, complete with buzzwords and historical illiteracy. You even got the substack author to bite, absolute top tier posting.
Turkheimer used to be very influential in behavior genetics (wrote a paper about the "3 rules of behavior gen."), then he felt guilty over his career and tried to deny everything about it.
The rumor was that there was a cancellation attempt but that's all it is, a rumor, so far as I know. I have a post in drafts about how he has essentially been bullied into abandoning his old work but it feels a little too personal to publish, I dunno.
*sigh* Is it really so hard to live with the truth, no matter how horrible it might be? Refusing to accept reality isn't going to change it.
...And honestly, reading what his research was about, the implications of the results don't even seem to be that bad. The main point seemed to be that, while intelligence is genetic, being raised in a shitty environment is so awful for intelligence that it makes the genetic variance completely irrelevant. The only real implication is that we're throwing away a lot of potential value by letting children grow up in poverty.
1. the idea that some men are made of gold, some of silver, some of bronze; some are destined to rule, and some serve
2. certain traits make you a better more important person. intelligence isn't just a force multiplier, intelligent people are more worthy.
genetic/hereditarian ideas can wind up boosting these old sins and even here people are painfully unaware of it. its not like humanity accepts difference as "each man's gift from God," but will sort people into worthy masters and destined slaves, no matter how smart they think they are.
like they will still see obesity as a moral failing even if its genetic. thats why its so dangerous. youd need to be a saint to avoid it while holdng the belief
...And why would you consider those to be sins in the first place? Human lives obviously don't have equal practical value, and some are more replaceable than others. Pretending otherwise is just incredibly inefficient. When you have limited resources to be allocated, you want to allocate them in a way that offers the most returns. That applies to both resources being invested in people as well as the people themselves.
the fun thing is people who say this always think they are the allocators and the irreplaceable ones deserving of resources. The idea they might be shut out never occurs to them. Or that people might be selfish or evil and define "most returns" as to what goes to me and mine.
we arent saints. equality is needed as medicine, cs lewis said. we don't take it, we get sicker as a society. it may be a good thing to make it inefficient to put chains on others, or to be evil
Oh, reading the post (and knowing nothing of the subject) I kept thinking that this discussion is happening because schizophrenia and genes is right next door to intelligence and genes. And we can't talk about the later...
I see that much of the discussion about causation in this context is still based on verbal arguments and common sense. On the other hand I keep hearing that DAGs and the other machinery developed by Pearl and others is widely applied to epidemiology. Did anyone try to throw a bunch of potential risk factors, genetic or not, into a causal discovery framework to see what happens?
I don't think the debate about whether they're "causal" is in the sense where the opposite of that is "correlational". For example, in the omnipresent virus situation in Argument 6B, the genes would still be "causal" in a Pearlian sense.
I see. But in general are people using causal discovery (as opposed to just doing inference on a given DAG) in epidemiology at all? I could not find much at a cursory glance to the main journals. It is interesting to me because I would like to see a real world application of causal discovery on actual data: I am trying to do that on astronomical data and it would be cool to have a model from other disciplines.
Indeed, people do use causal DAGs and causal inference to interrogate and improve GWAS methodology. However causal discovery problems are notoriously unidentifiable problem in genetics, so most researchers in epidemiology do not use causal discovery in the GWAS and rightly so. In fact, just finding putative genetic instruments for mendelian randomization is often fraught with problems because everything tends to be related to everything else. It makes a lot more sense in perturbational genomics.
The other environmental risk factors for schizophrenia are equally hard to change. Poverty? Okay, don’t be poor, thanks for the important life advice. Social defeat? “Doctor, are you saying I have to never let anyone defeat me?” “Yes, it’s my official medical recommendation that you become invincible.”
Poverty is not that hard to change. You work hard, seek an education in a field with reasonably high pay, do your job well without missing days, don't have kids without a partner. Keep looking for higher-paying jobs once you get on the ladder. People do all of these things constantly.
Not being defeated is impossible, but being defeated less often and winning more often are both quite doable.
It certainly helps to be smart, but anyone who ever had a varied career could probably tell you that the middle managers are fairly often a bit dense. It is however true that someone with an IQ below 85 or so is going to have tremendous difficulty getting a high-paying job. Even there, however, the ones who get married and stay married can usually get up to $20 an hour or more (minimum wage in Seattle), eventually, if they are reliable and hard-working, and with a partner that puts their combined income at around $80,000 a year.
I would hesitate to call a couple making $80,000 in Seattle meaningfully above poverty – I would also question how likely it is that a couple, both with IQs well below 100, would purposefully relocate to Seattle based off of this logic.
I don't think you're right about that. A two-bedroom apartment in Seattle or, say, Mill Creek, a "nice" (heartless wicked sterile) area in Shoreline where I used to do deliveries, can be had for about $1700-$2000 a month. A one-bedroom on Capitol Hill can be found for $1600/month. And $5,670 is the estimated after-tax income of this couple (I used ChatGPT for this calculation, I confess), leaving them approximately $3,700 a month in after-tax income after paying rent.
Nor is Seattle very expensive. I visit every summer, and if you know where to shop, neither food nor clothes nor furniture is expensive (dining out is expensive, but that's all). The Grocery Outlet on MLK Way will sell you just about everything for less than most people pay in the rest of the country.
Only Americans could consider $3700 a month income after tax and rent "poverty." It really shows how delusional the country has become about its affluence.
"This is both totally antithetical to the spirit of real clinical medicine as it’s practiced, and ethically odious to anyone who has witnessed the side effects of antipsychotics first-hand. "
You've perhaps already written it, but an essay on side effects of psychiatric drugs (or even of drugs in general) would be interesting and useful, and a good counterweight to "just take some pills, it's no big deal" thinking.
Every drug is different enough that I'm not sure anything short of a book would be helpful. I don't think there are a lot of people who say "it's no big deal" for antipsychotics in particular - these are very big deals (although there are maybe some exceptions - Seroquel at sleeping pill doses probably doesn't count as a real antipsychotic, although it still has horrible metabolic effects, and I'm still unsure how often it's okay to use low-dose Abilify for depression). I think the "it's no big deal" perspective makes much more sense with antidepressants, although of course it's never great to trivialize side effects for anything and there are a few ways they can be very big deals if things go wrong.
low dose(5mg) abilify saved my life. it totally stopped my recurring depressions that ssri, snri and ndri' had failed to improve, and it fixed my delayed sleep phase disorder.
And what is considered an effect and what is a side effect also varies with intent.
The most famous and salient example is probably Viagra, which was first trialled as a medication against angina (or so?), but is now more famous for a side effect they noticed during that trial.
Less memetic, but probably more important is all.the weird side effects of aspirin. It started as a pain killer, but apparently is also helps with preventing heart attacks and cancer.
And what is considered an effect and what is a side effect also varies with intent.
The most famous and salient example is probably Viagra, which was first trialled as a medication against angina (or so?), but is now more famous for a side effect they noticed during that trial.
Less memetic, but probably more important is all.the weird side effects of aspirin. It started as a pain killer, but apparently is also helps with preventing heart attacks and cancer.
The author's arguments against GWAS are not very convincing. It's a god of the gaps situation, where he says that in lack of a definitive list of genes, we should assume that its not genetic. This assertion falls flat because many traits are, in fact, highly polygenic, and for those where we have sufficient data the "definitive list" has in fact been produced. Polygenic scores for height explain nearly 80% of variance, which is essentially what the heritability studies would suggest. We even have mathematical theorems that describe the number of samples we'd need to capture the heritability of other traits, including schizophrenia, as well (Steve Hsu's compressed sensing).
It also mentions that the genes have to be of small effect to be missed by GWASs. I plan to have a post next week on why this has to be true and we shouldn't find it suspicious.
Ooh! Let me predict why individual genes that cause schizophrenia must have at most a small effect:
Schizophrenia is terrible for reproduction, so a gene with large effect (in the more-schizophrenia direction) would be wiped from the gene pool near-instantaneously.
I more or less agree with all of your arguments presented here, but I disagree with the conclusion. I don't think the solution is to assert that "genetics cause schizophrenia", but rather as a society we should be a whole lot more careful about using the word "causes" in scientific research (including smoking/lung cancer).
I understand your frustration with applying a different bar to smoking and psychological diseases, but one has to start *somewhere* to enact societal change in the level of confidence that scientists imply when they are speaking with the lay public. If someone is a psychology researcher they probably will start with psychology stuff. A cancer researcher may simultaneously be pushing back against the "smoking causes lung cancer" narrative in a way that you don't see because your day job doesn't involve following prominent cancer researchers who are labelled (possibly inappropriately) as Big Tobacco puppets.
There are some things that scientists are quite confident about (nearly all of mathematics, most of physics, a lot of chemistry, some molecular biology, etc.), and there are some things that we have really good correlational data on but don't fully understand (nearly all of psychology, etc.). For the latter set of things, it is very likely that one day, as you suggest in this article, we'll find that "computational center" and it will all make causal sense. At that time, we'll find that genetics were not causal, just risk factors like in your kidney example, and we'll be able to create a very clear causal chain for each specific instance of schizophrenia. If we say "genetics cause schizophrenia" today, then when that future day comes we'll have to say, "sorry, we were dumbing it down for you, but now we know for sure what causes it" and no one will believe you (fool me once, shame on you, fool me twice, shame on me).
I personally find that way too many scientists are far too eager to assign causation long before they should. IMO, we shouldn't say we know causation until we can predict future outcomes with near 100% certainty (like we can with all of mathematics, most of physics, etc.) At the moment, our predictive capacity for both lung cancer and schizophrenia is appallingly low and doesn't get anywhere near reaching the bar where I think using the word "causal" is appropriate.
What word would you like to use for "provides explanatory power sufficient for correct prediction 70% of the time and has a clear and plausible mechanism"? Not to say genes necessarily fit that for schizophrenia but it's important we have a way to communicate that concept.
Until we have such a word, "cause" is the right one as long as you couch it in the nuance that things can have multiple causes and each can have not bear 100% predictive power.
Btw you're also wrong about how often harder sciences are willing to use "cause" by convention in this way - it's normal practice to use cause this way and equally normal practice for everyone to understand "cause" means "has predictive power and a logic-consequence-linked mechanism"
> Btw you're also wrong about how often harder sciences are willing to use "cause" by convention in this way - it's normal practice to use cause this way and equally normal practice for everyone to understand "cause" means "has predictive power and a logic-consequence-linked mechanism"
While I am skeptical that it is well understood by scientists that "cause" actually means "has a moderate amount of predictive power", I won't challenge that at the moment since I think that is less important than what laymen think when they see an "X causes Y" statement.
Gravity cause objects to fall.
Genes X+Y+Z cause Schizophrenia.
These two statements are wildly different in terms of their predictive power, but if we use the same terminology for both laymen will assume predictive power for them is similar.
I think to the layman, it is very useful to make a clear distinction between "near 100% predictive power" and "significantly less than 100% predictive power". There are some genes that I do think we could call "causal" in the sense that ~100% of the people with gene X will suffer from disease Y and people without gene X have ~0% chance of getting disease Y. In this scenario, saying "gene X causes Y" correctly informs the layman on how to think about gene X and disease Y.
Except that it doesn't predict it. If you have the genes you are still very unlikely to have the disease. Cause seems better in this sense as a nonexistent phenomenon does not need a cause (cause is generally only assumed in the presence of the symptom).
No one's making the claim "If you have the genes we predict you will get it" it's "if you have the genes we predict you will get it X% of the time" and this necessarily incorporates the fact that shizophrenia is ulta-multifactorial and has a wide distribution.
But this is still useful because we would NOT say "if you are 6ft tall we predict you'll get it X% of the time", wed say "your height has no .meaningful impact on our prediction of whether you get it".
If you wanted to know your risk of schizophrenia, learning about your genes would be the piece of information that caused by far the largest update in your estimate.
I think this is all splitting semantic hairs of course - to me it seems perfectly fair and defensible to say predicts OR or causes, and just be ready to clarify. The universe is not simple and for all that we want to, things generally can't be described both accurately and in 4 words.
The crux of the matter is that, if you want to do something about schizophrenia, either for society at large or personally for yourself or your future children, things that impact the genes will have the greatest effect on the prevalence of schizophrenia
If schizophrenia requires a certain genetic makeup to manifest, then "schizophrenia is conditional on genetics". If it just increases the risk, then just say that. I'd prefer it if scientists used more clear and precise language, and this isn't really a situation where dumbing it down for laymen is necessary. It's not like you can change your genes (unless we develop the technology for that, in which case we should just leave it to their doctor to explain it for them).
1. Finding an intermediate link in the causal chain doesn't discount calling the upstream stuff "causes". Unless time is quantized at the Planck scale, there's *always* an intermediate cause.
2. We can already prevent (half of) the cases of schizophrenia, if the embryo selection people are right. (I'll say they are for the sake of argument.) Presumably, if embryonic gene editing were possible at large scale, we could just give a child all the schizophrenia genes we know of, and I predict they'd be almost certain to get it. Wildtype (non-mutant) schizophrenics aren't that far into the tail of the genetic distribution.
This is a reasonable hypothesis, and as soon as someone does some experimentation that supports it I would be much more keen on saying that genes X,Y,Z cause schizophrenia. I don't think it is appropriate to assign causation based on a hypothesis that doesn't have strong supporting evidence when we cannot predict outcome with near 100% accuracy.
Leaving that aside, the whole concept of disease and causality is complicated, and the very idea of something "causing" a disease is context-dependent.
For example, every child born in the U.S. gets tested for a condition called PKU. If you look at a diet Coke can, you will see a warning that it “contains phenylalanine.” PKU is a genetic disease, and the people who have it have a mutation in the gene for the enzyme that allows them to digest phenylalanine.
But take a step back. If instead being a tiny percent of the population, if the mutation were prevalent – for example, like the mutation that allows us to digest milk – then it wouldn’t even be considered a disease. It would be considered normal, and phenylalanine would simply be considered to be a toxin.
Similarly, if instead of 1% of the population, 99% of the population had the CCR5 mutation that made you immune to HIV, then HIV would not be an infectious disease but a genetic disease instead.
Diseases are intellectual constructs. They’re like boundaries of countries. Sometimes they’re based on the contours of natural geography, much like borders that wind along rivers or stop at mountains. Other times, they’re arbitrary, like vertical lines dividing some of the American Midwestern states. What’s the dividing line between pneumonia vs. bronchitis? What’s the difference between a heart attack and angina? Where we divide the diseases into categories and how many divisions we draw, as physicians, are not God-given. They’re man-made.
Schizophrenia is particularly germane example because it is a mix of what are probably very different processes. Catatonic schizophrenia is very different from classic forms. Doctors tend to lump very different diseases into one category if (as was true for a long time for schizophrenia) there isn't much you can do about it. Generally, diseases are categorized by what therapy they respond to, because pragmatically, if you're going to treat the patients the same, you lump them together. And if not, you separate them. (In some instances, especially in psychiatry, diagnosis can be driven by reimbursement considerations too.)
Here is an example of a disease that some pharma companies invented: high blood pressure. Until the 1970s, there was a great deal of debate over whether hypertension was a disease that needed to be treated, especially in the elderly. Some physicians thought that as we aged, and as our blood vessels became stiffer, hypertension was a natural effort by the body to maintain blood flow to all the important parts of the body. It wasn’t until a strenuous effort by Merck and other companies to change people’s minds that it became accepted that hypertension had to be treated.
I should note that it is not clear still how, when, and with what we should treat hypertension. As more data comes out, it is becoming clear that some drugs work better than others (and some are actually harmful). Not too long ago, the guidelines were changed to make treatment of elderly patients less aggressive. The complexity of the consensus guidelines suggests that there are still many unanswered questions. The very fact that there are guidelines means the answer is no obvious - only when there is uncertainty is a guideline needed.
I agree this is true but I also think it's what I mean by isolated demands for rigor. In a world where we didn't say that viruses caused the flu, smoking caused cancer, or that genetic mutations in phenylalanine hydroxylase caused PKU, I would be okay with not saying that genes caused schizophrenia. The point of this post is that by ordinary standards, they do. I'm not really invested in completely reworking our use of causal language from the ground up, partly because that wouldn't work.
Not sure it matters much to the bottom line, but I’d be cautious about using the terminology associated with smoking risks as the sort of default baseline. Seems to me like this is an atypical situation, where there were enormous policy influences on the language and terminology associated with smoking; there was a huge (justified and good) campaign to discourage smoking, and the public health community was heavily involved in the messaging in ways that shouldn’t necessarily be assumed to be normative for every other terminological situation. I’m not saying that the scientific community wouldn’t have reached the same “smoking causes cancer” formulation even in the absence of the unusual public health campaign surrounding the issue; just that it would probably be safer to use a different and less policy-laden example as a semantic baseline for this sort of thing.
Sure, smoking was an atypical situation, but anything having to do with genetics is atypical in similar ways. There's a huge ongoing campaign to discourage admitting that genes matter for anything. Whether that's justified and good is controversial though.
This right here is the reason why Scott's arguments won't convince anyone. No one making those arguments actually gives a shit about the truth.
They have an agenda: "People cannot believe things are genetic". Then apply a mountain of motivated reasoning and sophistry to confuse people and make it seem like it's a complicated thing.
I'm far more hereditarian about psychological and behavioral traits than most liberals, so it's funny for me to take the non-hereditarian side of this one, but I'll at least offer some thoughts.
The reason we readily say that smoke has a causal, not merely a correlative, relation to cancer is not because of the statistics (although they are important). It's because we have a mechanistic explanation of the causal pathway. Tobacco has over 70 carcinogens that directly cause DNA damage, in addition to oxidative stress and chronic inflammation.
Now, of course, whatever genes do is also ultimately mechanistic, but here's where the similarity ends. We have no mechanistic account of how genes might cause schizophrenia. Of course, one might protest that that's just a statement about our knowledge. But it's worse than that. It just doesn't seem likely that whatever is going on neurologically has a causal pathway anything as straightforward as the effects of carcinogens. The interactions with the environment seem like they're far more intricately involved. It's as if smoking caused cancer, but only at certain altitudes, within certain temperature zones, when you ate certain foods, etc., etc. If the latter were the case, we'd be much more hesitant to just say "smoking causes cancer."
Thank you, this was the exact genre of example I was going to reply with: "smoking causes cancer but only if paired extensively with some other stuff". This argument applies pretty similarly to a significant proportion of mental illnesses in the DSM.
Neuroscience functions as a massive aporia in the chain of material reason required to come up with a properly mechanistic causal explanation. It's so massive that we might as well consider neuroscience to be a hard disjunction epistemically, in the sense that we literally cannot make causal arguments if they must rely on a "well X causes brains to do Y which causes Z behavioral patterns". This is why Freud and others both 2000 years before and 100 years after him still rely on a set of derivative psychological primitives that are functionally dependent on observation and permit meaningful intervention (lest we forget that the goal is ultimately helping people), but have "no scientific (= properly material, very nice sleight of hand Popper) basis".
So from a purely interventionist standpoint, polygenetic filtering is basically the only thing you can *do* with a notion of genetic causality. Thorny ethical issues aside, it would still be great to have a real mechanistic model of mental illness (Freud wanted this way back in the 1800s! And was sad we couldn't figure it out!), but we should be aware that it may also require a total reorientation of our categories of illness: maybe you have a sore throat and a cough from a cold virus, but it could also be bacterial, and these require different interventions even if the DSM would still label both as "sore throat and cough disorder".
Mind you, I have no doubt that genes are very, very important here. I'm just not sure their importance is well summarized by the English statement that schizophrenia is "mostly genetic."
I think this is what I'm trying to address in Argument 6B. I think we'll find that for each of the ~5000 genetic variants involved in schizophrenia, there's some long and convoluted story for how it contributes to causing it. I think there won't be anything beyond this. I don't think we should wait until we have all 5000 stories (which, to be clear, will be incredibly boring and involve pathways of a billion different proteins we don't understand) to start using the causal language.
By this logic, can we not effectively describe anything the human body does as a collection of 5000 convoluted stories involving billions of proteins? My understanding is that typically genetic causality is reserved for situations where we can actually identify the exact story involved, or at least a set of major correlations...
"My understanding is that typically genetic causality is reserved for situations where we can actually identify the exact story involved, or at least a set of major correlations..."
It was back in the dark ages when we thought of genetics in a mendelian way and could only identify the genetic causes of things that had only a few genes causing. Modern methods like twin and adoption studies and even more modern methods like GWASs can move past that past and allow us to identify genetic causes that are highly polygenic.
Polygenetic causes have been unrightfully slandered for to long and it's time it stopped.
The purpose of the distinction, to me at least, is the utility of it not the 'truthiness' of it. I don't need the complete story I just need the conventional wisdom of what I need to avoid/actively do. If it's conventional wisdom that embryonic screening eliminates these risk factors, so trivially true that you or I and anyone in the thread would bet money on it, then I'm going to seek out that solution.
Call it genetic or not, I don't care. I as a market actor just want a result for my time and/or investment.
My point is not that the causal pathways are many and complex. It's that they involve joint contribution from the environment in ways that just aren't true of smoking.
If smoking only caused cancer when you ate kumquats, we probably wouldn't summarize that just as "smoking causes cancer."
I don't disagree with you about what the 5000 neurological stories are likely to look like. I disagree with you about whether they are well summarized as "schizophrenia is mostly genetic."
More or less, but the specificity of this is significantly overstated, especially for women. The telephone game of "SZ onset range stretches across the lifespan, but men have a distinct peak around 18-30 and a thinner right tail than women" becomes "if you haven't developed schizophrenia by 25 you're fine" in the cultural consciousness, which is...not...quite...right. (Some studies manage to ignore all age of onset curves and work under this assumption themselves, which I'm sure gets us a lot of terrible results.)
The key issue at the heart of the debate: whether as describing it as mostly genetic, we can then use genetic scores to motivate clinical action. See Kendler et al., 2023: Relationship of Family Genetic Risk Score With Diagnostic Trajectory in a Swedish National Sample of Incident Cases of Major Depression, Bipolar Disorder, Other Nonaffective Psychosis, and Schizophrenia
Scott, obesity is also 80% genetic. Can I hear you say "fine, obesity is also genetic"? Do you bite this bullet?
Of course, it does not match what we colloquially mean by "genetic" at all, since obesity is 100% environmentally malleable. Can we *please* adopt a more sophisticated frame than "is genetic" vs "is not genetic"?
You are modelling the world as if everything is a sum of small contributing factors. But it's not; sometimes there are AND gates. Sometimes you need to have the genes AND to eat the right food. It is not possible, conceptually, to assign a "percent heritability" in such a situation.
They think this because there's a grain of truth in it. Sticking to a good diet requires non-trivial amounts of planning/willpower, so on average lazy people will be fatter. Of course, publicly saying this in polite society marks anybody as Worse Than Hitler, but people do still think unspeakable thoughts.
Do they need to moralize it though? People are ultimately products of circumstance, and it seems unproductive to demean people based on factors beyond their control. Especially when, again, obesity is 80% genetic. I'm the laziest person I know, and I still maintain a pretty average weight. I can't really pretend that I'm not obese because I'm a "better person".
If it's beyond his control to keep his diet and exercise in check, it's equally beyond my control to keep my moralising in check. After all, moralising is also an evolved function, and we moralisers are ultimately products of circumstance.
Another commentator further up usd the example of lactose vs phenylalanine. Polygenic screening might help with PKU, but not with lactose intolerance. Thus also obesity: if "obesity is genetic" means that most people lack the special combination of genetic factors necessary to avoid the worst metabolic damage caused by modern 'food', the genetics really aren't the problem.
Allow me to clarify: lactose 'intolerance' is the baseline human condition unless altered by a couple thousand years of animal husbandry. Good luck telling a couple from e.g. southeast asia they'll need to discard 95% of their embryos.
What's the problem with discarding many embryos? Assuming you can produce many fertilised eggs without too much hassle, of course. I think there's a limit to how many eggs a woman's body can produce for this purpose?
I think the bigger issue with something minor like lactose tolerance is that it's just not very important.
Conceptually, you make up some kind of score, say intelligence at weight 100, health at 200, height at 80, lactose tolerance at 10, etc, and out of all the embryos, you pick the one with the highest score.
Even if South East Asians cared about lactose tolerance as much as Europeans (ie same relative weight), you are right that the same selection process over their embryos are much less likely to result in a lactose tolerant embryo 'winning' the competition for the highest score.
Were you unaware of the worldwide prevalence of lactose intolerance and are now moving the goalposts? Or did you, from the beginning, think that polygenic screening 'helping' with lactose intolerance really would involve this kind of massive additional cost, labor, and suffering?
Almost all humans can digest lactose when young. Genetics can influence how long (possibly forever) one can keep that ability.
I'm not sure why you care so much about lactose tolerance?
I also don't really know what you are trying to argue for or against and what you think you have tried to caught me in?
What even were those original goalposts you accuse me of moving?
Btw, the whole point of polygenic screening is to pick every baby you raise to be the 'best' (by some score) out of a group of dozens of potential siblings.
So discarding eg 95% of embryos is sort of the point. (However, you only have so much selection power to spend, and I would imagine most people would want to spend it on health and good looks and intelligence etc, not on lactose tolerance.)
For what it's worth, I live in South East Asia. (Since you brought it up in your example.)
I agree with this. "is genetic" (with its more insidious relative "is mostly genetic") and "is not genetic" and its relative "is mostly not genetic" are just terrifically terrible framings of virtually any problem, semantically equivalent to "bridge collapse is design." It either smuggles in a lot of unexamined and nuanced argument about causation, or taken on its face it's word salad.
1. Out of curiosity. Kidney disease heritability. "We report heritability estimates of the CKD-defining traits eGFR (44%), UAE (20%), and UACR (19%), for the kidney biomarkers serum urea (31%), Scr (37%), and uric acid (48%), and for the serum electrolytes potassium (28%), calcium (27%), and sodium (22%) " They checked and basically every kind of family member with the disease elevates your risk, even "genetically unrelated" ones like spouses (assortative mating or maybe shared environment). https://www.sciencedirect.com/science/article/pii/S0272638620311628 It doesn't seem to be impressively heritable, but there's obviously some genetic causes of this, whatever they might be exactly.
2. There are some single mutations that cause schizophrenia alone, or schizophrenia like traits at least. https://www.pnas.org/doi/abs/10.1073/pnas.2112560118 "A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals".
3. Family studies yielding estimate of heritability, shared environment etc. tell you where to look for causes. They give you the overall importance of some group of causes, but doesn't tell you what they are except in a broad sense. In other words, they tell you where to dig for more. They also give you a decent idea about what kinds of interventions are going to be effective. When heritability is very high, it means that genetic selection will be effective. It scales linearly with the square root of the variance. If "family environment" doesn't show up or is very minor, then trying to modify risk factors in that area will not be effective unless you somehow introduce a new kind of thing that doesn't already vary between families. https://www.emilkirkegaard.com/p/high-heritability-does-mean-that
4. Assortative mating and measurement error are usually quite large downwards biases in family studies. This is particularly the case for self-report symptoms of mental health vs. more objective data (e.g. clinician ratings). I wrote a summary of such research. https://www.emilkirkegaard.com/p/heritabilities-are-usually-underestimated
> When heritability is very high, it means that genetic selection will be effective. It scales linearly with the square root of the variance.
Something that this post and thread have caused me to wonder about is what we're abbreviating when we say "heritability of schizophrenia". Heritability is a measurement of percentage of variance explained. But variance is a numeric quantity, one that is sensitive to the absolute values of the random variable being investigated, and schizophrenia is a categorical variable. I tend to imagine that genetics is something of a categorical variable too. Does the concept of variance apply?
You say it yourself, schizophrenia is quite hard to neatly define. So much so that perhaps it doesn't exist / isn't one unified thing.
I think most of these writers who are arguing that schizophrenia isn't genetic, and some of those arguing that schizophrenia shouldn't be prevented (only treated), they mean to instead argue "schizophrenia isn't real".
They don't make that argument, and instead get wrapped up in denying the practical facets you lay out, because they are the sorts of people who are not comfortable rejecting the existence of schizophrenia, for social-norm reasons. The people who feel "woke" social norms to treat-not-prevent are also the ones who have a cognitive bias towards saying it's intervention-able (not genetic).
But strip away their social and cognitive biases, and they probably would wish to unpack "what is schizophrenia actually? It's not well defined enough, there's more to learn. "
E. Fuller Torrey is not a random name. He's the name synonymous with the reinstitutionalization cabal in mental health policy discussion, the guy who (per his glowing NYT piece) wakes up every morning and combs all the newspapers for anything he can interpret as "violence caused by mental illness" so he can crow about it to lawmakers. Torrey knows exactly what he thinks schizophrenia is.
No publication with two or more writers has a single party line. Torrey got his glowing NYT piece, and someone with his opposite views could too. They wouldn't have the same writer, most likely.
Way to bring "woke" into the conversation. It is, after all, (much like Biden) responsible for all of the evils in the world. [edit: \S in case that wasn't obvious]
Regarding 6B, genes could be a proxy for a more satisfying cause of schizophrenia. It is not hard to think of ways this could work. As you say, one is that genes could make people more vulnerable to some virus that attacks the brain and causes schizophrenia. There are many other possibilities of this kind. What they all have in common is that you can think of them as genes that change the person’s environment, causing it to be more schizophrenogenic. (For instance the person in your example with the bad immune system lived in an environment that contained more dangerous viruses.) Here’s a list:
-Genes that cause someone to be physically unattractive, or to have other characteristics that make it less likely they will receive social approval: They’ve got poor gross motor coordination and are bad at playground games, and so they get less acceptance and approval from peers. They’re slow to learn to read, and have an especially hard time sitting still and shutting up in school, and so get less approval from their teachers. Kids with these genes live in an environment with fewer smiles per year.
-Genes that cause some disability that interferes with the person making sense of their environment, and is subtle enough not to get diagnosed in most people: prosopagnosia, difficulties putting your thoughts into words, some spacial orientation problem that makes you get lost easily. People with these genes live in a world that’s more confusing and harder to navigate.
-Genes for some as-yet-unrecognized disorder that’s like PKU (phenylketonuria), but instead of causing severe developmental delay causes, by age 20 or so, whatever sort of brain damage underlies schizophrenia. People with these genes live in a world where ordinary foods cause brain damage.
-Genes that cause people to have unusually strong reactions to stressors. For these kids, seeing a squirrel get run over is as upsetting as seeing a hanging would be for others. People with these genes live in a world with an unusually large number of truly traumatic events.
The idea that social problems are harder to fix than biology is a prime example of Americentrism. Other countries have made far more progress than the US in reducing drug abuse, poverty or social conflict (i.e. instances likely to lead to social defeat). I think this is because the US is unusually individualistic and conservative (and Conservative) for a developed country.
I also think it's rather flippant to suggest people undergo IVF to address genetic problems. I have two daughters by IVF. IVF is very rough on the mother, far more so than the side effects of schizophrenia drugs (which I've also had the misfortune of experiencing). This may improve with better IVF procedures, but we can also discover better drugs.
The effects of schizophrenia drugs are not subtle for most people. Patients usually hate them because they make them feel leaden, blank and drowsy. The newer crop causes a lot of weight gain. And most clinicians, including me, get so they can spot someone on Zyprexa or one of the others -- something about weight gain centered in the belly, and something odd about the way they walk -- maybe it's they don't swing their arms? Or is it that they don't look from left to right at all as they walk? Or their steps are too short, or they don't lift their feet off the ground as high as most people while walking? I'm not sure what the signs are the people can spot, but there definitely are some. And it's not as though they work like magic.
Maoist China really did practically eliminate opioid addiction. The late Mark Kleinman (of "When Brute Force Fails: How to Have Less Crime and Less Punishment") pointed to it as disproof of the "disease model" of addiction.
I know this got addressed in a paragraph above, but didn't Scott just get finished with demonstrating (with stats and maths) that, because of the low incidence of schizophrenia, the causes in any specific individual with schizophrenia will mostly be environmental.
Running the numbers with Scott's methodology by way of example, this means that you could screen 500 people for schizophrenia risk factors using a microarray or something, set the cutoff at a 0.95 genetic risk factor, wind up with 25 'candidate' schizophrenics (of which 4 will actually develop schizophrenia) and still miss one actual schizophrenic.
Which, in this example, means that your expensive microarray test has an 84% false positive rate, and a 20% false negative rate in practice.
And if you bump your threshold to 0.99, then all you get is 7 candidate schizophrenics, of which (in this example) none happened to actually develop the condition.
Doesn't this put screening for purely genetic factors for schizophrenia firmly in the 'scientifically true but useless' category?
No. I won't check your numbers because I think that's the opposite way of going about it.
We don't want to use genetic screening to _create_ schizophrenics, we want to _prevent_ them!
If you're a high risk couple and your child would have a dunno 2% chance of schizophrenia, screening would set that to ~0%. _That's_ undeniably useful.
It's a large relative reduction in risk. But it's not exactly undeniably useful; the number of children you'd have to have for this treatment to make an observable difference is larger than the number of children it's possible for a single couple to have.
Why is it not useful? If the price is right even if you'd need to have 200 kids for it to make a difference, an entire life of schizophrenia is probably costs everyone involved more than $200,000 worth of screening.
Somewhere earlier in the comments, someone who seemed "involved in testing" said it was presently halving your chance of a child becoming schizophrenic.
A distinction I've been thinking about which I've been unsure about but which seems reasonable/important to me:
Schizophrenia is related to psychosis-propensity, arguably caused by psychosis-propensity but also arguably distinct from it in that schizophrenics tend to get convinced they are being persecuted and then retreat into themselves.
It seems to me that one could hypothesize that the mostly-genetic, biological brain-brokenness causes the psychosis propensity, but then the other aspects of schizophrenia are caused by a psychosocial dynamic where e.g. outsiders react badly to the hallucinations and therefore confirm the schizophrenic's suspicions that they are in on the conspiracy.
If true, I don't know how this affects the conclusions in your article. I think it depends on how damaging the psychosis is on its own, vs how damaging the downstream social dynamic is. If most of the damage is with the psychosis-proneness then this is just kind of nitpicky. But if most of the damage is with the social dynamic, then e.g. it raises the question of whether one could cure most of schizophrenia by just averting that social dynamic, and therefore it starts seeming reasonable to think of schizophrenia as environmentally Caused.
Not all psychotic delusions are of persecution, though. I had a patient who believed his teeth were being reabsorbed by his body. He didn't think of that as something someone had done to him -- just thought of it as a weird physical problem he had. I had another one who felt like his thoughts were merging with other people's, or that maybe he was thinking their thoughts or they were thinking his. But again, he had no belief that some person was *doing* this to him. if anything, he thought of it as a magical power he had developed and did not want. And some people have delusions of grandeur.
Do the people with other psychotic delusions (especially entirely non-social ones like teeth being reabsorbed) develop the same negative symptoms as full-blown schizophrenics do?
My proposal isn't that there is no such thing as biological psychosis/delusion-proneness. Rather my proposal is that the way it plays out depends heavily on what the resulting delusions mean (semantically speaking, as in the difference between being sent hidden messages vs one's teeth being reabsorbed) and how these meanings intersect with society.
So your idea is that schizophrenics first have hallucinations, but that their delusions of persecution and other symptoms are a reaction to everybody telling them the are dead wrong that there's a voice whispering to them, or that hallucinatory stuff they see is not there? I've seen a lot of psychotic people, and heard their stories of how it started and how people around them reacted, & I'm pretty sure it doesn't work that way. For one thing, lots of people don't tell anyone about their hallucinations, because they are afraid of being thought crazy, or just because they are somewhat isolated, mistrustful people who do not confide in other people. Delusions often seem to be ideas that people develop on their own to explain the hallucinations. People recognize that their hallucinations are a novel, weird phenomenon, and have a need to explain them. Most delusions have a strong negative tinge, but it seems plausible to me that to most people the hallucinations are unwelcome, and so they form theories about why somebody would be inflicting a whispering voice on them. As for other people's reactions to somebody's hallucinations, if the person discloses that they have them -- harsh and critical reactions from family and friends are rare. Most people realize they're hearing about a psychiatric phenomenon, and get worried and scared, not critical, and do not get caught up in trying to prove to the person they're wrong. Something else I would add is that most schizophrenics have a lot of subtle things wrong and odd about how they act. They're not regular articulate friendly people who are functioning normally except for hearing voices. They're often isolated, difficult people, with poor hygeine, odd mannerisms, and unusual opinions. They often have trouble communicating clearly. I have had people who were trying their hardest to explain to me what it's like being them, and why they're sure someone has implanted recording devices in their brain, and I simply cannot follow what they are saying. They stay on the subject, and don't ever become incoherent, but they ramble and repeat themselves and cannot convey in a crisp way what their experience is like. You get the feeling their ability to put things into words isn't working right. Overall, you get the feeling that the person's brain is not working right.
"For one thing, lots of people don't tell anyone about their hallucinations, because they are afraid of being thought crazy, or just because they are somewhat isolated, mistrustful people who do not confide in other people."
One complication here is that you can't look at the past of people who eventually develop schizophrenia, because my proposed model totally allows that e.g. a prior propensity towards distrust increases the risk that the delusions will enter into a distrust-oriented feedback loop. So it could be that schizophrenia is polycausal, psychosis -> schizophrenia <- general distrust. One would have to design a measure of pure psychosis (notoriously difficult) in order to distinguish.
"So your idea is that schizophrenics first have hallucinations, but that their delusions of persecution and other symptoms are a reaction to everybody telling them the are dead wrong that there's a voice whispering to them, or that hallucinatory stuff they see is not there? ... Delusions often seem to be ideas that people develop on their own to explain the hallucinations."
I think it's plausible that it's a combo. Like if someone feels like the TV is leaving them threatening messages, then that would raise the hypothesis of being persecuted to attention, but then depending on other's reaction, it could either remain considered unlikely-but-possible or turn into clearly-true.
"As for other people's reactions to somebody's hallucinations, if the person discloses that they have them -- harsh and critical reactions from family and friends are rare. Most people realize they're hearing about a psychiatric phenomenon, and get worried and scared, not critical, and do not get caught up in trying to prove to the person they're wrong."
Acting worried and scared can also in some frames of mind be interpreted as being in on it, though. Not sure to what extent schizophrenic people interpret it that way though. I would think of it through a Bayesian frame; when I've heard of information-controlling communities (e.g. Stalinism, Leverage Research, etc.), I've often seen people emphasize a culture of fear and confusion as much as they've emphasized aggression. So under rational priors, it doesn't seem like worried reactions are all that much evidence against this.
"Something else I would add is that most schizophrenics have a lot of subtle things wrong and odd about how they act. ... Overall, you get the feeling that the person's brain is not working right."
I don't think this contradicts my model, since there are two different ways this could be expected to happen under my model:
1. The factors that cause general psychosis-propensity also cause their brain not to work right, leading to the symptoms you mention.
2. The non-psychosis factors which predispose the environment to react poorly to psychosis also cause other social dysfunction.
While one needs to understand that there are a lot of philosophical nitpicks and therefore it's hard to describe anything as true, I also think it's worth clearly mapping out the philosophical nitpicks. For example, if they don't get clearly mapped out then people might not realize they are there (try telling people schizophrenia is 80% heritable and then ask them about the twin concordance rate), and even if they do realize they are there, mapping them out is the first step to generating theories about how to most accurately take them into account.
I think it also deescalates conflicts. If you've found an important-seeming nuance that doesn't get described very clearly, you might want to generate clearer descriptions. This could lead to some cooperate work if people assist you, but it could also lead to ideological conflict if people dismiss it as philosophical nitpicks and you then start writing big books about it
It is arrogant not to say unkind to attribute a disease entity that is itself controversial to an individual’s make up at birth; it smacks of eugenics.
I don't mean to be unkind to your comment, and I apologize if I'm misinterpreting you, but it sounds to me like you're working backwards from your moral feelings to decide what is true or false in nature. Can you make a non-moral argument against what Scott said?
Re your thoughts on viruses: in my experience teaching students, when talk about causality, they talk about levers they think we can pull on. They’re not interested in causal inference for levers we cannot pull. Many people don’t know about polygenic embryo selection as a lever you can pull or have convinced themselves it’s immoral to pull on it. It’s not a consistent definition of causality, but it’s a sensible position to look for levers. You just happen to have a niche position on which levers are easy to pull, the rest of the disagreements come from that.
Of course a widespread virus being necessary would change our idea of which lever to pull first, ie people are trying vaccines for Epstein Barr now rather than do embryo selection for genetic risk of multiple sclerosis. Because it’s much easier and proven and (for some) not as ethically dubious
I don't think that embryo selection is a useful lever here. Schizophrenia is wildly polygenic and rare, so you selecting one out of the half-dozen viable embryos that come out of IVF will have next to no effect on the resulting child's genetic risk (let alone their risk in practice). Plus IVF is difficult, uncomfortable, invasive and expensive.
So the cod intuition lines up well with reality in this case.
> so you selecting one out of the half-dozen viable embryos that come out of IVF will have next to no effect on the resulting child's genetic risk (let alone their risk in practice).
As I believe Scott has already noted in these posts, that's not true. For rare disorders, selection doesn't do much 'on average', but that's also where you least need it; and where you most need it, it does the most. (Similar to regular PGD screening for Mendelian disorders: would you argue that 'PGD is not a useful lever against Huntington's' because screening against Huntington's would do nothing in >99% of screens?)
Under a liability-threshold model you can easily get large effects on both risk if the parental mean burden is high, because now there is no floor effect + the nonlinearity of the underlying normal. If the parental burden is very low so they have ~0% risk, then obviously selection can do little, all viable embryos will have ~0% risk; but if the parental burden is high, eg both are full-blown schizophrenics, then the offspring risk is extremely high (~40% IIRC) and the embryos will vary a lot around that mean high risk, and it can be reduced accordingly.
So your 'cod intuition', I'm afraid, smells like one too.
That's a very cute insult* and I'm tempted to respond in likewise fashion, but...
Running the numbers and ignoring some massive, nested, caveats** # , you're not wrong that screening would indeed be helpful for full-blown schizophrenics wanting to lower their child's risk. Using Scott's previous methodology and a population of 500 (because I'm lazy), the cutoff value ends up being ~0.95. If you set the genetic risk to 0.99, this gives you an environmental cutoff of 0.80 (which is high, and again seems to indicate that identifying the environmental factors and lowering those is a Very Good Idea (tm)). Similarly, using an environmental risk of 0.99, you get a genetic cutoff of 0.94, which represents the lower floor below which the environment makes no difference. The 'average' schizophrenic environment is accordingly between the maximum and cutoff: 0.89. Similarly, the 'average' schizophrenic risk score is 0.96. This means that the average variance to target is something like 0.02 which, when you use 5000 additive genes, means that finding an embryo with ~120 schizophrenia-associated genes set to the safe configuration will lower the total risk below the genetic cutoff.
This is still a lot of variants to find, and someone else will have to do the math on the likelihood that two people with an 'average' of 4800/5000 risk-associated variants will be able to produce enough embryos to hit that target. But it seems at least more superficially plausible than I thought.
*I've never actually smelled a cod before - they're rare and expensive fish where I'm from.
**Caveat the first: the chances of two schizophrenics having kids together is something like 0.01%***. Which means that, in the US, there are something like 35 000 total patients for this treatment. So not a great use of resources.
***If the chances are higher, and full-blown schizophrenics are finding each out in the general population at a much higher rate than random chance, then the obvious answer would be for them to be counselled to, you know, not do that if they want to have children without schizophrenia. Maybe also tamp down on those schizophrenic environmental factors a little (see below).
# Caveat the second: as with Scott's twin example, the best advice that you could give anyone worrying about passing on their schizophrenic tendencies to their children would be to adjust the environmental factors as much as possible, since full-blown schizophrenia needs both a high genetic risk and a high environmental risk. Which, considering that these would-be parents are worried enough to go and get a genetic screening test done, is probably already in hand. The next best advice would be to adopt or (if counselling a single person) look for a partner with a low risk score instead of going whole-hog on embryo selection.
> Re your thoughts on viruses: in my experience teaching students, when talk about causality, they talk about levers they think we can pull on. They’re not interested in causal inference for levers we cannot pull.
I asked my mother once what girls considered to be aspects of female attractiveness. The intent of my question was how girls evaluated the attractiveness of other girls, but instead I got a response covering actions girls take to maintain their own appearance. When I asked why facial structure wasn't even mentioned, the response was "girls don't spend time on facial structure because they can't change it".
Back on topic, "schizophrenia is mostly genetic" is giving you accurate information if you're thinking about interventions you might do to prevent or cure schizophrenia. The options are to be somebody else, or suck it up. And that's exactly the message that "schizophrenia is mostly genetic" delivers! Unless you have the ability to pull the genetic lever, you will not be able to meaningfully intervene in schizophrenia.
The fact that an intervention is possible doesn't mean it can have a significant effect. Saying that schizophrenia isn't genetic because that would imply that you can't address it just means you can't tell the difference between reality and what you wish reality would be like. There are plenty of problems you can't address.
>Unless you have the ability to pull the genetic lever, you will not be able to meaningfully intervene in schizophrenia.
Most likely true, but sometimes luck is kinder. E.g. if one of the relevant genes codes for an enzyme, and e.g. there is a small molecule drug that inhibits the enzyme, sometimes there can be a way to modify the situation.
'In a society where everyone inhaled radioactive dust all day, smoking would be an utterly insignificant cause of lung cancer compared to all the radioactive dust inhalation'
Slight nitpick - cigarette smoke IS 'radioactive dust', see e.g. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672370/, where they estimate a smoker may be exposed to an additional 10 Sv, or 1000 rem, in 25 years.
This discussion feels a bit confused. You and your opponents certainly would both agree on a sufficently precisce statement of the claim in statistical language. So when you say you're arguing about whether "schizophrenia is largely genetic" you aren't arguing about whether the facts comport with some agreed on meaning of that phrase but whether that phrase has a meaning which is made true by those facts. And yet, you aren't actually just making a boring corpus data/polling based claim that most competant speakers do give the phrase such a meaning.
I feel like what's going on is the same thing that goes wrong in debates about whether trans-women are women. The people in the debate think they are arguing over a fact about the external world like whether smoking causes cancer but in fact, as you pointed out in a great piece, they are really making normative arguments about what would be the more desierable way to use language (should we assign a meaning to woman/schizophrenia is genetic that includes...?).
In other words, what you described as why you care is actually the argument: using the word the way your opponents prefer causes these harms because it misleads people about what responses will be effective. I agree and find that relatively convincing but that's the actual debate and it would be better to phrase the other stuff as: responses to potential arguments that the usage you favor is also misleading/confusing.
It seems like there's a lot of muddled discussion over "cause." Causal inference is an entire field with a pretty simple and well-hashed-out definition of a "causal effect." From Miguel Hernan's "Causal Inference: What If?":
>We compare (usually only mentally) the outcome when an action A is taken versus the outcome when the action A is withheld. If the two outcomes differ, we say that the action A has a causal effect, causative or preventive, on the outcome. Otherwise, we say that the action A has no causal effect on the outcome
Concretely: Alice smokes cigarettes, and gets lung cancer. If she would not have gotten lung cancer in the counterfactual world where all else was the same, then cigarettes caused Alice's lung cancer.
Of course, barring a time machine or an ersatz replacement (e.g. a cross-over study with a washout for a drug, or a twin study), we usually can't determine individual causal effects. Sometimes individual causal effects are not even that interesting. Maybe Bob developed lung cancer after being hit by a stray gamma ray.
However, we can estimate average causal effects at the population level with a variety of tools, ranging from excellent (e.g. an RCT) to sometimes-questionable (e.g. a haphazardly-specified regression model applied to survey data of questionable accuracy).
> Causal inference is an entire field with a pretty simple and well-hashed-out definition of a "causal effect." From Miguel Hernan's "Causal Inference: What If?":
>>We compare (usually only mentally) the outcome when an action A is taken versus the outcome when the action A is withheld. If the two outcomes differ, we say that the action A has a causal effect, causative or preventive, on the outcome. Otherwise, we say that the action A has no causal effect on the outcome
This isn't correct as a description of how we think about causality or of how we _should_ think about causality. Many systems are regulated: if you make some kind of change to the system, the system will respond by making a countervailing adjustment.
Say you're driving a car and you start going down a fairly steep hillside. Everyone understands that the slope of the hill causes the car to pick up speed. Except, by the definition you just offered, it doesn't: in the absence of the change in slope, the car will keep going along at whatever speed the driver wanted. In the presence of the change in slope, that is also the case. The driver will be holding the brake down, but that's notionally a causal effect on the brake, not a causal effect on the mostly-unchanged speed of the car.
On an earlier ACX comment thread, there was a commenter arguing that it cannot be the case that the money supply has a direct causal effect on the price level, because sometimes they change by different amounts.
The concept that there might be more than one thing with a causal effect on the price level didn't seem to register.
Of course, if more than one thing has a causal effect then no one item can have a 1:1 correspondence (which seems to be what many people assume about monetary policy).
If "the system" is coupled 1:1 with the action, then no, it's not a causal relationship. Stated more clearly:
"If a car with a human driver heads downhill, does the car change speed, compared to the same car being driven on flat ground?" Answer: No. Therefore, the intervention (human in car driving down a hill) does not cause the outcome (change in speed). It's interesting to ask *why* that isn't the case (hence the brake) but it doesn't change the causal nature of the action.
This is exactly the kind of confusion that Hernan's article cleared up for me. The car/hill question muddles the exact causal comparison being made--it makes a "downhill causes speed increase" argument based on applying basic physics to a car WITHOUT a driver, then assumes that a given action has the same causal effect in a different situation. They aren't the same causal question, and they don't have the same causal answer.
> Actually it’s more complicated than this: if you look at the simulation argument from last time, it’s hopefully obvious that every case is caused both by genetic and by environmental factors, or that it’s not really meaningful to try to disentangle them. I don’t know whether real schizophrenia is like this.
Real schizophrenia is definitely not like the simulation in a relevant way which I will detail below:
Your model involved assigning two types of risk levels to people, summing them, and then diagnosing scizophrenia if the summed risk exceeded a threshold. The threshold was higher than the maximum value of any individual risk component, and therefore it wasn't possible for any component to be solely responsible for a schizophrenia diagnosis. (But, by design, it was easy for one component to contribute five times as much "problem" as the other component.)
The problem is that your risk levels were ordinal numbers, not cardinal numbers. This could only be valid as a model of schizophrenia if schizophrenia were diagnosed solely by comparison to everybody else. Objective criteria, such as hallucinations, invalidate the assumption.
(It's also weird that your model involves adding an ordinal genetic risk to an incommensurable ordinal environmental risk. We try to avoid adding ordinal numbers. By assuming that genetic and environmental risk are normally distributed, you can convert centiles to standard deviations. But I think you'd end up unable to say whether a standard deviation of environmental risk was more or fewer units of risk than a standard deviation of genetic risk, which is kind of the opposite of the point of the simulation.)
In reality, we are surely interested in a model of schizophrenia where you get small numeric contributions from many causes and schizophrenia happens when a numeric threshold is exceeded, not where you get large comparable-but-not-theoretically-measurable contributions and schizophrenia happens when a comparative threshold is exceeded (that is to say, when a certain number of people are doing worse than you).
"Objective criteria, such as hallucinations, invalidate the assumption."
Except people with hallucinations, or delusions, or even the whole suite of classical Schneiderian first-rank symptoms get diagnosed with half the DSM aside from schizophrenia. These can pop up in people whose longest-standing diagnosis is bipolar disorder, or psychotic depression, or dissociative identity disorder, or borderline PD, or really anything cluster A, or one of the rarer psychoses (e.g. delusional disorder), or a NOS wastebasket. This doesn't necessarily mean what they have is fundamentally Unlike schizophrenia; it means whoever they had the longest therapeutic relationship with used a different term. If we drew lines based on Underlying Truth and not on subjective impressions of "how is this guy like the last guy?", there wouldn't be so many people whose diagnostic histories switch between SZ and bipolar.
(I think a significant and underrecognized moving part in whether psychotic people get diagnosed with SZ or something else is their "relatability"/ingroup status to the clinician, rather than whether they're schizospec or not.)
> If we drew lines based on Underlying Truth and not on subjective impressions of "how is this guy like the last guy?", there wouldn't be so many people whose diagnostic histories switch between SZ and bipolar.
Those people can't exist in Scott's model either. The comparison isn't to the last guy you saw, it's to everyone.
When I went to a class/group mental health thing for ADHD a few years ago, one of the things I learned was that ADHD is considered "epigenetic": you need the genes, but the genes have to be activated by environmental factors (lead exposure was mentioned) before you really "get" ADHD. Would calling schizophrenia "epigenetic" satisfy both sides of the argument? Also, is this something people still think is true about ADHD?
This sounds like a conflation between epigenetics and any old gene x environment interaction. Epigenetics is concerned with changes in the regulation of the expression of genes. These are changes that aren't hard coded into the genome but are achieved through modifications like DNA methylation, that influence whether and how much of the downstream product is produced. The environment as we tend to think about it can be involved in epigenetic regulation but isn't necessarily.
Gene x environment interactions can take many more casual pathways. Let's say there's something about the way the frontal cortex develops (genetically influenced) that makes it more or less vulnerable to lead exposure. That would be a gene x environment interaction that isn't epigenetic.
I also think the story you were told about ADHD is ahead of our current understanding. As far as I know, there are both genetic and environmental risk factors, and someone with ADHD is likely to have both, but I'm not aware of any established universal casual pathways that involve environmental triggers of gene regulation, or evidence that such pathways are necessary. It's more of a "we think this is how it must work because this is our operating hypothesis for most things with genetic and environmental contributions," but that's at the gene x environment level generally. I'm curious now and I'll look into it but adding specificity and certainty to causes of disease hypotheses for popular consumption is common.
> Would we really? If schizophrenia was caused by an omnipresent virus, but the only people who got it, got it entirely because of genetic differences from the rest of the population, why would we call the virus “the cause” rather than the genes? Is it just because we’re used to calling pathogens the causes of things from our long history with infectious disease? It might be equally reasonable in this case to think of schizophrenia as a genetic immunodeficiency. I don’t know exactly how to think about things like this.
I mean, it kind of sounds like you do know how to think about things like this, but you don't want to do it.
Suppose there were oxygen lying around everywhere (as in fact there is!), and some people had genes that caused them, when exposed to oxygen, to harness it to cells in their circulatory system and generate energy in specific areas through controlled chemical reactions, while other people had genes that caused them, when exposed to oxygen, to catch fire and burn to death.
Would that be a genetic problem? Could we fairly attribute it to the genes?
Of course; everything you ever do is caused by your genes, because there is no theoretical alternative. The range of possible reactions of an organism to different environments is one more thing that is fully specified by its genes.
Well, considering that DSM-5 basically defines schizophrenia as having positive (delusions, hallucinations, etc) and negative (apathy, anhedonia, etc) symptoms while also being fairly sure that those things aren't being caused by something else... There's probably multiple, distinct conditions getting lumped together here.
> even though smoking causes 80% of lung cancer, if Alice gets lung cancer and Bob smokes exactly the same as Alice, Bob will have a much lower than 80% chance of getting lung cancer. The solution isn’t to stop describing smoking as causing lung cancer, it’s to get better intuitions.
This example makes me queasy; the two 80%s do not refer to related numbers, and neither of them is related to the problem you're discussing in the post. I want to think about the link between smoking and lung cancer in terms of risk increase, something along the lines of "in these two otherwise comparable groups of nonsmokers and habitual smokers, the smokers get five times as much lung cancer". It's never relevant how much of lung cancer is caused by smoking; you'd need to normalize that against the number of people who smoke. This is just the confusion between P(smoker | lung cancer), which in the example is at least 80% (though actually more†), and P(lung cancer | smoker), which is Bob's chance of getting lung cancer from being a smoker.
But while confusing the two directions of a conditional probability is a common problem that occurs when people try to think about probability, it is not the same as what is otherwise the focus of this post, which is the meaning of claims like "80% of the variance in random variable X is explained by random variable Y, a component of X".
This makes the thesis "this is equally true of everything else" a bit weird. The smoking / cancer example provided in support isn't analogous to the schizophrenia / heritability claim and doesn't transfer. It could be an example illustrating that we need to get better intuitions about everything, and, sure, I guess that would be nice...
† Why more? By assumption, 80% of lung cancer patients developed their cancer by smoking, and they are all, by definition, smokers. This gives us a lower bound of 80%. But there will be some smokers who developed lung cancer even though their smoking didn't contribute to it, the same way nonsmokers develop lung cancer without any contribution from smoking, and those smokers-with-lung-cancer-unrelated-to-smoking will raise the rate above 80%.
Addendum: I think it's about as likely that we can train people to have good probability-related intuitions as that we can train them to have good four-dimensional mental visualization abilities. Or in other words, it will never happen.
Logic is sort of a liminal case. There are many people who can process basic logical relationships in their minds without difficulty. And there are many other people who aren't capable of processing logical relationships and can't be trained to do so. 3D visualization is similar: some people are very good at it, and others can't do it at all.
Probability and 4D visualization are like that, except without the population that is able to do it.
None of those arguments make up the true rejection. Instead, like you say, if genetics could be admitted as the cause, then it would likely be possible to describe any workable solution as EUGENICS, which is obviously far too horrible to contemplate.
This comment here is the only one a ctrl-f for "eugenic" turns up. Top comment, imo.
This really is the whole story ('story' on purpose, like 'narrative'). It's socially undesirable to think about genetics for somet hings, and in some contexts. We've over-updated in response to those guys in Germany that one time .If they'd had a single-use genie that could only eliminate genetic causes of diseases, and they'd chosen to eliminate schizophrenia, we'd note in history books that there used to be this weird thing that went wrong with people but it stopped happening in 1942 for some reason -- and we'd be glad.
I don’t think it’s that thought-through; to most people, “eugenics” is just some Nazi thing that was also in Moonraker. It’s more a concern that most people view “genetic” to mean “fundamentally part of who you are,” and “environmental” to mean “randomness/luck.” If it’s environmental, then someone who’s fundamentally healthy just caught schizophrenia the way you’d catch a cold. If it’s genetic, there’s no non-schizophrenic person underneath; it’s part of their soul.
Sure, but most people don't set the agenda. The so-called intellectual elite does it, and it's not short on awareness about "Nazi things", given the steady stream of proclamations that fascism is about the most pressing threat to civilization, until we all drown due to global warming of course.
I don’t see any particular issues with this statement. Many forms of epilepsy are highly heritable. I’m currently trying to solve my husband’s and sister-in-law’s epilepsy and there’s a ton of data that indicate that at least propensity for seizures is highly genetically determined.
"This is possible, but I think it’s false. We know many apparent risk factors for schizophrenia: cannabis use, birth canal asphyxia, social defeat, toxoplasma infection, poor prenatal nutrition. If you try to combine these into one big picture, it doesn’t work."
What the - cocial defeat causes schizophrenia! How? Why? Is this another case of X is not about X, it's about signalling?
Thanks! Even so, I find it kind of suprising. Though perhaps the supposed mechanism applies to more than just schizophrenia? Somehow that sounds more plausible to me.
> The only thing that makes sense to me (and I’m definitely not an expert, and E. Fuller Torrey is, so take this with a grain of salt) is thinking of schizophrenia as cumulative damage to some abstract computational organ.
If that's on the right track, then lots and lots of genes would presumably be relevant, including glutamate receptors, myelination, dendrite structure, synapse structure, neuron resting potential, and on and on.
well-argued as usual. You address only briefly our weird reluctance to acknowledge that schizophrenia in fact does have a large genetic component. This reflects something about current society... in past eras, genetic contributions to behavior were taken for granted and often exaggerated. What's the deal here?
Schizophrenia is one of the many, many examples given in 𝘛𝘩𝘦 𝘉𝘭𝘢𝘯𝘬 𝘚𝘭𝘢𝘵𝘦 of things that are denied to be genetically influenced despite mountains of evidence to the contrary. The controversy was old by then.
Current society is ideologically committed to the position that nothing has a genetic component. That's the reason it's unacceptable to admit that schizophrenia has one. Think of schizophrenia as analogous to the Galilean moons.
I haven't read the book, but I find this example of cultural disconnection with reality striking. I suspect this particular disconnection (denying a relationship between genes and mental processes) dwells predominantly in the Tribe of the Left, perhaps because of perceived historical resonances?
No, it's definitely on the right too. They idiotically insist that free will exists and that everyone "deserves" what they get. No one deserves anything. All we can do is try to make things a little better for the people who are alive.
Much of what you say about the comparison with smoking causes cancer seems obviously right. But I guess the meat (or perhaps, heat) of this argument is about what happens downstream of the statement, "schizophrenia is caused by X": where money for researching therapies ought to go, or what advice to (potential) sufferers should be.
The statement "schizophrenia is mostly genetic" is, on the face of it, a suggestion to direct research dollars to genetics research; for sufferers it is perhaps perceived by Fuller as a counsel of despair. (I wonder if that is a motivator for him making the argument?)
Two things in your post leapt out at me as worthy of comment:
(1) "Kidney disease is just a catch-all term for “anything causing your kidney to work less well than it should”. If you examined its heritability, it would probably be substantially genetic."
Assuming this is true, this seems like an argument against saying "schizophrenia is mainly genetic," because that's not something we commonly say about kidney disease (is it?).
(2) "schizophrenia is caused by some extremely common virus...everybody has all the time...immune system controls the virus...genes for bad immune systems...virus causes schizophrenia."
I just wanted to raise the obvious analogy of HPV here. Once it was discovered that HPV was a key factor in cervical cancer, research moved to HPV prevention, culminating with the HPV vaccine, which as far as I know is now doing an admirable job of reducing infections and the downstream cancers. This seems to me to illustrate what I was saying above: the argument about what we should *say* causes condition X is really an argument about how we should go about researching and treating condition X.
Back on a more general level, the issue you point up of different common medical terms for diseases/conditions/syndromes being on completely different levels of the symptom-condition-cause spectrum just makes any generalisation hard to do. Particularly for something like schizophrenia, where it's still unknown whether that word refers to a causally disparate collection of different symptoms; a single, fairly well-defined syndrome; or a monocausal disease. Any conclusion you might draw about how to talk about particular kinds of diseases may or may not apply to schizophrenia...
I am sad to see this bunch of non-arguments that neither grasp the philosophical question, the science communication problem or the scientific problem.
The philosophical question is, when multiple prerequisites are necessary, but neither is on their own sufficient, what do we consider the cause of something? This is a persistent problem in medicine. When an old person dies of a rhinovirus infection, what is the cause of death? The rhinovirus or old age? A young person would have surived the virus without any problem whatsoever, so it is reasonable to say old age, but then again, without the virus, the person might still be alive, so it would be equally reasonable to say the virus. The sad fact is that there is no scientific way of assigning what amounts to moral blame. Scott would like to use the numbers™, but heritability is a statistical expression of variance, not quantitative causal contribution or population attributable fraction, it rests mostly on outdated evidence and is misleading regarding the preventative effects environmental interventions may have. Neither of these points is adressed in the post.
The science communication question is whether we should advertise heritability estimates as relevant. The original article claims we should not, and nothing Scott argues changes that very much. Environmental interventions still can have large effects on incidence in diseases with high heritability. Scott ignores this for some reason.
Lastly, the scientific problem involves the high heritability estimates of twin studies, which were not replicated by GWAS. It is yet unclear whether they will be replicated by whole-genome sequencing studies, but the likelihood is low in my opinion (WGS studies claim better sensitivity to rare variants, but this is unlikely a major contributor do disease burden due to selection pressure). Polygenic scores do not explain much more than the GWAS estimates, either. The missing heritability problem is easily resolved when assuming twin studies simply give overestimates due to GIGO. This has been argued for a decade now (doi: http://dx.doi.org/10.2190/HS.43.2.f). So what are we left with here, exactly? An isolated demand to strongly believe in outdated results based on poor methodology. This is motivated reasoning at its finest.
Which brings me to the last point, "if you are already doing IVF" - no, most people are not "already doing IVF". If you need IVF you either missed the on-ramp to having kids or there is something biologically wrong to begin with (some might argue that the former is an expression of the latter, but I digress). IVF is a disagreeable procedure for women to go through. It likely leads to inferior pergnancy outcomes compared to, oh, just having sex. Preimplantation genetic testing is an experimental procedure with little long term data that barely passes ethical muster in obvious cases of monogenetic diseases. Recommending PID to a patient willy-nilly based on an abstract desire to improve their offspring might (at least ought to) get your clinical license yanked.
Polygenic screening was never proven effecntive in a clincal trial. The 50% reduction in risk you were sold is not based on RCT evidence. Selecting against schizophrenia might select for something else, for better or worse. Your mileage may still vary overwhelmingly.
I used to appreciate this blog because of the thoughtful discussion of medical evidence it offered on psychiatric treatments and diseases. Reading this series of articles both suggests that these skills do not translate well to other fields of medicine and casts doubt on the quality of previous discussions.
"Lastly, the scientific problem involves the high heritability estimates of twin studies, which were not replicated by GWAS. It is yet unclear whether they will be replicated by whole-genome sequencing studies, but the likelihood is low in my opinion." Based on what exactly? Our intuition that there should be selection against rare variants? Although you sound confident about the solution to the missing heritability problem, I don't believe that your view is shared by a majority of the geneticists who are working on this issue. From one recent study: "Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease." https://pubmed.ncbi.nlm.nih.gov/35256806/
It's possible that twin studies are biased, but I think the jury is still very much out on this question.
> if we knew for sure that all of the genes involved in schizophrenia were for an autoimmune condition, we might say “schizophrenia is an autoimmune disease”.
My understanding of polygenic scores is that it is a statistical method.
My reluctance for a (voluntary) eugenic solution depending on these scoring is, that we don't understand these genes and if there is a side effect? It is like deleting programming code without knowing if it maybe also had beneficial effects? Maybe in this autoimmune genes are also supergood for surviving covid or preventing allergies. Maybe they are involved in creativity and erradicating slightly crazy genes would lead to a boring dystopia of bureaucrats out of tune with the spirit world?
"Maybe they are involved in creativity and eradicating slightly crazy genes would lead to a boring dystopia of bureaucrats out of tune with the spirit world?"
I'd categorize this as something like "unambiguously true" -- the positive schizotypy/creativity relationship is clear enough at this point, and if you distinguish "disorganized schizotypy" (a weird cluster-space of "not clearly positive and not clearly negative", loading on some combination of eccentricity and thought disorder) it seems to be so as well. Even without focusing on a schizotypy-creativity connection, high schizotypy is a thing many people self-report liking about themselves (whether they describe it in those terms or otherwise) and find helps them get to self-actualization and fulfillment. Schizotypal PD is famously one of those PDs that gets diagnosed by coincidence in people who report with other concerns, who consider the PD diagnosis a weird consequence of "I went to therapy for depression and they told me all my best characteristics are this instead for some reason".
"PRS discrimination against schizophrenia" should, without evidence that schizophrenia-genes and schizotypy-genes come apart (I think they might at the tails, i.e. that there are additional genetic factors in whether schizotypal people develop schizophrenia and what it looks like if they do, but I think this would be a minority of what we currently consider "schizophrenia genes"), be read as "PRS discrimination against schizotypy". When you *actually look at* schizotypal screening questionnaires or diagnostic criteria, it becomes apparent this isn't something you need to throw everything away to Prevent. If anything, it starts sounding parodically dystopian -- "we need to eradicate people who are eccentric and suspicious!".
My point here is that here is we have two pieces of evidence about what that genetics might be that are hard to reconcile. Between them, they would appear to rule out quite a few things.
E.g. on some plausible models...
- African-Americans would have similar risk to people in Africa (nope)
- genetically different populations would have different frequencies of the risk alleles, and hence different disease rates (nope)
(Thinks for a moment) but immigrants more often move to big cities than the rural countryside, so if whatever's causing schizophrenia is some toxin or pathogen encountered in cities, immigrants will encounter it more often.
Yes, this is weird. I feel like a lot of this discussion is dancing around the central point that saying "schizophrenia is 80% genetic" will be treated by the media as equivalent to "black brains are genetically worse than white brains." (And will definitely be treated that way by /pol/, etc...) Researchers' hesitation to claim this does not surprise me at all.
My favourite example is that wearing earrings is very heritable in modern human population. Based on whether person has two X chromosomes or not, one can predict quite well whether they are wearing earrings or not.
>You also can’t point to any individual lung cancer patient and say “smoking caused this person’s lung cancer”.
Actually we can! Tobacco smoke causes characteristic types of mutations in cells, and if we see those mutations in someone's cancer, it's pretty certain that it was caused by smoking.
The natural way to describe such a situation would be: the virus causes schizophrenia, and certain people's genes cause them to get schizophrenia.
Does that distinction help for the issue at hand? I think it does help clarify what we mean by causation. As for what we mean by "genetic", not directly, but it does point toward a more precise way of describing the situation: "genetically mediated". Would we be having this argument if the question was about schizophrenia being genetically mediated? I don't think so.
I'll note that the vast majority of smokers don't get lung cancer (LC), so even the perfectly reasonable sounding "smoking causes lung cancer" is suspect. It's true that smoking massively increases the odds of LC (i've seen ORs from 20x-40x), the base rate is so low that even for smokers the lifetime risk of LC is less than 1% (at least by my quick and sloppy estimates from CDC/NIH numbers. My hope is that by being wrong on the internet I can get someone else to do this, and even if I'm off by 50x I'm still right.)
The only use I've gotten out of calling things 'causal' is to indicate that modifying one variable will meaningfully affect another variable. It's about actions one can take that are expected to do the thing you think they should. I'm okay with saying "smoking causes lung cancer" because I believe that modifying smoking habits will clearly and directly decrease LC risk, whatever mechanisms or moderators or whatever are "actually" responsible.
From my perspective, we are in this odd position where we know that a substantial aggregate genetic influence on schizophrenia exists (and that such substantial aggregate influences exist for nearly all complex disorders, even if not to the same extent), but we seem unable to make it tangible. The influence dissolves into genes of tinier & tinier effects, and this seriously limits what we can practically do with all this. It’s obvious that hundreds and thousands of gene influence the risk of developing schizophrenia.
We need to distinguish between several different strands of the debate here. “Are genetic influences in aggregate a cause of schizophrenia?” is one question (and I’d say yes, in the same sense of cause as smoking causes lung cancer) but that is a different question from whether “Is the etiology of schizophrenia 80% genetic?” The latter question is rather ambiguous but that’s how many ppl talk about schizophrenia. My view is that it is 80% genetic only in the strict sense of the heritability statistic for a population, and that the heritability statistic becomes kinda meaningless if you try to turn it into a statement about what component of “etiology” (etiology ≠ phenotype variation) is genetic.
A second thing we need to distinguish is that we mean different things by the term “genetic disorder.” It could mean something very general, like any disorder where a substantial portion of the risk/vulnerability comes from aggregate genetic influences. A second more specific sense is where identification of causal genetic variants provides a coherent way to understand the mechanisms or pathophysiology of a condition. Schizophrenia genetics program was kinda based on the hope that we could move from the former sense to the latter sense, and it has become rather clear by now that this is not likely to happen. The influence of any particular gene is too small & current polygenic scores explain like 6-7% of risk. What people are hoping now is that genetic associations can provide clues to understanding what pathways are involved, like disruption of synapses or immune dysregulation. I don’t mind if we consider schizophrenia as a genetic disorder in the first sense (which means many other complex disorders are also genetic) but we shouldn’t simply assume that because it is genetic, the latter sense is also true.
Scott thinks the evidence suggests that it's possible to halve the risk of schizophrenia by polygenic selection - do you disagree? It doesn't seem compatible with your statement that polygenic scores explain 6-7% of the risk of schizophrenia
I misremembered the actual figure; it is a bit higher than 6-7%. It’s 7-9%.
“For schizophrenia, which possesses the most well powered GWAS to date, the best-performing PRS (polygenetic risk score) method explained just 8.5 % of the variance in liability for the disease, falling to 7.3 % when non-European ancestry cohorts were included” (Andreassen et al., 2023) https://onlinelibrary.wiley.com/doi/10.1002/wps.21034
In the context of polygenic embryo screening, we are talking about relative reduction.
With regards to using polygenic embyro screening, under certain conditions, there could possibly be a 50% reduction of relative risk of schizophrenia, but this would amount to an absolute reduction in risk of about 0.5% for a random embryo (i.e. not someone with a biological relatives). For someone with a first-degree relative with schizophrenia a 50% relative reduction could be quite meaningful though.
"Our model shows that a 52% RRR is attainable using the LRP strategy with n=5 embryos. However, this translates to only ≈0.5 percentage points reduction on the absolute scale: a randomly-selected embryo would have a 99% chance of not developing schizophrenia, compared to a 99.5% chance for an embryo selected according to LRP." Lencz, 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510582/
Thank you, this is great. Though I think I'd disagree that a relative risk reduction could only be meaningful if there's an absolutely high risk. Reducing the risk of my child developing schizophrenia from 1% to 0.5% is something that I would (personally, ymmv, etc) find meaningful.
Correction: Polygenic risk score explains 7-9% of variance in risk.
“For schizophrenia, which possesses the most well powered GWAS to date, the best-performing PRS (polygenetic risk score) method explained just 8.5 % of the variance in liability for the disease, falling to 7.3 % when non-European ancestry cohorts were included” (Andreassen et al., 2023) https://onlinelibrary.wiley.com/doi/10.1002/wps.21034
Awais, I am curious to hear your thoughts about the high prevalence of schizophrenia/psychotic disorders in 22q11.2 deletion syndrome, which has been well-established for a number of decades now. This is the strongest known single genetic risk factor for schizophrenia, to the extent where ~25% of individuals with 22q are diagnosed with schizophrenia by adulthood (this was referenced briefly in Torrey's original commentary). Between the different Substack posts on this topic amongst Scott, yourself, and Dr. Hyman's editorial, there has been no further discussion about the link between 22q and schizophrenia, which to me seems an important omission when are are talking about whether schizophrenia is genetic or not.
Hi Anthony. I mentioned 22q11.2 deletion syndrome as an example of a rare genetic alteration with a large effect. It's certainly important, and it reveals that genetic effects can be large, and it provides a scientific opportunity to study what pathways are disrupted as a result of 22q11.2 deletion. As I wrote in the heritability post, "Clearly, only a very small subset of people with schizophrenia have a genetic etiology *in this sense*. 22q11.2 deletion syndrome would be one contender. Other CNVs and rare variants with larger effects could be candidates as well, etc." Since most cases of schizophrenia are not associated with genetic variants/alterations of large effects, we are limited in what can be inferred from 22q11.2 deletion syndrome.
Agree that preventing SCZ is good, and polygenic screening probably helps more than other known interventions, and most of the arguments you reject ought to be rejected, except #7. Violating assumptions of heritability estimates is not a small point.
First, the limitations of adoption studies are not just the importance of the intrauterine environment. An adoptee's adult behavior is caused by a combination of 1. intrauterine environment, 2. early-life experiences before adoption, 3. post-adoption environment, 4. direct genetic causal effects on behavior, and 5. indirect genetic causes on behavior (e.g. gene → physical appearance → another trait). I would not confidently rule out any of these factors without experimental evidence directly controlling for them, which in the case of gene-by-environment interactions (#5) is essentially impossible.
For twin studies, it feels extremely implausible that the equal environment assumption is even close to true. Glancing at the paper you cited, they seem to find that the ways in which identical twins' environments are more similar only have small relationships with behavior. However, the value of this analysis depends on accurately identifying how identical twin's environments are similar. It seems this paper neglected some plausible ways in which identical twin's environments are more similar than fraternal twins (genes → attractiveness → people being nice to you, genes → athleticism → being on a sports team, genes → disease susceptibility → feeling sick). If some of these mechanistic explanations are correct (likely in combination or for particular sub-groups), it wouldn’t be reasonable to say that genes cause schizophrenia.
If you want to say X causes Y, a randomized controlled trial is a nearly universally accepted way to do so. With smoking, we have controlled trials in animals and some limited smoking-cessation interventions in humans. Also as you say, we have mechanistic evidence about mutations & that adds confidence. Sure, this is an example of imperfect evidence that most people accept and act upon, but it also feels like much stronger evidence than the purely genetic basis of schizophrenia.
The reason I feel strongly about this is that a blanket acceptance of heritability estimates leads to assertions about the innate intellectual ability of races. In this case, the arguments for the violation of heritability estimates are extremely plausible (e.g. in an adoption study, black kid gets adopted into a white family, but is still treated as black by society, and consequently his environment comes with him).
PS I love this blog & massively respect what you do.
“But as we often discuss here, this is backwards - society is fixed and biology is mutable.”
…the examples in the 2014 piece are fine, but come on – “society is fixed while biology is mutable” is just as wrong as the opposite statement.
The boring but truer statement is: both society and biology are mutable to some extent, but it varies to which extent. The variation is partly based on which society we are talking about, partly based on which biological factor/s we are talking about, and partly based on what kind of problem/s we are talking about.
I'll never forget how startled I was when I learned in college that no one with congenital or early blindness has ever been diagnosed as schizophrenic. A quick search just now confirmed that this is still believed to be true. Are we any closer to understanding why? Has investigation of this oddity yielded any progress toward understanding the cause(s) of schizophrenia?
> We know many apparent risk factors for schizophrenia: [...] social defeat
"Social defeat" struck me as the odd one out in that list. I clicked on the link, which was just to the wikipedia article on the concept, and it in turn had this in its list of sources:
That merely proposed the hypothesis that social defeat can increase the risk, and presented data in support. It didn't claim that we "know" it's a risk factor. Instead, it ends with suggestions for how to test the hypothesis in the face of the ethical problem of subjecting humans to social defeat and the inability to test for schizophrenia in other species of animals it is permitted to experiment on.
You seem to be completely right, but you make it a hard read. Why not start with "People in schizophrenia research are adamantly opposed to saying it's a largely genetic disease, even though the evidence says it is. Why is that?" You probably do want to put the long-winded analysis at the bottom as a massive footnote to the first sentence, but the interesting part is the psycho-politics of why people resist considering schizophrenia a largely genetic condition. And indeed, you barely scratch the surface of that. I'd think that if you did as much careful sniffing of how people talked about schizophrenia as you did dissecting the analysis of the data, you'd get a pretty good idea.
I came across something recently called the "eggshell skull rule" in Law which I feel is relevant to describing human intuitions about causation that other comments have mentioned. The idea behind the rule as described by wikipedia is:
"If a person had a skull as delicate as that of the shell of an egg, and a tortfeasor who was unaware of the condition injured that person's head, causing the skull unexpectedly to break, the defendant would be held liable for all damages resulting from the wrongful contact, even if the tortfeasor did not intend to cause such a severe injury. "
So if the genetic correlates of schizophrenia are ultimately best described as vulnerabilities -- things that do require one or more other significant factors to result in schizophrenia -- then I suspect that many people would intuitively find it much more comfortable to just describe them as genetic vulnerabilities rather than as genetic causes. And that's even if the most straightforward path to preventing schizophrenia were still to prevent or correct the genes somehow.
Second, anecdotally, I narrowly avoided a schizophrenia diagnosis a couple years ago (and did get a schizotypal plus transient psychosis diagnosis) despite having symptoms that, based on most descriptions I've read, do not fit schizophrenia well at all in my opinion: chronic pain, chronic headaches, fatigue, pins-and-needles, dizziness, difficulty thinking, and involuntary muscle contraction, all of which are weirdly exacerbated by common allergens. I specifically did not at the time have visual or auditory hallucinations, delusions, or disorganized thinking (by my estimate still, years later, though the psychiatrists considered my pain to be hallucinatory and my belief that it was associated with common allergens to be delusional) And based on that experience of how easily schizophrenia can be "read into" various symptoms as well as stories I've come across like this one: https://www.washingtonpost.com/wellness/2023/06/01/schizophrenia-autoimmune-lupus-psychiatry/ where a woman spent twenty years with a schizophrenia diagnosis when all her symptoms were caused by lupus and enormously improved for the first time by finally, y'know, treating the lupus, I've come to doubt the usefulness of schizophrenia as a label.
When schizophrenia is in practice reduced to "What might be interpreted as psychosis plus general impairment," as seems to be the case to me, while at the same time being thought of as something basically genetic, then there seems to be enormous potential for it to act as a diagnostic thought-stopping cliche. Maybe at a high level "what might be interpreted as psychosis plus general impaiment" is best correlated with genetics, but if it's actually the case that there are dozens of specific genetic conditions or genetic vulnerabilities each of which manifests apparent psychosis plus general impairment under certain conditions, in response to certain things, or in the absence of certain treatments, then wouldn't it be better to not treat schizophrenia as a monolithic "thing" with a "cause" at all, but rather as characteristic presentation of many things, most of which are ultimately genetically-based?
So I guess I'm on the side of: "The studies are probably right, but in a philosophical sense we shouldn’t describe it as mostly genetic."
I assume the real issue is that “genetic” is ambiguous between things like sickle cell or Tays-Sachs where there is a very specific gene variant whose presence or absence is definitive, and things that involve complex interactions between many genetic variants and the environment. It’s not like the former. And we don’t have good use to make of the latter category yet, so it isn’t one that we have broadly developed useful vocabulary for describing.
If people need a low tech method, not reproducing with people who have a family history of schizophrenia should help. On the other hand, if the percentage of schizophrenia is the same worldwide, it doesn't seem to help much, or is harder than it sounds, or helps the same amount everywhere.
I really do understand why you're so defensive of polygenic screening. I wouldn't judge any individual parents for choosing the option, and obviously in 2024 you are in no meaningful sense affecting the genetic fabric of society by doing so. But all the same, I worry about what it does to humanity in the long term if it becomes normalised, and I think you're wrong not to.
To get it out of the way there's the obvious thing where if it becomes possible, bigots might select against having (non-cripplingly) autistic, or gay, or etc. children in sufficient numbers to endanger the long-term survival of those traits. But that's not even what I'm most worried about. I'm worried that trying to do polygenic screening with our current half-baked understanding of genetics is the equivalent of doing advanced chemistry with a kitchen blender.
That is to say: can we reliably select against schizophrenia without selecting against various non-harmful forms of neurodiversity? Or indeed, random unrelated benign traits which happen to be genetically correlated with schizophrenia but have to do with the shape of your nose or left-handedness or something? On a societal level I worry about this a lot. I find it *most* concerning with people selecting against severe autism than against schizophrenia, because severe autism is more clearly on the same directly-related spectrum as personality types which humanity would be immeasurably poorer for not having. But A) I'm not sure schizophrenia isn't also correlated with positive /benign traits, and B) I don't think I trust society to be responsible with these tools if they get normalised, and *only* use them to screen out "safe" conditions.
People with the mentioned mental illnesses don't reproduce a lot, so selecting someone in the 90th percentile of autism instead of 99th may well lead to more autism genes in the generations afterwards.
My family has a history of schizophrenia, including members of both my immediate and extended family. We also have a history of high academic achievement, which includes advanced degrees in hard sciences and at least one department head at a major US university. I have noticed other families of high academic achievers with schizophrenic children.
Is there any data that links schizophrenia and high academic achievement within a family? I feel like I have seen this mentioned before. If so, is there any possibility that selecting against schizophrenia would select against gifted people as well?
You are ignoring the massive role that psychological injuries play in people later developing symptoms of psychosis. People with 5 Adverse Childhood Experiences are anywhere from 60 to 150 times more likely to have these symptoms, than people with no ACE's. https://pubmed.ncbi.nlm.nih.gov/17586579/ Schizophrenia is hugely influenced by being emotionally neglected, sexually abused, having a raging alcoholic as a parent, and other emotional wounds. It is not fundamentally in the genes.
I find it plausible that ACES play a causative role, but surely such estimates (60x - 150x) are inflated by confounding? Especially considering some of the heritable liability for SCZ is shared with other psychiatric disorders. I'd love to see some methodologically tight work on the subject, if you have any good refs.
I suppose one argument for not saying schizophrenia is genetic is to prevent that from becoming a dogma that can't easily be displaced? Like suppose some researcher has a theory about the cause or a treatment for schizophrenia but it's not linked to genes in any clear way and so when she goes to apply for funding she gets rejected because "everybody knows it's genetic".
You probably aren't arguing that schizophrenia should be specifically and always described as a genetic disease you just don't want people to be in denial about the role of genetics but perhaps (and to be clear I haven't read them) they are arguing against a more extreme version of your position.
Is it fair to say that genes do not cause two-leggedness? The heritability is near zero, on the same meaning of heritability. For bonus-points, y'all obviously agree accent is more heritable and therefore more genetic than two-leggedness, right?
Can't have any isolated demands for rigor here, and in certain communities any demand for statistical rigor is isolated, so please everybody get with the program.
I'm a public health professional. I think there is no difference between cause and risk-factor for scientists or professionals, but there is a big difference when creating public messages. Many people interpret "cause" to mean 100% correlation, as in, smoking 100% always causes cancer. When you say "risk-factor" people are better at understanding that there is some amount of probability around the factor. So generally you see a preference for saying risk-factor.
I think this is the core of the failure in communication. The human mind does not seek truth, it seeks satisfaction.
For a person not affected by schizophrenia, it's perfectly normal to think that "Schizophrenia is a disease that crazy* people have, and runs in the family" (*I'm not endorsing that word, but it is in common usage)
If you are affected, or work on it, that's not nearly good enough. A satisfying definition would include the idea that it's a bucket of conditions, not just one thing, and that it can cause a range of symptoms of varying degree.
When you work on a problem, you want to be able to work backwards and forwards with different suppositions to see what works.
Cause is like Proof - it's a place where you can stop thinking about something. If you say "I have evidence of something", that means you may have to keep looking. If you say "I have PROOF", then you can stop looking.
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I wonder how the various parties would engage with the terms Major Contributing Factor vs Minor Contributing Factor.
It is unfortunate there is no special word like "causes" in English that means "always causes but is not always the cause of." Successfully feeding someone into a wood-chipper always causes death, but death is not always caused by being fed into a wood-chipper. You could say genes cause schizophrenia, but don't wood-chipper cause schizophrenia.
>it’s a million times more than the drug abuse and social defeat issues
A million is a lot, this is meant rhetorically, like "a bazillion"...right? After the "Unintuitive Properties" post, I don't totally trust my surprise at seeing 10^6 mixed in with the other numbers.
Not directly relevant, but thank you for at least mentioning COPD. Everybody thinks tobacco will give you cancer, and it totally can, but it's way more likely to give you the other thing which will also kill you but in a very different (still horrible) way. We stress cancer way more, probably because cancer is an easier and more familiar thing to understand than an umbrella category for two overlapping disease states.
I think that the resistance to genetics as a cause for diseases is because it is very unsatisfying to blame genetics.
If the cause of your disease is environmental and beyond your control, you can always blame society. You are the victim of systemic injustice because society did not protect you well enough.
If the cause is environmental and thought to be within your control, you can always be blamed yourself. You should have known better than to smoke.
If the cause is genetic, that does not make for a very satisfying narrative outside of Nazi circles. Blaming your parents for not using screening or CRISPR is frowned upon, so you can just call it bad luck.
To the degree genetics as a cause is actionable, it would proscribe actions (gene screenings, selective abortions, DNA edits) which would make huge parts of society uncomfortable.
But we all accept genetic causes for certain diseases (e.g. Down Syndrome), and indeed screenings and selective abortions are common (if not without some controversy).
Didn't you write an article about how mainstream media rarely lies and apply a standard of "lying" under which one could claim the national enquirer rarely lies? (In that they didn't lie if they accurately reported what it was their source said to them without comment on the accuracy of that source)
There’s a disease that occurs only in people with a known, single gene (actually one allele). Because we know that gene, we know exactly what’s happening when it kills someone.
And yet it doesn’t kill everyone it could; people with the bum gene are still alive. Though if it did wipe them all out, we’d probably *still* blame the vector, not the victims’ genes.
The disease is mad cow, and the cause is ingesting misfolded prions. We are so impressed by a concrete explanation that most people don’t even know every victim (save one, IIRC) was genetically identical in one spot. If that’s not a genetic disease, how is schizophrenia?
Nobody wants a GWAS disease. It’s too fuzzy and it smacks of either missing something on the causal side or the definition being too broad. Like other unsatisfactorily explained diseases (MS, chronic fatigue, etc.), it’s better to admit ignorance than blame a thousand insignificant genes in the victim affecting an entirely hypothetical no-voices system in his brain.
Genetic screening for dominant genes whose pathological effects appear in adulthood reduces the frequency of those genes. That is an unalloyed good only if we certain than any possible beneficial effect of those genes is outweighed by its pathological effects. But we can't be certain of that.
Imagine a future ultracontagious virus that kills everybody who doesn't have the gene for Huntington's Chorea (WIV is working on that right now -- maybe...). With 100% screening of embryos for the gene for Huntington's Chorea, human beings go extinct.
"health care should be about treating schizophrenia, not preventing it"
I was trying to figure out why anyone would oppose polygenic screening and this sounds like the real reason. A doctor or therapist can't make a career transition to genetic screening tech, so they correctly see "we could cure schizophrenia" as a threat to their employment.
Providers would absolutely love to “cure” mental illness in all its forms because of the great suffering they see. The idea that they want to see people ill is quite frank insane.
"PGC objects to such uses because its goal is to improve the lives of people with mental illness, not stop them from being born, says University of North Carolina at Chapel Hill psychiatrist Patrick Sullivan, PGC’s founder"
Genetics has nothing to do with schizophrenia, save for growing up among the deviations from “society’ as it is accepted and wanting to be ‘someone else’. Some young actors have been diagnosed schizophrenic after taking on a role and keeping it. You can pretend to be someone else and end up really believing it. To someone who craves attention, they can create as many different “voices” as they want. Not being accepted in society is what keeps them so sad and hides away in the group they created for themselves. When someone is sick or not all there as with drugs, some sayings can stay with the person. I have helped a person see where there voices originally came from. A friend kept telling her she never listens so she wasn’t. They have to be active in their life and at least able to laugh once in a while to be able to even talk to them about it.
Ash Clif_high. He says he has the ‘schizophrenic gene’. But he is not schizophrenic . Basically if you cannot get them to create their life, they will just stay apathetic and reactionary. The medication for psychotics is a tranquilizer,......this keeps them quiet and depressed unless they can form some life while on them. Drugs is definitely not the answer. They need acceptance and confidence and acknowledgement. Cal mag and B vitamins really help.
Once argued with someone who said it was "reductive" to say that "genes are among the causes of risk of skin cancer." And at that point I gave up because at a certain point demands for further nuance just become a reason not to have thoughts.
Is there really a clear definition of "schizophrenia"? This was all very interesting -- no irony -- but without a clear definition of the supposed disease, talking about its "causes" seems somewhat beside the point.
I have a question: if schizophrenia is mostly genetic, then why is there so little evidence of it in ancient texts? (Whereas other mental illnesses are described in Greek and Roman sources etc.) Doesn't that suggest that there are factors new in the environment that cause it (perhaps in interactions with genes or recent gene mutations). As well, all twin studies are compromised by the shared womb and in the case of adoption, by shared adoption trauma, and while genes run in families, so do environmental factors, stress levels, nutritional factors, parenting styles, and intergenerational traumas.
From Iain McGilchrist (The Master and His Emissary, page 404):
"... schizophrenia has in fact increased in tandem with industrialization and modernity. In England, schizophrenia was rare indeed, if it existed at all, before the eighteenth century, but increased dramatically in prevalence with industrialization. Similar trends can be observed in Ireland, Italy, and the United States, and elsewhere ... What is beyond reasonable doubt, however, since it has been established by repeated research over at least half a century, is that schizophrenia increased pari passu with industrialization; that the form in which schizophrenia exists is more severe and has a clearly worse outcome in Western countries; and that, as recent research confirms, prevalence by country increases in proportion to the degree that the country is "developed", which in practice means Westernized. Descriptions of melancholia, or of manic-depressive (now called bipolar), are immediately recognizable in accounts from ancient Egypt, Greece and Rome, yet there are no descriptions of schizophrenia ... The relative risk of developing schizophrenia in an urban rather than a rural setting is nearly double, and the evidence suggests that is it more likely that the urban environment causes psychosis than that high-risk individuals migrate to urban areas."
I can't believe that you would reduce THE Ronald Fisher to a tobacco statistician. Back in the day it might have been a reasonable position to say that the causation hasn't been proven to a high degree of confidence. Just because it turned out to be true, doesn't mean it was wrong to caution against premature regulation!
> But age is certainly more than correlational with flu
Minor but: but your example is wrong. If you changed age and held everything else equal then you wouldn’t get the flu less. It’s because age is correlated with other health properties (like a weaker immune system) and you’re assuming these change too when you change age.
I haven’t read the Aftab post or Torrey paper, but it seems that something is being assumed at the outset of the arguments you’re responding to—and your responses to them—that hasn’t been established yet, as far as I’m aware; namely, that there are “genes that cause schizophrenia” (as stated in Argument 3). Has this actually been established?
I’m reading Chris Palmer’s book, Brain Energy and he has a chapter on genetics in which he claims that since the human genome project, we haven’t been able to find specific genes related to mental disorders, though researchers have tried very hard to do so. My understanding based on my reading of Palmer’s theory is that epigenetics—the turning on or off of genes that are mostly common in all of us—are what produce psychiatric symptoms when epigenetic regulators like mitochondria are defective. Interested in your (or anyone’s) thoughts on this, as well as the whole “mental illnesses are metabolic disorders of the brain” idea promoted by Palmer. After all, the satisfying nexus, or the thing that “all schizophrenia causes have in common” might be, according to this idea, mitochondrial dysregulation—which happens to be treatable by various methods, including (but not limited to) medication.
Thanks, from a schizoaffective with his illness in remission for 5 years!
In my opinion, this all comes back to the irresponsible shirking of physical brain scans which we have the technology and enough information to do. It's frankly bureaucratic stupidity from my seat.
But if you want my wild stab, I think it's environment poisoning. Some persons are more inclined to sensitivity writ large. It's not necessarily a weakness toward anything, but all things. You can really see this in autism more clearly which is highly related to schizophrenia.
So causal things more apt to create disability would include, in no particular order, metal poisoning, mother stress, mother drugs, father age, heavy toxins/molds, toxin history of mother and father, nutrition, lack of natural sunlight, lack of functional digestion, metabolism dysregulation, working your body (mostly mother) in regularwork performance .. and yes, I'll risk it potentially even up to and including getting poked with a needle up to around age 2 or 3 in particular.
I think the second part to this that's even less understood is general resonance (sounds, light etc.) & DNA template creating thought patterns that work something not too disimilar but definitely unlike a motor bike dirt track. It's for this same reason children pick up on language and behavior they didn't explicitly learn, it's for the same reason we cannot pinpoint on a DNA chart where the pain is. for the same reason a person can have anomic aphasia and still 'mostly get it' though confusing the language interplay variables, for the same reason we aren't assigned implicit sexual interest, but 'tune in to it.' The same reason we can look at a composed work of music for instance created by an autistic and a non-autistic and can recognize the patterned thinking differences more clearly in some ways than with direct language interplay.
while I won't go so far as to say we 'feel everything' or just as silly 'we are our attitude' I will suggest these things play out, our genetic baseline of prerecorded bits of sequenced thinking jumbled from both parents, and our ability to react heathily over time.
"This is possible, but I think it’s false. We know many apparent risk factors for schizophrenia: cannabis use, birth canal asphyxia, social defeat, toxoplasma infection, poor prenatal nutrition. If you try to combine these into one big picture, it doesn’t work."
There's a theory that does: Cell Danger Response Theory by Robert Naviaux. All the above are related to over/under-engagement of the healing process in response to stress/trauma. He even lists toxo as a possible disorder from the CDR malfunctions. In short: When you have a chronic stressor in your life for over 6 months or of sufficient magnitude your body cannot complete the healing process and it gets stuck at one of 3 sequential stages. 1 Cell shutdown and hardening, 2 cell replication , 3 cell differentiation and establishment of connections to other cells.
As the 334th comment I expect this to get buried, but in any case there is a literature you may find helpful regarding the erotetic nature of explanation: We generally aren't explaining things in extreme specificity and/or extreme universality (a God's eye view). Instead, we are evidentially-limited beings with goals, and we choose the scope and granularity to explain something to a situated human for a specific purpose.
That provides a framework to understand the fact that the same question may have more than one answer. It also allows one to make systematic sense of why some causally-relevant factors are placed in the background rather than called "causes," and why the background and foreground can change.
We take the background for granted. Those conditions are "normal" while the thing we call the cause is the intrusion on the normal state, or a violation of the state we prefer (in other words "normal" can refer to frequency of occurrence or normative preference). The distinction between cause and background condition is often NOT in the modal logic of implication. It is rather based on our own interests and preferences about where to intervene to change things, or our preference for assigning responsibility/blame as agents.
It had never occured to me that biology was sometimes easier to fix than environment...
Now it see it everywhere.
For example obesity is both a stigma and a medical condition surrounded by truckload of environmental (if not moral) advice and one a someone invents a drug that just fixes obesity and it is not a problem anymore
I don’t think the cause | risk factor distinction is explained well using the language of necessary and sufficient conditions, but here’s an alternative:
Causes are events which lead to the dice rolling (for a given outcome to happen). A given cause doesn’t have to be the *only* way for the event to happen.
Risk factors influence the odds of the roll. Alternatively, risk factors can also refer to any change in the success criteria. Smoking causes lung cancer, but being a heavy smoker is also a risk factor for lung cancer because repeated rolling of the dice increases the probability that one will hit.
My gut says this definition is pretty close, but I’m concerned that (e.g.) smoking would, given a deep enough understanding of the underlying biomechanics, only be a risk factor. Maybe the more expert commenters can evaluate better.
I stumbled onto this Substack just today. I perceive many readers/commentators are way smarter than me. I only want to say, I had a terrible schizophrenic sister as well as a brother with bipolar disorder. None of this information was around forty years ago. My grandfather committed suicide (in his younger life he had electroshock therapy for severe depression). My dad wasn’t right but it was the 50’s and 60’s. I have considered these disorders hereditary based on my personal experience (and some reading). As a mom, I made sure my kids (now fine adults) knew what to look for if they felt/believed such and such. I wanted them to know our family history and be aware because it seems to me once the disease is in full swing, the patient becomes the proverbial ‘I’m not mentally ill’ person who is very hard to help. It’s a terrible burden I would advise for genetic testing when available.
"psychiatrists are technically neurologists gone weird":-)
Is Schizophrenia as ontologically defined as the Flu is? There have been plenty of cases of it being misused as a political diagnosis, in the Soviet Union for instance, and even if there's a known ontology it would still be equivocation if it's never clinically tested for and the diagnosis is still only based on symptoms.
It's necessarily not as ontologically defined, because schizophrenia is a syndrome and the flu is a cause. I think an apples-to-apples comparison would be if it's as well defined as "flulike symptoms", to which the answer is that nobody bothers to define flulike symptoms and they just say "you'll know it when you see it".
Sounds fake. How do I know that syndromes are even a real class of things, vs a word used to pretend there is a class of things that is conveniently shaped to plug that specific hole in human ignorance.
To take a wild stab in the dark:
Possibly you could break down a bunch of syndromes into component symptoms, put them in a list, add in other symptoms, collect a huge amount of data from a lot of people as objectively as possible, and see where the clusters are. If infection with the influenza virus is associated with a particular cluster of symptoms, it might make sense to call that cluster "flu-like symptoms" (which may be somewhat different than the cluster we currently call that). If other root causes correlate with that cluster, then it might make sense to take the most common one and use that for the name; it might be "flu", but might theoretically be something else.
Not that we've done that, but it seems like it might be possible?
I'm sure it's possible. It's just been kind of frustrating to see even celebrated rationalists backslide (or remain?) at the level of showing how a math problem can be solved, not doing the math, then championing a result.
The mathematician's problem of enjoying the interesting work of proving that a solution exists, but refusing to do the tedious work of coming up with the actual solution? :-)
Practically speaking, I'd worry about falling afoul of HIPAA or an IRB or something, to get that much data.
Definitely, it's conveniently shaped to plug a specific hole in human ignorance. I think most psychiatrists would probably agree that schizophrenia is a messy concept and it would be great to have less messy concepts, but we're not there yet.
I would encourage you to think of schizophrenia differently, though. I think of syndromes as a way to know who's going to benefit from specific treatments. We have studies showing that, for people who've been diagnosed with schizophrenia, they seem to be less likely to die if they take antipsychotics [1] (modulo a U-shaped dose-response curve, though I suspect reverse causation on the high end, since people with worse schizophrenia tend to end up on higher doses). Obviously, you can disagree with the studies here, but you can disagree with studies about anything; these seem relatively robust compared to a lot of other treatments in medicine.
There are also other benefits to taking antipsychotics in schizophrenia, as well as risks; much ink has been spilled over balancing them, and it's certainly an interesting topic to read about. The same can be said about other treatments for schizophrenia, like psychotherapy or neuromodulation. I will caution that, when interpreting literature in psychiatry, it's important to look at a lot of studies, and look at overall patterns; you will come to incorrect conclusions if you pay too much attention to a single study. But this is a digression.
In other words, schizophrenia is a concept that, among other things, lets doctors find people who will live longer if they give them antipsychotics, and living longer is kind of hard to argue with.
[1] https://academic.oup.com/schizophreniabulletin/article/41/3/656/2375074 - and there are lots of other studies about this question
When diagnosing a patient, what criteria do you use to decide when to say "this person has schizophrenia", vs "this person has <some different type of brain problem>"?
https://en.wikipedia.org/wiki/Diagnosis_of_schizophrenia
According to DSM-5, the person has to be experiencing at least two of the following -- either delusions, hallucinations, or disorganized speech -- over much of the time of a period of at least one month.
In other words, by symptoms.
There's a bit more to it as well, in terms of ruling out other conditions: for example, autoimmune encephalitis can cause symptoms resembling schizophrenia.
Thank you. Came here to say much the same.
We speak of schizophrenia as if it is a single, well defined pathology (ie. essential nature) when we really still have no basis for such an assertion. The 'diagnosis' being a catch all for a constellation of diverse signs and symptoms with a wide and variable range of expression of largely indeterminate causation(s). (The plurality there - alone- being obvious reason for pause and reconsideration.)
All of which is why we -properly- speak of people having met "criteria consistent with" a diagnosis of schizophrenia. Because, as a matter of fact, we have no warrant to say that they even have the exact same thing. At best we recognize that their particular brain AND mental dysfunctions are being expressed in a recognized and patterned manner.
Dementia is another term often used to describe a clinical presentation with an equally vague and diverse set of conditions yet viewed as somehow being of specific and 'well defined' nature my dint of having been given a name.
Also, autism is vague in the same way. Or better named "autism spectrum disorder". My daughter is on the spectrum, supposedly, but it took years to get the diagnosis, because she was atypical (as are many girls). I'm still not convinced that that is exactly what is going on with her, but it was a helpful diagnosis for us, since we were then able to get her appropriate therapies, and we could point to her dx to convince people to be more understanding of her differences. Our family participated in the SPARK (genetic) project, but we've never heard from them about any particular gene that they identified in our case. More and more, I am suspecting that the environmental factors that I worried may have caused her disorder, might actually have.
I'm also interested in schizophrenia, since a branch of my family also has several members with that. Scott, have they actually identified the relevant gene/s? How many are there? I'd be interested in getting tested just for curiosity's sake. Are there multiple genes, for example? Could different branches of the family show one or some, and not display the symptoms?
Im in a similar situation to yours. I have two daughters both w ASD dx, one profoundly so, one much more typically presenting. We did genetic testing on our more effected child revealing no "de novo" or single cause of the ASD. This doesn't mean her condition isn't mostly genetic. It just means the state of genetic counseling is in the practice of finding and communicating very noticeable obvious differences between an effected individual and the general population. Per Wendy Chung (on The Drive with Peter Attia, who was a lead researched in SPARK I believe) says the current guess is there are 1,000 implicated genes in ASD and researchers are maybe 1/3 the way in mapping them all. Interestingly these genes seem to be generalist, which I take to mean if you have an adequate collection of these genes, you're at risk for developing some kind of neurodevelopmental disorder (ASD, ADHD, schizophrenia, depression). The current state of genetic understanding cant yet tell us exactly which condition/s is most likely to develop per se. But I have very little scientific training or understanding so take all that with a grain of salt. Some links that may be of interest:
https://peterattiamd.com/wendychung/
https://www.researchgate.net/publication/358716011_Genome-wide_analyses_of_ADHD_identify_27_risk_loci_refine_the_genetic_architecture_and_implicate_several_cognitive_domains
https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2718628
I’m surprised that despite a dozen arguments on this list, not one of them is the arguably-correct one: that heritability might be a bad match for human intuitions of what “mostly caused by” means. (e.g. the low concordance probability of schizophrenia in twins, which is counterintuitive. We can respond to this either by saying concordance probabilities are a bad operationalization of “caused by genes,” or by saying the biggest cause of schizophrenia is “shitty luck” or “nonlinear responses to inputs that don’t add up to 1.” Of course, this buys you a whole heck of a lot of other paradoxes instead.)
I thought that was Argument 8.
The concordance is (theoretically) even lower for unrelated people raised in identical environments, so by this logic it makes even less sense to say that it's mostly environmental.
It's possible for two children in the same environment to have (at least somewhat) different childhoods and traumas, and for one of the children to be more traumatized/abused/neglected than the other(s).
Polygenic screening doesn't prevent schizophrenia in a meaningful way, though. It just prevents those embryos with high risk from developing into people (modulo your beliefs about when personhood begins).
That sounds very "meaningful" if you have to select one or two from a dozen one way or another.
They might each be entitled to an equal probability of selection. It might be immoral to use any method besides RNG to make the choice.
That seems at odds with how most people would resolve other moral choices.
For instance, in triage situations, it's normally considered good for doctors to treat the person with the best survival chance rather than picking randomly.
Conversely, it's normally considered obligatory for them to treat as many people as they can--it would be pretty weird to have a situation where it's morally obligatory to give an EQUAL survival chance to everyone, but NOT morally obligatory to make that survival chance be as high as you reasonably can. By analogy, it would be weird if you had a free choice about HOW MANY embryos to incubate, but not a choice of WHICH embryos to incubate.
And I have difficulty imagining anyone arguing that you ought to choose the other parent of your child at random, to give all possible potential children an equal chance, instead of having a baby with your spouse. (You could argue that the difference here is that the embryos aren't fertilized yet, and your obligations only start when they are--but that seems to make the objection from the previous paragraph even more acute.)
If you believe personhood occurs early in embryonic development you shouldn't create superfluous embryos, yes. However, supposing you have already made that error, I don't think assigning equal or near-equal survival chances to each are all that unreasonable. The reductio ad absurdum of your own position would be that if there's some small number of gene combinations that maximize life, all other things being equal ONLY those gene combinations should ever exist. I think most people value hetereogeneity in life to an extent that allows you to leave a large number of QALY's on the table, at which point it's not clear to me that there's an airtight argument for favoring non-schizophrenics over schizophrenics anymore.
I wasn't trying to promote any specific position, but I notice that the position you have chosen to argue against is "it is OBLIGATORY (not merely permissible) to choose the embryo with more QALYs", and there is plenty of room for that position to be wrong without the "it is obligatory to choose by RNG" position being correct. (Also I'm not sure I buy that your reductio really is absurd, but I don't feel strongly enough to want to defend it right now.)
Re "supposing you have already made that error," imagine a story where, due to some SF/F premise, it is possible to suddenly accidentally create several obviously-fully-developed people, where you meant to create one. In all the stories like this that I can recall, the characters take it as morally obvious that you are now obligated to preserve ALL of the people you created (if possible). I cannot recall a single one where it was suggested that you are morally obligated to choose randomly which one to keep, but are free to discard the rest. I predict that a story where all the characters agreed on that standard would evoke moral disgust in most readers.
In the absence of some pressing reason why all lives couldn't be preserved, yes, you're right.
It's possible that RNG selection actually ends up with less heterogeneity in the end! The only acceptable way to choose embryos is to invent metrics of uncertain value or real-world relevance and then laboriously search for the embryo that maximizes all of them (weighted, of course, with the results of your preliminary work to determine how to choose weights without immorally privileging things like general health, QALYs, intelligence, etc).
I don't know what "entitled" means here.
Iterate over the possible meanings and choose the one that doesn't lead to you responding to this.
I'll take a stab at it then: Embryos aren't "entitled" to anything and you can use absolutely any metric you please for determining which ones get to develop and be born.
This is an argument against polygenetic screening in general, not against screening for the genes that corollate with schizophrenia in particular.
I guess I would phrase that as "it prevents schizophrenia at the family level" or something.
I'll agree with that. But it is categorically different from preventing lung cancer by banning cigarettes, or preventing car accident deaths by requiring car seats.
But... why would we care? You can carve reality in an infinity of ways - several infinities, most likely. "it is categorically different" has value only so far as this category pays dividends.
I'm sorry if I'm over-reaching here, but a common argumentation technique is to carve reality at an arbitrary point, they use this categorization as a supporting argument for something else.
In this particular case polygenic testing prevents schizophrenia in future children in all ways that count - pretty much functionally identical with how folic acid or abstaining from smoking and alcohol prevent a bunch of other conditions. We don't use a magnifying glass on how exactly alcohol is bad for you. So why mention that it's categorically different at all?
> You can carve reality in an infinity of ways - several infinities, most likely.
What would this distinction mean? Usually, you'd come up with a category, like "ways in which it is possible to carve reality", and then consider whether the number of things in the category was finite or not. Clearly it isn't, but since there's only one category, there's only one quantity involved.
>I'm sorry if I'm over-reaching here, but a common argumentation technique is to carve reality at an arbitrary point, they use this categorization as a supporting argument for something else.
It’s not as arbitrary as you think. You can prevent schizophrenia “at the societal level” by killing everyone who might get schizophrenia. Who could possibly be against this? You will never have to deal with a schizophrenic again! We can create a schizophrenia-free society!
More seriously, I’m not one of those people who believes in objective morality, but if I was, I would be very concerned that IVF clinics are literally Auschwitz.
To people who are okay with abortion, selecting (and therefore killing) embryos isn't the same thing as killing people who have already been born.
I’m not necessarily opposed to IVF, but I think it’s a relevant consideration to bring up if one is arguing that the objections are stupid. It didn’t even click for me reading the post that we were talking about murdering embryos until we get the right one until I saw the top comment in this chain.
I thought one of Scott's recent posts shows that not to be true (or at least not as easy as it seems). Nazi Germany tried to kill all schizophrenics, and they have the same rate as countries that did not. IIRC the rate returned to normal extremely fast as well, like the 50s or 60s.
He's not saying "kill everyone who might get schizophrenia so they won't have kids with schizophrenia" he's saying "kill everyone who might get schizophrenia, then there will be no schizophrenics left in society." Because you killed them all. When more pop up you'll kill them too.
Yes, but in your example the categorization pays dividends immediately and obviously.
My beef isn't with support or condemnation of abortion (for what's worth, I'm European and I find the whole debate strange and exotic, and rather strongly disagree with both extremes). My beef is with sneaking the categorization as an argument for the belief instead of the consequence of the belief.
If OP said "I think we should make a distinction because in one case we're killing embryos and this is bad", this would be owning your position and, agree or not, it's a valid point to make.
Instead, OP suggested in a public forum that it's a categorical difference, with the possible intention of supporting his belief with this categorization. That's circular logic, and it's also use of a Dark Art. Which is ok on Facebook or X, but I thought here should be gently censured.
I'll write a post sometime in the next few weeks about why I don't think it's categorically different from those things at all. If I forget until March, please remind me!
Please do write on this. Ive been internally grappling with the above thread for some time. My entryway has been Michael Sandel and the ethics chapter from the Walter Isaacson biography of Jennifer Doudna
In a counterfactual where people did IVF without screening, they'd still be choosing some embryos over others. Some embryos wouldn't develop into people either way. This just affects which embryos are which. But, in a eugenic sense, these embryos-turned-people could in turn reproduce and spread their genes with different risks for schizophrenia, and in different counterfactuals different embryos in the next generation won't exist at all.
...Who the hell has been saying epilepsy isn't genetic? It's pretty damn obviously genetic. Barring the ones from people getting whacked on the head really hard.
I had never heard that argument either. I have heard there is a drug (lamotrigine) which treats both epilepsy and bipolar, with the latter being closely linked to schizophrenia.
Most drugs used as mood stabilizers, like lamotrigine, were originally developed as anticonvulsants. (The big exception is lithium, which for decades was the only available mood stabilizer.) Bipolar and schizophrenia are both responsive to treatment with antipsychotics, but I don't know that I'd otherwise describe the disorders as "closely linked."
There was a major study in the Lancet 'Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis Cross-Disorder Group of the Psychiatric Genomics Consortium'. This identified shared risk loci with cross-effects on 5 disorders including Bipolar and schizophrenia.
Quoting from Wikipedia's quote of William T. Carpenter:
"Genetic studies do not support the view that schizophrenia, psychotic mood disorders and schizoaffective disorder are distinct etiological entities, but rather the evidence suggests the existence of common inherited vulnerability that increases the risks for all these syndromes. Some susceptibility pathways may be specific for schizophrenia, others for bipolar disorder, and yet other mechanisms and genes may confer risk for mixed schizophrenic and affective [or mood disorder] psychoses, but there is no support from genetics for the view that these are distinct disorders with distinct etiologies and pathogenesis."
https://en.wikipedia.org/wiki/Schizoaffective_disorder#Causes
OP was responding to Awais Aftab who said
> Take the case of epilepsy. Epilepsy is a recurrent abnormal, excessive, and synchronized electrical discharge in the brain. It has a heritability of 70-88%, at par with schizophrenia. However, epilepsy is not broadly characterized as a genetic disorder. The 2017 ILAE Classification of Epilepsies recognizes six etiologic categories: genetic, structural, metabolic, immune, infectious, and unknown.
I guess his idea was that since most epilepsies don't have a ILAE classification of "genetic", schizophrenia shouldn't be called genetic (but Scott's classification of schizophrenia is not simply "genetic", it's "probably mostly genetic").
> By comparison, you can very clearly halve your children’s risk of schizophrenia through polygenic selection, which costs only a few hundred dollars if you’re already doing IVF.
Last time I looked into it, polygenic risk scores for schizophrenia were only able explain ~2% of variance of schizophrenia. It’s really hard to recruit enough schizophrenics for variants in a GWAS to reach genome wide significance. And even with GWAS, you can’t measure things like copy number variants or rare variants. I think it’s at least another few decades until we can screen out schizophrenic embryos.
You can get 40-50% risk reduction with 5 embryos given the current state of PRS models [1][2] (Disclosure: I work at Orchid). I don't have a reference handy but Genomic Prediction has estimated similarly for their models.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510582/ external models
[2] https://portal.orchidhealth.com/risk-calculator our simulation
> And even with GWAS, you can’t measure things like copy number variants or rare variants.
I should also mention, we do WGS so CNV and rare variants get sequenced (with the usual sequencing caveats). That said, the science behind linking rare variants to disease is very much a work in progress so I don't want to claim that has a big impact on Schizophrenia prevention right now.
Let's assume you are the kind of high-performing family that delays childbearing until after it is normally physically possible and spends multiple tens of thousands of dollars to try to make up for that.
What is the baseline rate of schizophrenia? According to the WHO, the rate of schizophrenia among adults is 0.45%. But it seems likely to me that the rate of eventual schizophrenia among _your_ children would be markedly less. Say it's 0.3%.
Does a 50% risk reduction matter? That would mean that for every 667 children you have, you prevented schizophrenia in one of them. And since it cost a few hundred dollars each time, you spent maybe $170,000 to do it. (Assuming you actually managed to have 667 children, which is an assumption I'm not sure we should overlook.)
It doesn't take a lot to conclude that this is not a cost-effective intervention.
According to this study [1], schizophrenia is associated with about 10-20 years lower life expectancy. So that would be $8500-$17000 per life year, running with your number of $170,000 to prevent a case of schizophrenia, which most people in North America or Europe would consider to be cost effective - and this is ignoring quality-of-life, which would make that cost-effectiveness look more attractive.
[1] https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(17)30078-0/fulltext
1. .45% is a global lower bound that's pretty sensitive to classification and the ability of the medical system to diagnose cases. In the US it's 1.2%. So you can use this, but it's pessimistic.
2. I have no particular reason to think a downgrade of the risk to .3% is accurate, but sure.
3. Like a sibling comment mentioned, $170,000 is incredibly cheap for a lifetime of severe disease prevention. Financially, that dwarfs the QALY ROI of most medical interventions from the past 50 years.
And this is harder to quantify, and you are going to just have to take my word from personal experience on this — Schizophrenia has an *incredibly* hard toll on the family of the affected individual. We need to not just count the QALYs of the individual. We need to count the parents, siblings, the entire support network.
4. Either way, (1) and (2) are irrelevant from the perspective of the families that are actively seeking out Schizophrenia PRS; they are seeking it out *because* of a family history. Having an affected brother or sister will tripe your child's risk. Having 2+ affected 1st degree relatives can get the risk up to 9-10%.
Do you think it's an unreasonable intervention if you can spend $17,000 to prevent Schizophrenia? I feel like even you would grant this one.
> Schizophrenia has an *incredibly* hard toll on the family of the affected individual. We need to not just count the QALYs of the individual. We need to count the parents, siblings, the entire support network.
I don't actually believe that, in the case where one couple has 80 kids (assuming odds a bit worse than 1.2%), the schizophrenia of one of those kids is going to take a major toll on the family. They just won't do the things that you expect of a more typical couple with one child who is schizophrenic.
A similar argument scales down; a 0.6% chance that your one child will develop schizophrenia is essentially impossible to distinguish from a 0.006% chance of the same. You can never have enough children for the odds to make an observable difference. Making changes that are not even theoretically detectible is generally a waste of whatever effort you went to to make the change.
Now, the 0.6% difference is perceptible if you are the government. But then your cost-benefit analysis would want to measure different effects; the fact that parents whose existing child develops schizophrenia sink a lot of resources into that child, if they have them, isn't really relevant. What is the benefit of cutting the number of schizophrenics in half on an ongoing basis? Does it exceed an ongoing cost of $250 per birth in the country? (Or... much much more than that, since applying this policy to everyone would mean replacing all natural conception with IVF implantation?)
At the society level, we will see diminishing returns; cutting the population of schizophrenics in half will probably not also cut the problems caused by schizophrenia in half.
I have a very minor amount of personal experience with schizophrenia in that a homeless woman who appeared to be pretty severely detached from reality once visited my home (staying outside and making no attempt to enter) and we had to call the police to have her removed. If there were 50% fewer schizophrenics, we might estimate that that would have had a 50% chance of happening. But it was a one-off event. I will estimate the value of preventing it at $5. She was known to the police and probably had bothered, and still bothers, other people. But I don't believe that the total amount of bother so generated exceeds $170,000, or $42,000 (close to the relevant figure at $250 per birth and a 1.2% pre-filtering rate). The general value of preventing some cases of schizophrenia isn't very high. Most of the value of prevention is specific, captured by the patient and their close relatives.
> Like a sibling comment mentioned, $170,000 is incredibly cheap for a lifetime of severe disease prevention. Financially, that dwarfs the QALY ROI of most medical interventions from the past 50 years.
I will stipulate this, but I don't think it's a good argument that the benefits exceed the costs. I think it's an example of luxury beliefs making society generally worse off. There was an econlog post a while back making the observation that (1) we have a standard for the value of lives saved by medical interventions, and (2) that standard straightforwardly implies that (under some popular assumptions) the benefit of a full halt to all production, if it stopped the spread of covid, exceeded the cost (which is easy to calculate; a loss of all production in some country is equal to that country's GDP), and then (3) that if we actually did halt all production, many more people would die than were believed to be at risk from the fully unimpeded spread of covid.
One obviously correct lesson to draw from that would be that the value of many lives is not a linear multiple of the value of one life; you can't just scale a number of lives saved by a standard "value of saving one life". But another lesson, less popular than the first one, is that our standard VSL is too large. This is unsurprising; the VSL is derived mainly by a process of first choosing how much we want to spend and then seeing how many lives we can attribute to our spending. When the goal is to spend money, prices are likely to be systematically too high.
So, I tend not to agree with the elements of your point (3). Point (4) is perfectly valid. But point (4) is also something of an argument that families without a family history of schizophrenia are *correctly* not filtering their embryos for schizophrenia; it's not an argument that everyone should start doing it.
> A similar argument scales down; a 0.6% chance that your one child will develop schizophrenia is essentially impossible to distinguish from a 0.006% chance of the same. You can never have enough children for the odds to make an observable difference. Making changes that are not even theoretically detectible is generally a waste of whatever effort you went to to make the change.
Sure, but you're not just selecting against Schizophrenia risk when you do these sorts of selections, you're selecting for/against a hundred different things like it. And on that level if you have a 0.6% chance of *bad thing* for each bad thing for each unselected individual but only a 0.006% chance for each selected individual there's a close to 50% chance of at least one *bad thing* with your child if unselected while you only have a risk of 0.6% of at least one bad thing if you select your embryo.
Now in reality there are tradeoffs because you are limited in the amount of embryos you have to choose from so you can't just independently select on all traits, and therefore you almost certainly won't be able to get the risk of "at least one bad thing" down to 0.6%, but it's perfectly plausible to get the risk down to say 20% instead of 50%, which is most definitely noticably on the individual level.
I don't think people with low risk should be prioritizing schizophrenia risk when doing their embryo selection. But if you *do* have high genetic predisposition to schizophrenia, as can be easily determined, it makes sense to do some embryo selection to lower that risk. Or at least, it makes more sense than any other preventative measures you might take to prevent schizophrenia.
Heritability/Variance explained and PGS (polygenic scores) are two different (but not unrelated) things. For embryo selection/gene modification it's the second you care about, not the first. My understanding is for Schizophrenia we have very good PGS score estimates so we can do embryo selection.
One extreme example to see they are not the same is: consider a gene variant at a locus which is 99.99999999% protective against Schizophrenia, in other words if you carry a copy of this variant you have 99.99999999% reduced risk of Schizophrenia. Such a variant is going to have a very high PGS score. Suppose however this variant is only present in 10 people on the planet, so the total amount of variation in Schizophrenia it explains will be very close to 0.
Now because this variant is so rare you can't use it for embryo slection (with probability very close to 1 no embryo will carry it), but you can use it for e.g. in vivo gene modification. In reality you have lots of loci which are a lot more attuned version of this, so in many cases (including Schizophrenia) you can get pretty good control on the child's risk of developing the disease even if the heritability is low by itslef.
> One extreme example to see they are not the same is: consider a gene variant at a locus which is 99.99999999% protective against Schizophrenia, in other words if you carry a copy of this variant you have 99.99999999% reduced risk of Schizophrenia. Such a variant is going to have a very high PGS score. Suppose however this variant is only present in 10 people on the planet, so the total amount of variation in Schizophrenia it explains will be very close to 0.
This is a good theoretical example, but in reality won't the PGS score be zero because nobody has ever identified the variant?
Is Argument #9 even true? Did anyone NOT call epilepsy genetic?
I wouldn't have immediately thought of it as genetic, but I rarely think about epilepsy causes at all.
My late father was epileptic. Today I am the family-tree geek in our extended clan and, with three decades' worth of researching/compiling under my belt, am confident in identifying exactly one person from whom my father may have inherited it: his maternal grandfather. That guy died in 1909 in his late 30s, and from various family lore and old letters and newspaper articles (he'd been a local celebrity) the retroactive diagnosis of epilepsy has decent odds of being correct. Maybe in the range of 75-25.
If that retroactive diagnosis is correct then we have a strong possibility for when/how my great-grandfather became epileptic: in a swimming accident when he was about 20. He was on a group outing at a local swimming hole which was actually an old quarry, a friend started struggling in the water, great-grandpa dove in to help him but had badly misjudged the water depth at the point that he dove in. He slammed his head on a quarry shelf, was knocked unconscious, took days to recover, and was subject to random "episodes" (in the language of the day) for the rest of his life. (All of which is, again, documented both from family lore and a local newspaper article about the incident which occurred in upstate New York.)
I have not found any hints of any epilepsy-type issues among any of that great-grandfather's forebears. Of course that can't conclusively prove a negative but, I do have those folks well-documented in general and going back a good ways.
All of the above leaves me with a question: if we do stipulate that my great-grandfather was epileptic, and that it was caused by that incident rather than a genetic disposition -- then does that enable, or refute, the possibility that my father inherited it from him?
I'm curious how the part about "schizophrenia is so famously hard to define that we’re not even sure it exists" squares with "studies from 1970s China find exactly the same heritability as Western studies". If it's that hard to define, isn't it likely they're using different definitions in different studies, making direct comparisons pretty hard?
I haven't read the 1970s China study, but I would guess they were using the DSM (given how old it is, probably DSM-1) or some other definition comparable to what Westerners use.
More fundamentally, I don't think that difficulty getting an intensional definition necessarily correlates with trouble picking it out when you see it. Porn is the classic example of "impossible to define but I know it when I see it", and I think there would be very high inter-rater reliability on which art is vs. isn't porn (I'm not saying there aren't ambiguous cases, I'm saying most art is either the Mona Lisa which definitely isn't porn, or Hot Vixens In Your Area which definitely is). Likewise, there's huge debate over what definition we should use for "a woman" and some people can't come up with any definition that really satisfies them, but people basically agree on 99% of cases of who's a woman and who isn't.
I don't know if this is a good comparison, considering the distinctions for those examples aren't particularly meaningful. What's art and what's porn is ultimately just subjective, and I personally consider a lot of stuff to be both. I also think gender is stupid and shouldn't exist, and we really should just be referring to chromosomes when it's relevant for medical and scientific contexts.
But schizophrenia is a consistent condition with a consistent mechanism of action, as far as we're aware, anyways. If completely different brain dysfunctions do cause indistinguishable symptoms, that does complicate things a bit. If that is the case, said conditions should be given different names, and then we can meaningfully judge if each of them is caused by genetics.
Disagree. In the ontology of https://slatestarcodex.com/2019/12/04/symptom-condition-cause/ , schizophrenia is a condition, like lung cancer. We don't give lung cancer caused by smoking a different name from lung cancer caused by radiation or lung cancer caused by random bad luck. I think we'll find that schizophrenia is a specific cluster of symptoms caused by a specific kind of damage to a specific abstract system, but that many things can be the upstream cause of that damage.
I don't think the distinction you draw between "symptom", something that a patient reports, and "condition", [definition unclear], is useful. Or rather, it's useful to you as a practicing doctor, because you're mostly working off of patient reports. But you definitely can say that "pulmonary edema is a symptom of X", and people do it all the time. They say that because it's caused by X, and that's what "symptom" means. That gives us a simple and useful distinction between symptoms and causes: if you remove a cause, the symptom will go away, but if you remove a symptom, the cause will remain in place and the symptom will come back.
But what's the distinction between a symptom and a condition? A symptom is a state of being that's easy to perceive, and a condition is a state of being that might be hard to perceive? What happens when you can clearly see a symptom visibly present on the surface of the patient, but the patient doesn't report it to you?
The pulmonary edema example looks to me more like a causal chain than a set of three different kinds of things. The pulmonary edema is a cause of breathing difficulty and a symptom of heroin overdose. The breathing difficulty is a symptom of pulmonary edema. The heroin overdose is a cause of pulmonary edema. Where did the concept of a "condition" come into the analysis?
Regarding argument number 3 specifically, neuroscientist Kevin Mitchell wrote a great book called Innate in which he explains how many mental disorders seem to be caused by non-specific genetic mutations that increase developmental noise. His book is full of insights.
Highly recommend Kevin Mitchell’s work in general. I’ve been reading his blog for 10+ years and his intuitions as a behavioral geneticists have always made a lot of sense to me.
Schizophrenia serves an important social function by generating people who assert and act according to blatantly false ideas for non-predatory reasons:
* Based function: This allows sociopaths to prototype new con games while scapegoating non allied persons who act similarly enough to be confused for them
* Woke function (theoretical): This allows neurotypicals to discern deeply entrenched con games and the people who play them
I don't think you would get very far testing con games on schizophrenics.
You don't test them on schizophrenics. You watch the schizophrenics do crazy things and you see which ones have unanticipated effects while taking notes from a distance. Then you make a hypothesis about why it had those effects, and try to deploy those same behaviors to selective intentional effect. Schizophrenics will consistently find and exceed the boundaries of human social life even at personal cost, and more prudent people have the opportunity to observe and selectively learn from these tests, which are unlikely to occur otherwise.
So if society thinks that if you insult Zeus, then he'll strike you with lightning, but a schizophrenic insults Zeus all the time and remains un-electrified, then we might start to suspect that we can get away with the same behavior?
That sounds plausible as a useful side-effect, but I'm dubious that evolution would select for it? There's also a bunch of sayings about how God protects fools and madmen, which I'd guess would be a memetic immune response, basically "don't try this at home, kids".
More likely the first person to tell someone not to insult a metaphor or concrete bad things would happen, and have people believe them, had something wrong with them, but it worked, and leaders noticed it worked, and that's how you ended up with that particular religious tradition at all.
It does seem evolutionarily implausible because it would probably only operate on a group selection basis. I don't really have an answer to that. I just have a theory that fits my observations at the moment. I guess this should make me happy because it is weak evidence group selection is possible which gets me further away from nightmare world interpretations and closer to Kropotkin mutual aid as fitness stuff.
I'm generally fine with group selection as an abstract mechanism; my main problem with it is that it's very easy for people to come up with Just-So stories about how something is adaptive, in ways that it's hard to investigate scientifically. But it's not on the same level as perpetual motion machines.
I think historically we see the opposite. Schizophrenic delusions are often religious and it's more likely people see schizophrenics worried about how Zeus is going to strike them with lightning at anytime and end up believing the same than the opposite.
The only schizophrenic I knew claimed to have experiences of this general type, but was not the sort of person who would inspire anyone to believe what she said. Maybe that's just my WEIRD mindset, though. Perhaps in a pre-rational ancestral habitat, she'd have had higher status and a better life, and have been treated as something of an oracle.
That's not plausible as a useful side effect of schizophrenia just because people curse the gods all the time. By definition, it is their fault when something bad happens to you!
There is always a distinction drawn between offending the gods and doing something that sure sounds like it falls into the same category as what offends the gods.
Here's a classic scene from the Iliad (Perseus's edited version of Samuel Butler's prose translation):
> When they had thus armed, each amid his own people, they strode fierce of aspect into the open space, and both Trojans and Achaeans were struck with awe as they beheld them. They stood near one another on the measured ground, brandishing their spears, and each furious against the other. Alexander aimed first, and struck the round shield of the son of Atreus, but the spear did not pierce it, for the shield turned its point. Menelaos next took aim, praying to Father Zeus as he did so. "King Zeus," he said, "grant me revenge on Alexander who has wronged me; subdue him under my hand that in ages yet to come a man may shrink from doing ill deeds in the house of his host."
> He poised his spear as he spoke, and hurled it at the shield of Alexander. Through shield and cuirass it went, and tore the shirt by his flank, but Alexander swerved aside, and thus saved his life. Then the son of Atreus drew his sword, and drove at the projecting part of his helmet, but the sword fell shivered in three or four pieces from his hand, and he cried, looking towards Heaven, "Father Zeus, of all gods you are the most spiteful; I made sure of my revenge, but the sword has broken in my hand, my spear has been hurled in vain, and I have not killed him."
> With this he flew at Alexander, caught him by the horsehair plume of his helmet, and began dragging him towards the Achaeans. The strap of the helmet that went under his chin was choking him, and Menelaos would have dragged him off to his own great glory had not Zeus' daughter Aphrodite been quick to mark and to break the strap of oxhide, so that the empty helmet came away in his hand.
Alephwyr's premise is flawed; every boundary is going to be tested by a non-schizophrenic whose personality happens to lean in that direction before it gets tested by a schizophrenic. Schizophrenics are too rare for it to be otherwise.
Honestly the much more plausible theory would seem to be just be that some of the genes for schizophrenia are evolutionarily useful *in moderation* , but not when they manifest as full schizophrenia. Since schizoaffective disorder is much easier to explain evolutionarily. I know there was a slatestarcodex article on the idea before. IIRC the article also mentioned how both autism and schizophrenia have a component of both de novo harmful mutations and genes that run in families (which must have some trade off to stick around)
Genes running in families could be genes that were de novo a few generations ago and just haven't had time to disappear yet.
I'm assuming you're trying to say that schizophrenia was naturally selected for? In which case, you're probably wrong, because the genetic conditions responsible for schizophrenia seem to be heritable. If it was a product of natural selection, the genes responsible would be endemic among humanity, with the condition activating due to epigenetic factors instead. This is how homosexuality seems to work, as far as I'm aware.
If you think "how are the most common forms of neurodivergence as common as they are" is a mess, boy, you'll find "how is primary or exclusive homosexuality as common as it is" an even worse one.
(This is because gay people know full well that when we identify clear-enough genetic causes for any form of being weird, society starts to salivate about eradicating it and damn the knock-on effects, don't you want to prevent the worst-case scenario, how heartless are you for not wanting that?, and gay people have more class consciousness and access to social power than autistic or schizotypal people, so prevent doom by bringing this up any time people research the causes of homosexuality hard enough.)
>and gay people have more class consciousness and access to social power than autistic or schizotypal people,
I think this is the only reason that being gay is socially acceptable but being schizophrenic isn't.
The frequency of schizophrenia seems to be around 1%, which is near the limit of where you can expect something caused by de novo mutations. Homosexuality is closer to 3%, which is indeed harder to explain. My understanding is that it's among the least heritable behavioral traits though.
A beautiful example of the classic "hot take" format, complete with buzzwords and historical illiteracy. You even got the substack author to bite, absolute top tier posting.
Sorry for having a question made of popular words
Turkheimer … didn't he write something similar about the intelligence not being genetic either?
Turkheimer used to be very influential in behavior genetics (wrote a paper about the "3 rules of behavior gen."), then he felt guilty over his career and tried to deny everything about it.
There's definitely something weird going on with Turkheimer, but I had never heard the details before Is the story written up somewhere?
I don't think so. I just noticed that he wrote more critical stuff later on in his career and a few people commented on that.
The rumor was that there was a cancellation attempt but that's all it is, a rumor, so far as I know. I have a post in drafts about how he has essentially been bullied into abandoning his old work but it feels a little too personal to publish, I dunno.
*sigh* Is it really so hard to live with the truth, no matter how horrible it might be? Refusing to accept reality isn't going to change it.
...And honestly, reading what his research was about, the implications of the results don't even seem to be that bad. The main point seemed to be that, while intelligence is genetic, being raised in a shitty environment is so awful for intelligence that it makes the genetic variance completely irrelevant. The only real implication is that we're throwing away a lot of potential value by letting children grow up in poverty.
theres two problems humans are vulnerable to:
1. the idea that some men are made of gold, some of silver, some of bronze; some are destined to rule, and some serve
2. certain traits make you a better more important person. intelligence isn't just a force multiplier, intelligent people are more worthy.
genetic/hereditarian ideas can wind up boosting these old sins and even here people are painfully unaware of it. its not like humanity accepts difference as "each man's gift from God," but will sort people into worthy masters and destined slaves, no matter how smart they think they are.
like they will still see obesity as a moral failing even if its genetic. thats why its so dangerous. youd need to be a saint to avoid it while holdng the belief
...And why would you consider those to be sins in the first place? Human lives obviously don't have equal practical value, and some are more replaceable than others. Pretending otherwise is just incredibly inefficient. When you have limited resources to be allocated, you want to allocate them in a way that offers the most returns. That applies to both resources being invested in people as well as the people themselves.
the fun thing is people who say this always think they are the allocators and the irreplaceable ones deserving of resources. The idea they might be shut out never occurs to them. Or that people might be selfish or evil and define "most returns" as to what goes to me and mine.
we arent saints. equality is needed as medicine, cs lewis said. we don't take it, we get sicker as a society. it may be a good thing to make it inefficient to put chains on others, or to be evil
Oh, reading the post (and knowing nothing of the subject) I kept thinking that this discussion is happening because schizophrenia and genes is right next door to intelligence and genes. And we can't talk about the later...
Funny, when I was reading this I was thinking, "these seem like the kind of specious arguments IQ/sex/race/evolutionary psychology deniers use."
I see that much of the discussion about causation in this context is still based on verbal arguments and common sense. On the other hand I keep hearing that DAGs and the other machinery developed by Pearl and others is widely applied to epidemiology. Did anyone try to throw a bunch of potential risk factors, genetic or not, into a causal discovery framework to see what happens?
I don't think the debate about whether they're "causal" is in the sense where the opposite of that is "correlational". For example, in the omnipresent virus situation in Argument 6B, the genes would still be "causal" in a Pearlian sense.
I see. But in general are people using causal discovery (as opposed to just doing inference on a given DAG) in epidemiology at all? I could not find much at a cursory glance to the main journals. It is interesting to me because I would like to see a real world application of causal discovery on actual data: I am trying to do that on astronomical data and it would be cool to have a model from other disciplines.
Indeed, people do use causal DAGs and causal inference to interrogate and improve GWAS methodology. However causal discovery problems are notoriously unidentifiable problem in genetics, so most researchers in epidemiology do not use causal discovery in the GWAS and rightly so. In fact, just finding putative genetic instruments for mendelian randomization is often fraught with problems because everything tends to be related to everything else. It makes a lot more sense in perturbational genomics.
Could you expand on “causal discovery problems are notoriously unidentifiable”? Why is that?
The other environmental risk factors for schizophrenia are equally hard to change. Poverty? Okay, don’t be poor, thanks for the important life advice. Social defeat? “Doctor, are you saying I have to never let anyone defeat me?” “Yes, it’s my official medical recommendation that you become invincible.”
Keep writing paragraphs like that.
Poverty is not that hard to change. You work hard, seek an education in a field with reasonably high pay, do your job well without missing days, don't have kids without a partner. Keep looking for higher-paying jobs once you get on the ladder. People do all of these things constantly.
Not being defeated is impossible, but being defeated less often and winning more often are both quite doable.
Except that getting an education in a field with reasonably high pay is highly IQ-dependent and IQ is largely genetic
It certainly helps to be smart, but anyone who ever had a varied career could probably tell you that the middle managers are fairly often a bit dense. It is however true that someone with an IQ below 85 or so is going to have tremendous difficulty getting a high-paying job. Even there, however, the ones who get married and stay married can usually get up to $20 an hour or more (minimum wage in Seattle), eventually, if they are reliable and hard-working, and with a partner that puts their combined income at around $80,000 a year.
I would hesitate to call a couple making $80,000 in Seattle meaningfully above poverty – I would also question how likely it is that a couple, both with IQs well below 100, would purposefully relocate to Seattle based off of this logic.
I don't think you're right about that. A two-bedroom apartment in Seattle or, say, Mill Creek, a "nice" (heartless wicked sterile) area in Shoreline where I used to do deliveries, can be had for about $1700-$2000 a month. A one-bedroom on Capitol Hill can be found for $1600/month. And $5,670 is the estimated after-tax income of this couple (I used ChatGPT for this calculation, I confess), leaving them approximately $3,700 a month in after-tax income after paying rent.
Nor is Seattle very expensive. I visit every summer, and if you know where to shop, neither food nor clothes nor furniture is expensive (dining out is expensive, but that's all). The Grocery Outlet on MLK Way will sell you just about everything for less than most people pay in the rest of the country.
Only Americans could consider $3700 a month income after tax and rent "poverty." It really shows how delusional the country has become about its affluence.
Re 6B: A good analogy might be peanut allergies. Is it meaningful to argue the anaphylaxis was caused by peanuts instead of the allergy?
Yeah, this is what I was trying to get at in Footnote 3, but your example is better.
"This is both totally antithetical to the spirit of real clinical medicine as it’s practiced, and ethically odious to anyone who has witnessed the side effects of antipsychotics first-hand. "
You've perhaps already written it, but an essay on side effects of psychiatric drugs (or even of drugs in general) would be interesting and useful, and a good counterweight to "just take some pills, it's no big deal" thinking.
Every drug is different enough that I'm not sure anything short of a book would be helpful. I don't think there are a lot of people who say "it's no big deal" for antipsychotics in particular - these are very big deals (although there are maybe some exceptions - Seroquel at sleeping pill doses probably doesn't count as a real antipsychotic, although it still has horrible metabolic effects, and I'm still unsure how often it's okay to use low-dose Abilify for depression). I think the "it's no big deal" perspective makes much more sense with antidepressants, although of course it's never great to trivialize side effects for anything and there are a few ways they can be very big deals if things go wrong.
Spontaneous song-and-dance seems like quite a big deal: https://www.youtube.com/watch?v=OG6HZMMDEYA
Think about the dancing plague of 1518!
low dose(5mg) abilify saved my life. it totally stopped my recurring depressions that ssri, snri and ndri' had failed to improve, and it fixed my delayed sleep phase disorder.
And what is considered an effect and what is a side effect also varies with intent.
The most famous and salient example is probably Viagra, which was first trialled as a medication against angina (or so?), but is now more famous for a side effect they noticed during that trial.
Less memetic, but probably more important is all.the weird side effects of aspirin. It started as a pain killer, but apparently is also helps with preventing heart attacks and cancer.
And what is considered an effect and what is a side effect also varies with intent.
The most famous and salient example is probably Viagra, which was first trialled as a medication against angina (or so?), but is now more famous for a side effect they noticed during that trial.
Less memetic, but probably more important is all.the weird side effects of aspirin. It started as a pain killer, but apparently is also helps with preventing heart attacks and cancer.
Contrary opinion:
http://unwashedgenes.blogspot.com/2021/01/the-genetics-of-schizophrenia.html?m=1
The author's arguments against GWAS are not very convincing. It's a god of the gaps situation, where he says that in lack of a definitive list of genes, we should assume that its not genetic. This assertion falls flat because many traits are, in fact, highly polygenic, and for those where we have sufficient data the "definitive list" has in fact been produced. Polygenic scores for height explain nearly 80% of variance, which is essentially what the heritability studies would suggest. We even have mathematical theorems that describe the number of samples we'd need to capture the heritability of other traits, including schizophrenia, as well (Steve Hsu's compressed sensing).
https://www.pgscatalog.org/score/PGS000758/
A polygenic score for height with r^2 of .71, after accounting for sex.
This is mostly based on the same twin argument I think I debunked at https://www.astralcodexten.com/p/some-unintuitive-properties-of-polygenic
It also mentions that the genes have to be of small effect to be missed by GWASs. I plan to have a post next week on why this has to be true and we shouldn't find it suspicious.
Ooh! Let me predict why individual genes that cause schizophrenia must have at most a small effect:
Schizophrenia is terrible for reproduction, so a gene with large effect (in the more-schizophrenia direction) would be wiped from the gene pool near-instantaneously.
I more or less agree with all of your arguments presented here, but I disagree with the conclusion. I don't think the solution is to assert that "genetics cause schizophrenia", but rather as a society we should be a whole lot more careful about using the word "causes" in scientific research (including smoking/lung cancer).
I understand your frustration with applying a different bar to smoking and psychological diseases, but one has to start *somewhere* to enact societal change in the level of confidence that scientists imply when they are speaking with the lay public. If someone is a psychology researcher they probably will start with psychology stuff. A cancer researcher may simultaneously be pushing back against the "smoking causes lung cancer" narrative in a way that you don't see because your day job doesn't involve following prominent cancer researchers who are labelled (possibly inappropriately) as Big Tobacco puppets.
There are some things that scientists are quite confident about (nearly all of mathematics, most of physics, a lot of chemistry, some molecular biology, etc.), and there are some things that we have really good correlational data on but don't fully understand (nearly all of psychology, etc.). For the latter set of things, it is very likely that one day, as you suggest in this article, we'll find that "computational center" and it will all make causal sense. At that time, we'll find that genetics were not causal, just risk factors like in your kidney example, and we'll be able to create a very clear causal chain for each specific instance of schizophrenia. If we say "genetics cause schizophrenia" today, then when that future day comes we'll have to say, "sorry, we were dumbing it down for you, but now we know for sure what causes it" and no one will believe you (fool me once, shame on you, fool me twice, shame on me).
I personally find that way too many scientists are far too eager to assign causation long before they should. IMO, we shouldn't say we know causation until we can predict future outcomes with near 100% certainty (like we can with all of mathematics, most of physics, etc.) At the moment, our predictive capacity for both lung cancer and schizophrenia is appallingly low and doesn't get anywhere near reaching the bar where I think using the word "causal" is appropriate.
What word would you like to use for "provides explanatory power sufficient for correct prediction 70% of the time and has a clear and plausible mechanism"? Not to say genes necessarily fit that for schizophrenia but it's important we have a way to communicate that concept.
Until we have such a word, "cause" is the right one as long as you couch it in the nuance that things can have multiple causes and each can have not bear 100% predictive power.
Btw you're also wrong about how often harder sciences are willing to use "cause" by convention in this way - it's normal practice to use cause this way and equally normal practice for everyone to understand "cause" means "has predictive power and a logic-consequence-linked mechanism"
"Predicts".
Try saying "genetics predicts schizophrenia", or "smoking predicts lung cancer". That's what Granger causality boils down to, for that matter.
Seems fair enough.
Very well then.
Schizophrenia is primarily predicted by genetics.
Schizophrenia is a primarily genetic disorder
Works for me.
I like "predicts" too!
> Btw you're also wrong about how often harder sciences are willing to use "cause" by convention in this way - it's normal practice to use cause this way and equally normal practice for everyone to understand "cause" means "has predictive power and a logic-consequence-linked mechanism"
While I am skeptical that it is well understood by scientists that "cause" actually means "has a moderate amount of predictive power", I won't challenge that at the moment since I think that is less important than what laymen think when they see an "X causes Y" statement.
Gravity cause objects to fall.
Genes X+Y+Z cause Schizophrenia.
These two statements are wildly different in terms of their predictive power, but if we use the same terminology for both laymen will assume predictive power for them is similar.
I think to the layman, it is very useful to make a clear distinction between "near 100% predictive power" and "significantly less than 100% predictive power". There are some genes that I do think we could call "causal" in the sense that ~100% of the people with gene X will suffer from disease Y and people without gene X have ~0% chance of getting disease Y. In this scenario, saying "gene X causes Y" correctly informs the layman on how to think about gene X and disease Y.
I'm not sure that 'predict' a good word here? Mostly for the usual correlation vs causation reasons.
Except that it doesn't predict it. If you have the genes you are still very unlikely to have the disease. Cause seems better in this sense as a nonexistent phenomenon does not need a cause (cause is generally only assumed in the presence of the symptom).
This isn't how probability and prediction works.
No one's making the claim "If you have the genes we predict you will get it" it's "if you have the genes we predict you will get it X% of the time" and this necessarily incorporates the fact that shizophrenia is ulta-multifactorial and has a wide distribution.
But this is still useful because we would NOT say "if you are 6ft tall we predict you'll get it X% of the time", wed say "your height has no .meaningful impact on our prediction of whether you get it".
If you wanted to know your risk of schizophrenia, learning about your genes would be the piece of information that caused by far the largest update in your estimate.
I think this is all splitting semantic hairs of course - to me it seems perfectly fair and defensible to say predicts OR or causes, and just be ready to clarify. The universe is not simple and for all that we want to, things generally can't be described both accurately and in 4 words.
The crux of the matter is that, if you want to do something about schizophrenia, either for society at large or personally for yourself or your future children, things that impact the genes will have the greatest effect on the prevalence of schizophrenia
If schizophrenia requires a certain genetic makeup to manifest, then "schizophrenia is conditional on genetics". If it just increases the risk, then just say that. I'd prefer it if scientists used more clear and precise language, and this isn't really a situation where dumbing it down for laymen is necessary. It's not like you can change your genes (unless we develop the technology for that, in which case we should just leave it to their doctor to explain it for them).
Two thoughts:
1. Finding an intermediate link in the causal chain doesn't discount calling the upstream stuff "causes". Unless time is quantized at the Planck scale, there's *always* an intermediate cause.
2. We can already prevent (half of) the cases of schizophrenia, if the embryo selection people are right. (I'll say they are for the sake of argument.) Presumably, if embryonic gene editing were possible at large scale, we could just give a child all the schizophrenia genes we know of, and I predict they'd be almost certain to get it. Wildtype (non-mutant) schizophrenics aren't that far into the tail of the genetic distribution.
I agree on (1).
> I predict they'd be almost certain to get it
This is a reasonable hypothesis, and as soon as someone does some experimentation that supports it I would be much more keen on saying that genes X,Y,Z cause schizophrenia. I don't think it is appropriate to assign causation based on a hypothesis that doesn't have strong supporting evidence when we cannot predict outcome with near 100% accuracy.
First of all, some schizophrenia is probably caused by antibodies - an immune reaction. (https://www.psych.ox.ac.uk/news/new-study-finds-antibodies-that-may-be-the-cause-of-schizophrenia-in-some-patients)
Leaving that aside, the whole concept of disease and causality is complicated, and the very idea of something "causing" a disease is context-dependent.
For example, every child born in the U.S. gets tested for a condition called PKU. If you look at a diet Coke can, you will see a warning that it “contains phenylalanine.” PKU is a genetic disease, and the people who have it have a mutation in the gene for the enzyme that allows them to digest phenylalanine.
But take a step back. If instead being a tiny percent of the population, if the mutation were prevalent – for example, like the mutation that allows us to digest milk – then it wouldn’t even be considered a disease. It would be considered normal, and phenylalanine would simply be considered to be a toxin.
Similarly, if instead of 1% of the population, 99% of the population had the CCR5 mutation that made you immune to HIV, then HIV would not be an infectious disease but a genetic disease instead.
Diseases are intellectual constructs. They’re like boundaries of countries. Sometimes they’re based on the contours of natural geography, much like borders that wind along rivers or stop at mountains. Other times, they’re arbitrary, like vertical lines dividing some of the American Midwestern states. What’s the dividing line between pneumonia vs. bronchitis? What’s the difference between a heart attack and angina? Where we divide the diseases into categories and how many divisions we draw, as physicians, are not God-given. They’re man-made.
Schizophrenia is particularly germane example because it is a mix of what are probably very different processes. Catatonic schizophrenia is very different from classic forms. Doctors tend to lump very different diseases into one category if (as was true for a long time for schizophrenia) there isn't much you can do about it. Generally, diseases are categorized by what therapy they respond to, because pragmatically, if you're going to treat the patients the same, you lump them together. And if not, you separate them. (In some instances, especially in psychiatry, diagnosis can be driven by reimbursement considerations too.)
Here is an example of a disease that some pharma companies invented: high blood pressure. Until the 1970s, there was a great deal of debate over whether hypertension was a disease that needed to be treated, especially in the elderly. Some physicians thought that as we aged, and as our blood vessels became stiffer, hypertension was a natural effort by the body to maintain blood flow to all the important parts of the body. It wasn’t until a strenuous effort by Merck and other companies to change people’s minds that it became accepted that hypertension had to be treated.
I should note that it is not clear still how, when, and with what we should treat hypertension. As more data comes out, it is becoming clear that some drugs work better than others (and some are actually harmful). Not too long ago, the guidelines were changed to make treatment of elderly patients less aggressive. The complexity of the consensus guidelines suggests that there are still many unanswered questions. The very fact that there are guidelines means the answer is no obvious - only when there is uncertainty is a guideline needed.
I have a post expanding on this at: https://clinicaltrialist.com/2017/11/13/whats-in-a-name/
I agree this is true but I also think it's what I mean by isolated demands for rigor. In a world where we didn't say that viruses caused the flu, smoking caused cancer, or that genetic mutations in phenylalanine hydroxylase caused PKU, I would be okay with not saying that genes caused schizophrenia. The point of this post is that by ordinary standards, they do. I'm not really invested in completely reworking our use of causal language from the ground up, partly because that wouldn't work.
Not sure it matters much to the bottom line, but I’d be cautious about using the terminology associated with smoking risks as the sort of default baseline. Seems to me like this is an atypical situation, where there were enormous policy influences on the language and terminology associated with smoking; there was a huge (justified and good) campaign to discourage smoking, and the public health community was heavily involved in the messaging in ways that shouldn’t necessarily be assumed to be normative for every other terminological situation. I’m not saying that the scientific community wouldn’t have reached the same “smoking causes cancer” formulation even in the absence of the unusual public health campaign surrounding the issue; just that it would probably be safer to use a different and less policy-laden example as a semantic baseline for this sort of thing.
Sure, smoking was an atypical situation, but anything having to do with genetics is atypical in similar ways. There's a huge ongoing campaign to discourage admitting that genes matter for anything. Whether that's justified and good is controversial though.
This right here is the reason why Scott's arguments won't convince anyone. No one making those arguments actually gives a shit about the truth.
They have an agenda: "People cannot believe things are genetic". Then apply a mountain of motivated reasoning and sophistry to confuse people and make it seem like it's a complicated thing.
You might be interested in some posts from Robin Hanson when he investigated smoking-cancer revisionism back in the '00s:
https://web.archive.org/web/20091231023359/http://www.overcomingbias.com/2009/12/animal-smoking-studies.html
I'm far more hereditarian about psychological and behavioral traits than most liberals, so it's funny for me to take the non-hereditarian side of this one, but I'll at least offer some thoughts.
The reason we readily say that smoke has a causal, not merely a correlative, relation to cancer is not because of the statistics (although they are important). It's because we have a mechanistic explanation of the causal pathway. Tobacco has over 70 carcinogens that directly cause DNA damage, in addition to oxidative stress and chronic inflammation.
Now, of course, whatever genes do is also ultimately mechanistic, but here's where the similarity ends. We have no mechanistic account of how genes might cause schizophrenia. Of course, one might protest that that's just a statement about our knowledge. But it's worse than that. It just doesn't seem likely that whatever is going on neurologically has a causal pathway anything as straightforward as the effects of carcinogens. The interactions with the environment seem like they're far more intricately involved. It's as if smoking caused cancer, but only at certain altitudes, within certain temperature zones, when you ate certain foods, etc., etc. If the latter were the case, we'd be much more hesitant to just say "smoking causes cancer."
Thank you, this was the exact genre of example I was going to reply with: "smoking causes cancer but only if paired extensively with some other stuff". This argument applies pretty similarly to a significant proportion of mental illnesses in the DSM.
Neuroscience functions as a massive aporia in the chain of material reason required to come up with a properly mechanistic causal explanation. It's so massive that we might as well consider neuroscience to be a hard disjunction epistemically, in the sense that we literally cannot make causal arguments if they must rely on a "well X causes brains to do Y which causes Z behavioral patterns". This is why Freud and others both 2000 years before and 100 years after him still rely on a set of derivative psychological primitives that are functionally dependent on observation and permit meaningful intervention (lest we forget that the goal is ultimately helping people), but have "no scientific (= properly material, very nice sleight of hand Popper) basis".
So from a purely interventionist standpoint, polygenetic filtering is basically the only thing you can *do* with a notion of genetic causality. Thorny ethical issues aside, it would still be great to have a real mechanistic model of mental illness (Freud wanted this way back in the 1800s! And was sad we couldn't figure it out!), but we should be aware that it may also require a total reorientation of our categories of illness: maybe you have a sore throat and a cough from a cold virus, but it could also be bacterial, and these require different interventions even if the DSM would still label both as "sore throat and cough disorder".
Mind you, I have no doubt that genes are very, very important here. I'm just not sure their importance is well summarized by the English statement that schizophrenia is "mostly genetic."
Indeed, genes are very, very important in all aspects of human life. Unfortunately we can't usually figure out the exact workings of how.
I think this is what I'm trying to address in Argument 6B. I think we'll find that for each of the ~5000 genetic variants involved in schizophrenia, there's some long and convoluted story for how it contributes to causing it. I think there won't be anything beyond this. I don't think we should wait until we have all 5000 stories (which, to be clear, will be incredibly boring and involve pathways of a billion different proteins we don't understand) to start using the causal language.
By this logic, can we not effectively describe anything the human body does as a collection of 5000 convoluted stories involving billions of proteins? My understanding is that typically genetic causality is reserved for situations where we can actually identify the exact story involved, or at least a set of major correlations...
"My understanding is that typically genetic causality is reserved for situations where we can actually identify the exact story involved, or at least a set of major correlations..."
It was back in the dark ages when we thought of genetics in a mendelian way and could only identify the genetic causes of things that had only a few genes causing. Modern methods like twin and adoption studies and even more modern methods like GWASs can move past that past and allow us to identify genetic causes that are highly polygenic.
Polygenetic causes have been unrightfully slandered for to long and it's time it stopped.
The purpose of the distinction, to me at least, is the utility of it not the 'truthiness' of it. I don't need the complete story I just need the conventional wisdom of what I need to avoid/actively do. If it's conventional wisdom that embryonic screening eliminates these risk factors, so trivially true that you or I and anyone in the thread would bet money on it, then I'm going to seek out that solution.
Call it genetic or not, I don't care. I as a market actor just want a result for my time and/or investment.
If you or someone you know are schizophrenic then embryonic selection isn't going to help at all.
We're talking about embryos.
I thought we were talking about causality.
My point is not that the causal pathways are many and complex. It's that they involve joint contribution from the environment in ways that just aren't true of smoking.
If smoking only caused cancer when you ate kumquats, we probably wouldn't summarize that just as "smoking causes cancer."
I don't disagree with you about what the 5000 neurological stories are likely to look like. I disagree with you about whether they are well summarized as "schizophrenia is mostly genetic."
Does "social defeat" mean, like... getting bullied at school? (Or at work, I guess?)
Getting bullied is a (small) risk factor for schizophrenia?
That's the claim! See https://en.wikipedia.org/wiki/Social_defeat
So if someone interprets an election result as social defeat, it could literally raise their risk of schizophrenia?
Seems like the defeats have to be early in life. People usually have their first psychotic break in their teens or 20's.
Ah, so if we get kids invested in politics early in life, and then they experience failure, that might affect part of a generation?
Well... that would explain a lot.
More or less, but the specificity of this is significantly overstated, especially for women. The telephone game of "SZ onset range stretches across the lifespan, but men have a distinct peak around 18-30 and a thinner right tail than women" becomes "if you haven't developed schizophrenia by 25 you're fine" in the cultural consciousness, which is...not...quite...right. (Some studies manage to ignore all age of onset curves and work under this assumption themselves, which I'm sure gets us a lot of terrible results.)
The key issue at the heart of the debate: whether as describing it as mostly genetic, we can then use genetic scores to motivate clinical action. See Kendler et al., 2023: Relationship of Family Genetic Risk Score With Diagnostic Trajectory in a Swedish National Sample of Incident Cases of Major Depression, Bipolar Disorder, Other Nonaffective Psychosis, and Schizophrenia
Scott, obesity is also 80% genetic. Can I hear you say "fine, obesity is also genetic"? Do you bite this bullet?
Of course, it does not match what we colloquially mean by "genetic" at all, since obesity is 100% environmentally malleable. Can we *please* adopt a more sophisticated frame than "is genetic" vs "is not genetic"?
You are modelling the world as if everything is a sum of small contributing factors. But it's not; sometimes there are AND gates. Sometimes you need to have the genes AND to eat the right food. It is not possible, conceptually, to assign a "percent heritability" in such a situation.
Why would anyone have any trouble with saying that obesity is mostly genetic?
Of course, as Scott points out, what's appropriate to say depends on context.
So genetics explains a lot of the variability in obesity today. And a lot of the variability 50 years ago.
But the difference between today and 50 years ago is not genetic.
I was under the impression that most people think fat people are fat because they're bad, lazy people... whatever that means.
They think this because there's a grain of truth in it. Sticking to a good diet requires non-trivial amounts of planning/willpower, so on average lazy people will be fatter. Of course, publicly saying this in polite society marks anybody as Worse Than Hitler, but people do still think unspeakable thoughts.
Do they need to moralize it though? People are ultimately products of circumstance, and it seems unproductive to demean people based on factors beyond their control. Especially when, again, obesity is 80% genetic. I'm the laziest person I know, and I still maintain a pretty average weight. I can't really pretend that I'm not obese because I'm a "better person".
>Do they need to moralize it though?
They do whatever the culture tells them to. These days in the West the conventional wisdom seems to tilt in the "moralizing bad" direction.
>I can't really pretend that I'm not obese because I'm a "better person".
That's why I said "on average", some people are of course more genetically lucky than others.
If it's beyond his control to keep his diet and exercise in check, it's equally beyond my control to keep my moralising in check. After all, moralising is also an evolved function, and we moralisers are ultimately products of circumstance.
Perhaps one day someone will develop a pill against moralizing.
And that's perfectly reasonable, and it's also why I hope humanity goes extinct!
When I was a kid, obesity was rare. You never saw the kind of massively obese people that are common now.
So have genes changed since then?
Genetics explains a lot of the difference in obesity in one country at one point in time.
Eg who was and who wasn't obese when you were a kid. And who is and who isn't obese now.
You are right the genetics does no explain the difference in obesity then vs now.
That point is already belaboured in Scott's text as number 5.
Another commentator further up usd the example of lactose vs phenylalanine. Polygenic screening might help with PKU, but not with lactose intolerance. Thus also obesity: if "obesity is genetic" means that most people lack the special combination of genetic factors necessary to avoid the worst metabolic damage caused by modern 'food', the genetics really aren't the problem.
Polygenic screening can help the next generation that isn't conceived, yet.
Allow me to clarify: lactose 'intolerance' is the baseline human condition unless altered by a couple thousand years of animal husbandry. Good luck telling a couple from e.g. southeast asia they'll need to discard 95% of their embryos.
What's the problem with discarding many embryos? Assuming you can produce many fertilised eggs without too much hassle, of course. I think there's a limit to how many eggs a woman's body can produce for this purpose?
I think the bigger issue with something minor like lactose tolerance is that it's just not very important.
Conceptually, you make up some kind of score, say intelligence at weight 100, health at 200, height at 80, lactose tolerance at 10, etc, and out of all the embryos, you pick the one with the highest score.
Even if South East Asians cared about lactose tolerance as much as Europeans (ie same relative weight), you are right that the same selection process over their embryos are much less likely to result in a lactose tolerant embryo 'winning' the competition for the highest score.
Were you unaware of the worldwide prevalence of lactose intolerance and are now moving the goalposts? Or did you, from the beginning, think that polygenic screening 'helping' with lactose intolerance really would involve this kind of massive additional cost, labor, and suffering?
I'm not quite sure what your point is?
Almost all humans can digest lactose when young. Genetics can influence how long (possibly forever) one can keep that ability.
I'm not sure why you care so much about lactose tolerance?
I also don't really know what you are trying to argue for or against and what you think you have tried to caught me in?
What even were those original goalposts you accuse me of moving?
Btw, the whole point of polygenic screening is to pick every baby you raise to be the 'best' (by some score) out of a group of dozens of potential siblings.
So discarding eg 95% of embryos is sort of the point. (However, you only have so much selection power to spend, and I would imagine most people would want to spend it on health and good looks and intelligence etc, not on lactose tolerance.)
For what it's worth, I live in South East Asia. (Since you brought it up in your example.)
> Sometimes you need to have the genes AND to eat the right food.
Sometimes the genes make it easier or more difficult to eat the right type or the right amount of food.
I agree with this. "is genetic" (with its more insidious relative "is mostly genetic") and "is not genetic" and its relative "is mostly not genetic" are just terrifically terrible framings of virtually any problem, semantically equivalent to "bridge collapse is design." It either smuggles in a lot of unexamined and nuanced argument about causation, or taken on its face it's word salad.
1. Out of curiosity. Kidney disease heritability. "We report heritability estimates of the CKD-defining traits eGFR (44%), UAE (20%), and UACR (19%), for the kidney biomarkers serum urea (31%), Scr (37%), and uric acid (48%), and for the serum electrolytes potassium (28%), calcium (27%), and sodium (22%) " They checked and basically every kind of family member with the disease elevates your risk, even "genetically unrelated" ones like spouses (assortative mating or maybe shared environment). https://www.sciencedirect.com/science/article/pii/S0272638620311628 It doesn't seem to be impressively heritable, but there's obviously some genetic causes of this, whatever they might be exactly.
2. There are some single mutations that cause schizophrenia alone, or schizophrenia like traits at least. https://www.pnas.org/doi/abs/10.1073/pnas.2112560118 "A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals".
3. Family studies yielding estimate of heritability, shared environment etc. tell you where to look for causes. They give you the overall importance of some group of causes, but doesn't tell you what they are except in a broad sense. In other words, they tell you where to dig for more. They also give you a decent idea about what kinds of interventions are going to be effective. When heritability is very high, it means that genetic selection will be effective. It scales linearly with the square root of the variance. If "family environment" doesn't show up or is very minor, then trying to modify risk factors in that area will not be effective unless you somehow introduce a new kind of thing that doesn't already vary between families. https://www.emilkirkegaard.com/p/high-heritability-does-mean-that
4. Assortative mating and measurement error are usually quite large downwards biases in family studies. This is particularly the case for self-report symptoms of mental health vs. more objective data (e.g. clinician ratings). I wrote a summary of such research. https://www.emilkirkegaard.com/p/heritabilities-are-usually-underestimated
> When heritability is very high, it means that genetic selection will be effective. It scales linearly with the square root of the variance.
Something that this post and thread have caused me to wonder about is what we're abbreviating when we say "heritability of schizophrenia". Heritability is a measurement of percentage of variance explained. But variance is a numeric quantity, one that is sensitive to the absolute values of the random variable being investigated, and schizophrenia is a categorical variable. I tend to imagine that genetics is something of a categorical variable too. Does the concept of variance apply?
Yes, but you need to use some tricks. Liability or threshold models. https://www.sciencedirect.com/science/article/abs/pii/S0167947315000250
You say it yourself, schizophrenia is quite hard to neatly define. So much so that perhaps it doesn't exist / isn't one unified thing.
I think most of these writers who are arguing that schizophrenia isn't genetic, and some of those arguing that schizophrenia shouldn't be prevented (only treated), they mean to instead argue "schizophrenia isn't real".
They don't make that argument, and instead get wrapped up in denying the practical facets you lay out, because they are the sorts of people who are not comfortable rejecting the existence of schizophrenia, for social-norm reasons. The people who feel "woke" social norms to treat-not-prevent are also the ones who have a cognitive bias towards saying it's intervention-able (not genetic).
But strip away their social and cognitive biases, and they probably would wish to unpack "what is schizophrenia actually? It's not well defined enough, there's more to learn. "
E. Fuller Torrey is not a random name. He's the name synonymous with the reinstitutionalization cabal in mental health policy discussion, the guy who (per his glowing NYT piece) wakes up every morning and combs all the newspapers for anything he can interpret as "violence caused by mental illness" so he can crow about it to lawmakers. Torrey knows exactly what he thinks schizophrenia is.
Huh, NYT is pro-institutionalization? I thought that violence caused by mental illness was a "far-right" talking point these days.
No publication with two or more writers has a single party line. Torrey got his glowing NYT piece, and someone with his opposite views could too. They wouldn't have the same writer, most likely.
Way to bring "woke" into the conversation. It is, after all, (much like Biden) responsible for all of the evils in the world. [edit: \S in case that wasn't obvious]
Regarding 6B, genes could be a proxy for a more satisfying cause of schizophrenia. It is not hard to think of ways this could work. As you say, one is that genes could make people more vulnerable to some virus that attacks the brain and causes schizophrenia. There are many other possibilities of this kind. What they all have in common is that you can think of them as genes that change the person’s environment, causing it to be more schizophrenogenic. (For instance the person in your example with the bad immune system lived in an environment that contained more dangerous viruses.) Here’s a list:
-Genes that cause someone to be physically unattractive, or to have other characteristics that make it less likely they will receive social approval: They’ve got poor gross motor coordination and are bad at playground games, and so they get less acceptance and approval from peers. They’re slow to learn to read, and have an especially hard time sitting still and shutting up in school, and so get less approval from their teachers. Kids with these genes live in an environment with fewer smiles per year.
-Genes that cause some disability that interferes with the person making sense of their environment, and is subtle enough not to get diagnosed in most people: prosopagnosia, difficulties putting your thoughts into words, some spacial orientation problem that makes you get lost easily. People with these genes live in a world that’s more confusing and harder to navigate.
-Genes for some as-yet-unrecognized disorder that’s like PKU (phenylketonuria), but instead of causing severe developmental delay causes, by age 20 or so, whatever sort of brain damage underlies schizophrenia. People with these genes live in a world where ordinary foods cause brain damage.
-Genes that cause people to have unusually strong reactions to stressors. For these kids, seeing a squirrel get run over is as upsetting as seeing a hanging would be for others. People with these genes live in a world with an unusually large number of truly traumatic events.
The idea that social problems are harder to fix than biology is a prime example of Americentrism. Other countries have made far more progress than the US in reducing drug abuse, poverty or social conflict (i.e. instances likely to lead to social defeat). I think this is because the US is unusually individualistic and conservative (and Conservative) for a developed country.
I also think it's rather flippant to suggest people undergo IVF to address genetic problems. I have two daughters by IVF. IVF is very rough on the mother, far more so than the side effects of schizophrenia drugs (which I've also had the misfortune of experiencing). This may improve with better IVF procedures, but we can also discover better drugs.
The effects of schizophrenia drugs are not subtle for most people. Patients usually hate them because they make them feel leaden, blank and drowsy. The newer crop causes a lot of weight gain. And most clinicians, including me, get so they can spot someone on Zyprexa or one of the others -- something about weight gain centered in the belly, and something odd about the way they walk -- maybe it's they don't swing their arms? Or is it that they don't look from left to right at all as they walk? Or their steps are too short, or they don't lift their feet off the ground as high as most people while walking? I'm not sure what the signs are the people can spot, but there definitely are some. And it's not as though they work like magic.
'Other countries have made far more progress than the US in reducing drug abuse, poverty or social conflict'
Nonsense.
Maoist China really did practically eliminate opioid addiction. The late Mark Kleinman (of "When Brute Force Fails: How to Have Less Crime and Less Punishment") pointed to it as disproof of the "disease model" of addiction.
Singapore has less of all three. Much less.
As I pointed out elsewhere, "social defeat" appears to just be a hypothesis rather than a well-established cause of schizophrenia.
I know this got addressed in a paragraph above, but didn't Scott just get finished with demonstrating (with stats and maths) that, because of the low incidence of schizophrenia, the causes in any specific individual with schizophrenia will mostly be environmental.
Running the numbers with Scott's methodology by way of example, this means that you could screen 500 people for schizophrenia risk factors using a microarray or something, set the cutoff at a 0.95 genetic risk factor, wind up with 25 'candidate' schizophrenics (of which 4 will actually develop schizophrenia) and still miss one actual schizophrenic.
Which, in this example, means that your expensive microarray test has an 84% false positive rate, and a 20% false negative rate in practice.
And if you bump your threshold to 0.99, then all you get is 7 candidate schizophrenics, of which (in this example) none happened to actually develop the condition.
Doesn't this put screening for purely genetic factors for schizophrenia firmly in the 'scientifically true but useless' category?
No. I won't check your numbers because I think that's the opposite way of going about it.
We don't want to use genetic screening to _create_ schizophrenics, we want to _prevent_ them!
If you're a high risk couple and your child would have a dunno 2% chance of schizophrenia, screening would set that to ~0%. _That's_ undeniably useful.
It's a large relative reduction in risk. But it's not exactly undeniably useful; the number of children you'd have to have for this treatment to make an observable difference is larger than the number of children it's possible for a single couple to have.
Why is it not useful? If the price is right even if you'd need to have 200 kids for it to make a difference, an entire life of schizophrenia is probably costs everyone involved more than $200,000 worth of screening.
No it won't.
Schizophrenia is massively polygenic - screening is going to do effectively nothing to any resulting kid's chance of getting schizophrenia.
Somewhere earlier in the comments, someone who seemed "involved in testing" said it was presently halving your chance of a child becoming schizophrenic.
Being polygenic doesn't meant screening is ineffective. Screening can take into account many genes!
A distinction I've been thinking about which I've been unsure about but which seems reasonable/important to me:
Schizophrenia is related to psychosis-propensity, arguably caused by psychosis-propensity but also arguably distinct from it in that schizophrenics tend to get convinced they are being persecuted and then retreat into themselves.
It seems to me that one could hypothesize that the mostly-genetic, biological brain-brokenness causes the psychosis propensity, but then the other aspects of schizophrenia are caused by a psychosocial dynamic where e.g. outsiders react badly to the hallucinations and therefore confirm the schizophrenic's suspicions that they are in on the conspiracy.
If true, I don't know how this affects the conclusions in your article. I think it depends on how damaging the psychosis is on its own, vs how damaging the downstream social dynamic is. If most of the damage is with the psychosis-proneness then this is just kind of nitpicky. But if most of the damage is with the social dynamic, then e.g. it raises the question of whether one could cure most of schizophrenia by just averting that social dynamic, and therefore it starts seeming reasonable to think of schizophrenia as environmentally Caused.
Not all psychotic delusions are of persecution, though. I had a patient who believed his teeth were being reabsorbed by his body. He didn't think of that as something someone had done to him -- just thought of it as a weird physical problem he had. I had another one who felt like his thoughts were merging with other people's, or that maybe he was thinking their thoughts or they were thinking his. But again, he had no belief that some person was *doing* this to him. if anything, he thought of it as a magical power he had developed and did not want. And some people have delusions of grandeur.
Do the people with other psychotic delusions (especially entirely non-social ones like teeth being reabsorbed) develop the same negative symptoms as full-blown schizophrenics do?
My proposal isn't that there is no such thing as biological psychosis/delusion-proneness. Rather my proposal is that the way it plays out depends heavily on what the resulting delusions mean (semantically speaking, as in the difference between being sent hidden messages vs one's teeth being reabsorbed) and how these meanings intersect with society.
So your idea is that schizophrenics first have hallucinations, but that their delusions of persecution and other symptoms are a reaction to everybody telling them the are dead wrong that there's a voice whispering to them, or that hallucinatory stuff they see is not there? I've seen a lot of psychotic people, and heard their stories of how it started and how people around them reacted, & I'm pretty sure it doesn't work that way. For one thing, lots of people don't tell anyone about their hallucinations, because they are afraid of being thought crazy, or just because they are somewhat isolated, mistrustful people who do not confide in other people. Delusions often seem to be ideas that people develop on their own to explain the hallucinations. People recognize that their hallucinations are a novel, weird phenomenon, and have a need to explain them. Most delusions have a strong negative tinge, but it seems plausible to me that to most people the hallucinations are unwelcome, and so they form theories about why somebody would be inflicting a whispering voice on them. As for other people's reactions to somebody's hallucinations, if the person discloses that they have them -- harsh and critical reactions from family and friends are rare. Most people realize they're hearing about a psychiatric phenomenon, and get worried and scared, not critical, and do not get caught up in trying to prove to the person they're wrong. Something else I would add is that most schizophrenics have a lot of subtle things wrong and odd about how they act. They're not regular articulate friendly people who are functioning normally except for hearing voices. They're often isolated, difficult people, with poor hygeine, odd mannerisms, and unusual opinions. They often have trouble communicating clearly. I have had people who were trying their hardest to explain to me what it's like being them, and why they're sure someone has implanted recording devices in their brain, and I simply cannot follow what they are saying. They stay on the subject, and don't ever become incoherent, but they ramble and repeat themselves and cannot convey in a crisp way what their experience is like. You get the feeling their ability to put things into words isn't working right. Overall, you get the feeling that the person's brain is not working right.
"For one thing, lots of people don't tell anyone about their hallucinations, because they are afraid of being thought crazy, or just because they are somewhat isolated, mistrustful people who do not confide in other people."
One complication here is that you can't look at the past of people who eventually develop schizophrenia, because my proposed model totally allows that e.g. a prior propensity towards distrust increases the risk that the delusions will enter into a distrust-oriented feedback loop. So it could be that schizophrenia is polycausal, psychosis -> schizophrenia <- general distrust. One would have to design a measure of pure psychosis (notoriously difficult) in order to distinguish.
"So your idea is that schizophrenics first have hallucinations, but that their delusions of persecution and other symptoms are a reaction to everybody telling them the are dead wrong that there's a voice whispering to them, or that hallucinatory stuff they see is not there? ... Delusions often seem to be ideas that people develop on their own to explain the hallucinations."
I think it's plausible that it's a combo. Like if someone feels like the TV is leaving them threatening messages, then that would raise the hypothesis of being persecuted to attention, but then depending on other's reaction, it could either remain considered unlikely-but-possible or turn into clearly-true.
"As for other people's reactions to somebody's hallucinations, if the person discloses that they have them -- harsh and critical reactions from family and friends are rare. Most people realize they're hearing about a psychiatric phenomenon, and get worried and scared, not critical, and do not get caught up in trying to prove to the person they're wrong."
Acting worried and scared can also in some frames of mind be interpreted as being in on it, though. Not sure to what extent schizophrenic people interpret it that way though. I would think of it through a Bayesian frame; when I've heard of information-controlling communities (e.g. Stalinism, Leverage Research, etc.), I've often seen people emphasize a culture of fear and confusion as much as they've emphasized aggression. So under rational priors, it doesn't seem like worried reactions are all that much evidence against this.
"Something else I would add is that most schizophrenics have a lot of subtle things wrong and odd about how they act. ... Overall, you get the feeling that the person's brain is not working right."
I don't think this contradicts my model, since there are two different ways this could be expected to happen under my model:
1. The factors that cause general psychosis-propensity also cause their brain not to work right, leading to the symptoms you mention.
2. The non-psychosis factors which predispose the environment to react poorly to psychosis also cause other social dysfunction.
While one needs to understand that there are a lot of philosophical nitpicks and therefore it's hard to describe anything as true, I also think it's worth clearly mapping out the philosophical nitpicks. For example, if they don't get clearly mapped out then people might not realize they are there (try telling people schizophrenia is 80% heritable and then ask them about the twin concordance rate), and even if they do realize they are there, mapping them out is the first step to generating theories about how to most accurately take them into account.
I think it also deescalates conflicts. If you've found an important-seeming nuance that doesn't get described very clearly, you might want to generate clearer descriptions. This could lead to some cooperate work if people assist you, but it could also lead to ideological conflict if people dismiss it as philosophical nitpicks and you then start writing big books about it
What an unkind and content-free comment which has degraded the general quality of conversation.
It is arrogant not to say unkind to attribute a disease entity that is itself controversial to an individual’s make up at birth; it smacks of eugenics.
I don't mean to be unkind to your comment, and I apologize if I'm misinterpreting you, but it sounds to me like you're working backwards from your moral feelings to decide what is true or false in nature. Can you make a non-moral argument against what Scott said?
User banned for this comment.
Would "genetics cause height" work better here?
Re your thoughts on viruses: in my experience teaching students, when talk about causality, they talk about levers they think we can pull on. They’re not interested in causal inference for levers we cannot pull. Many people don’t know about polygenic embryo selection as a lever you can pull or have convinced themselves it’s immoral to pull on it. It’s not a consistent definition of causality, but it’s a sensible position to look for levers. You just happen to have a niche position on which levers are easy to pull, the rest of the disagreements come from that.
Of course a widespread virus being necessary would change our idea of which lever to pull first, ie people are trying vaccines for Epstein Barr now rather than do embryo selection for genetic risk of multiple sclerosis. Because it’s much easier and proven and (for some) not as ethically dubious
I don't think that embryo selection is a useful lever here. Schizophrenia is wildly polygenic and rare, so you selecting one out of the half-dozen viable embryos that come out of IVF will have next to no effect on the resulting child's genetic risk (let alone their risk in practice). Plus IVF is difficult, uncomfortable, invasive and expensive.
So the cod intuition lines up well with reality in this case.
> so you selecting one out of the half-dozen viable embryos that come out of IVF will have next to no effect on the resulting child's genetic risk (let alone their risk in practice).
As I believe Scott has already noted in these posts, that's not true. For rare disorders, selection doesn't do much 'on average', but that's also where you least need it; and where you most need it, it does the most. (Similar to regular PGD screening for Mendelian disorders: would you argue that 'PGD is not a useful lever against Huntington's' because screening against Huntington's would do nothing in >99% of screens?)
Under a liability-threshold model you can easily get large effects on both risk if the parental mean burden is high, because now there is no floor effect + the nonlinearity of the underlying normal. If the parental burden is very low so they have ~0% risk, then obviously selection can do little, all viable embryos will have ~0% risk; but if the parental burden is high, eg both are full-blown schizophrenics, then the offspring risk is extremely high (~40% IIRC) and the embryos will vary a lot around that mean high risk, and it can be reduced accordingly.
So your 'cod intuition', I'm afraid, smells like one too.
That's a very cute insult* and I'm tempted to respond in likewise fashion, but...
Running the numbers and ignoring some massive, nested, caveats** # , you're not wrong that screening would indeed be helpful for full-blown schizophrenics wanting to lower their child's risk. Using Scott's previous methodology and a population of 500 (because I'm lazy), the cutoff value ends up being ~0.95. If you set the genetic risk to 0.99, this gives you an environmental cutoff of 0.80 (which is high, and again seems to indicate that identifying the environmental factors and lowering those is a Very Good Idea (tm)). Similarly, using an environmental risk of 0.99, you get a genetic cutoff of 0.94, which represents the lower floor below which the environment makes no difference. The 'average' schizophrenic environment is accordingly between the maximum and cutoff: 0.89. Similarly, the 'average' schizophrenic risk score is 0.96. This means that the average variance to target is something like 0.02 which, when you use 5000 additive genes, means that finding an embryo with ~120 schizophrenia-associated genes set to the safe configuration will lower the total risk below the genetic cutoff.
This is still a lot of variants to find, and someone else will have to do the math on the likelihood that two people with an 'average' of 4800/5000 risk-associated variants will be able to produce enough embryos to hit that target. But it seems at least more superficially plausible than I thought.
*I've never actually smelled a cod before - they're rare and expensive fish where I'm from.
**Caveat the first: the chances of two schizophrenics having kids together is something like 0.01%***. Which means that, in the US, there are something like 35 000 total patients for this treatment. So not a great use of resources.
***If the chances are higher, and full-blown schizophrenics are finding each out in the general population at a much higher rate than random chance, then the obvious answer would be for them to be counselled to, you know, not do that if they want to have children without schizophrenia. Maybe also tamp down on those schizophrenic environmental factors a little (see below).
# Caveat the second: as with Scott's twin example, the best advice that you could give anyone worrying about passing on their schizophrenic tendencies to their children would be to adjust the environmental factors as much as possible, since full-blown schizophrenia needs both a high genetic risk and a high environmental risk. Which, considering that these would-be parents are worried enough to go and get a genetic screening test done, is probably already in hand. The next best advice would be to adopt or (if counselling a single person) look for a partner with a low risk score instead of going whole-hog on embryo selection.
> Re your thoughts on viruses: in my experience teaching students, when talk about causality, they talk about levers they think we can pull on. They’re not interested in causal inference for levers we cannot pull.
I asked my mother once what girls considered to be aspects of female attractiveness. The intent of my question was how girls evaluated the attractiveness of other girls, but instead I got a response covering actions girls take to maintain their own appearance. When I asked why facial structure wasn't even mentioned, the response was "girls don't spend time on facial structure because they can't change it".
Back on topic, "schizophrenia is mostly genetic" is giving you accurate information if you're thinking about interventions you might do to prevent or cure schizophrenia. The options are to be somebody else, or suck it up. And that's exactly the message that "schizophrenia is mostly genetic" delivers! Unless you have the ability to pull the genetic lever, you will not be able to meaningfully intervene in schizophrenia.
The fact that an intervention is possible doesn't mean it can have a significant effect. Saying that schizophrenia isn't genetic because that would imply that you can't address it just means you can't tell the difference between reality and what you wish reality would be like. There are plenty of problems you can't address.
>Unless you have the ability to pull the genetic lever, you will not be able to meaningfully intervene in schizophrenia.
Most likely true, but sometimes luck is kinder. E.g. if one of the relevant genes codes for an enzyme, and e.g. there is a small molecule drug that inhibits the enzyme, sometimes there can be a way to modify the situation.
Great blog post!
'In a society where everyone inhaled radioactive dust all day, smoking would be an utterly insignificant cause of lung cancer compared to all the radioactive dust inhalation'
Slight nitpick - cigarette smoke IS 'radioactive dust', see e.g. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672370/, where they estimate a smoker may be exposed to an additional 10 Sv, or 1000 rem, in 25 years.
Someone should investigate fixing this by putting powdered lead into the filters. \S
This discussion feels a bit confused. You and your opponents certainly would both agree on a sufficently precisce statement of the claim in statistical language. So when you say you're arguing about whether "schizophrenia is largely genetic" you aren't arguing about whether the facts comport with some agreed on meaning of that phrase but whether that phrase has a meaning which is made true by those facts. And yet, you aren't actually just making a boring corpus data/polling based claim that most competant speakers do give the phrase such a meaning.
I feel like what's going on is the same thing that goes wrong in debates about whether trans-women are women. The people in the debate think they are arguing over a fact about the external world like whether smoking causes cancer but in fact, as you pointed out in a great piece, they are really making normative arguments about what would be the more desierable way to use language (should we assign a meaning to woman/schizophrenia is genetic that includes...?).
In other words, what you described as why you care is actually the argument: using the word the way your opponents prefer causes these harms because it misleads people about what responses will be effective. I agree and find that relatively convincing but that's the actual debate and it would be better to phrase the other stuff as: responses to potential arguments that the usage you favor is also misleading/confusing.
It seems like there's a lot of muddled discussion over "cause." Causal inference is an entire field with a pretty simple and well-hashed-out definition of a "causal effect." From Miguel Hernan's "Causal Inference: What If?":
>We compare (usually only mentally) the outcome when an action A is taken versus the outcome when the action A is withheld. If the two outcomes differ, we say that the action A has a causal effect, causative or preventive, on the outcome. Otherwise, we say that the action A has no causal effect on the outcome
Concretely: Alice smokes cigarettes, and gets lung cancer. If she would not have gotten lung cancer in the counterfactual world where all else was the same, then cigarettes caused Alice's lung cancer.
Of course, barring a time machine or an ersatz replacement (e.g. a cross-over study with a washout for a drug, or a twin study), we usually can't determine individual causal effects. Sometimes individual causal effects are not even that interesting. Maybe Bob developed lung cancer after being hit by a stray gamma ray.
However, we can estimate average causal effects at the population level with a variety of tools, ranging from excellent (e.g. an RCT) to sometimes-questionable (e.g. a haphazardly-specified regression model applied to survey data of questionable accuracy).
I found Miguel Hernan's article "Does Water Kill?" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207342/) to be very useful tool for clearing up how I think about causes, and it certainly applies here.
> Causal inference is an entire field with a pretty simple and well-hashed-out definition of a "causal effect." From Miguel Hernan's "Causal Inference: What If?":
>>We compare (usually only mentally) the outcome when an action A is taken versus the outcome when the action A is withheld. If the two outcomes differ, we say that the action A has a causal effect, causative or preventive, on the outcome. Otherwise, we say that the action A has no causal effect on the outcome
This isn't correct as a description of how we think about causality or of how we _should_ think about causality. Many systems are regulated: if you make some kind of change to the system, the system will respond by making a countervailing adjustment.
Say you're driving a car and you start going down a fairly steep hillside. Everyone understands that the slope of the hill causes the car to pick up speed. Except, by the definition you just offered, it doesn't: in the absence of the change in slope, the car will keep going along at whatever speed the driver wanted. In the presence of the change in slope, that is also the case. The driver will be holding the brake down, but that's notionally a causal effect on the brake, not a causal effect on the mostly-unchanged speed of the car.
Great example. Both Friedman and Sumner have written about this extensively in the context of monetary policy.
On an earlier ACX comment thread, there was a commenter arguing that it cannot be the case that the money supply has a direct causal effect on the price level, because sometimes they change by different amounts.
The concept that there might be more than one thing with a causal effect on the price level didn't seem to register.
Of course, if more than one thing has a causal effect then no one item can have a 1:1 correspondence (which seems to be what many people assume about monetary policy).
If "the system" is coupled 1:1 with the action, then no, it's not a causal relationship. Stated more clearly:
"If a car with a human driver heads downhill, does the car change speed, compared to the same car being driven on flat ground?" Answer: No. Therefore, the intervention (human in car driving down a hill) does not cause the outcome (change in speed). It's interesting to ask *why* that isn't the case (hence the brake) but it doesn't change the causal nature of the action.
This is exactly the kind of confusion that Hernan's article cleared up for me. The car/hill question muddles the exact causal comparison being made--it makes a "downhill causes speed increase" argument based on applying basic physics to a car WITHOUT a driver, then assumes that a given action has the same causal effect in a different situation. They aren't the same causal question, and they don't have the same causal answer.
> Actually it’s more complicated than this: if you look at the simulation argument from last time, it’s hopefully obvious that every case is caused both by genetic and by environmental factors, or that it’s not really meaningful to try to disentangle them. I don’t know whether real schizophrenia is like this.
Real schizophrenia is definitely not like the simulation in a relevant way which I will detail below:
Your model involved assigning two types of risk levels to people, summing them, and then diagnosing scizophrenia if the summed risk exceeded a threshold. The threshold was higher than the maximum value of any individual risk component, and therefore it wasn't possible for any component to be solely responsible for a schizophrenia diagnosis. (But, by design, it was easy for one component to contribute five times as much "problem" as the other component.)
The problem is that your risk levels were ordinal numbers, not cardinal numbers. This could only be valid as a model of schizophrenia if schizophrenia were diagnosed solely by comparison to everybody else. Objective criteria, such as hallucinations, invalidate the assumption.
(It's also weird that your model involves adding an ordinal genetic risk to an incommensurable ordinal environmental risk. We try to avoid adding ordinal numbers. By assuming that genetic and environmental risk are normally distributed, you can convert centiles to standard deviations. But I think you'd end up unable to say whether a standard deviation of environmental risk was more or fewer units of risk than a standard deviation of genetic risk, which is kind of the opposite of the point of the simulation.)
In reality, we are surely interested in a model of schizophrenia where you get small numeric contributions from many causes and schizophrenia happens when a numeric threshold is exceeded, not where you get large comparable-but-not-theoretically-measurable contributions and schizophrenia happens when a comparative threshold is exceeded (that is to say, when a certain number of people are doing worse than you).
"Objective criteria, such as hallucinations, invalidate the assumption."
Except people with hallucinations, or delusions, or even the whole suite of classical Schneiderian first-rank symptoms get diagnosed with half the DSM aside from schizophrenia. These can pop up in people whose longest-standing diagnosis is bipolar disorder, or psychotic depression, or dissociative identity disorder, or borderline PD, or really anything cluster A, or one of the rarer psychoses (e.g. delusional disorder), or a NOS wastebasket. This doesn't necessarily mean what they have is fundamentally Unlike schizophrenia; it means whoever they had the longest therapeutic relationship with used a different term. If we drew lines based on Underlying Truth and not on subjective impressions of "how is this guy like the last guy?", there wouldn't be so many people whose diagnostic histories switch between SZ and bipolar.
(I think a significant and underrecognized moving part in whether psychotic people get diagnosed with SZ or something else is their "relatability"/ingroup status to the clinician, rather than whether they're schizospec or not.)
> If we drew lines based on Underlying Truth and not on subjective impressions of "how is this guy like the last guy?", there wouldn't be so many people whose diagnostic histories switch between SZ and bipolar.
Those people can't exist in Scott's model either. The comparison isn't to the last guy you saw, it's to everyone.
When I went to a class/group mental health thing for ADHD a few years ago, one of the things I learned was that ADHD is considered "epigenetic": you need the genes, but the genes have to be activated by environmental factors (lead exposure was mentioned) before you really "get" ADHD. Would calling schizophrenia "epigenetic" satisfy both sides of the argument? Also, is this something people still think is true about ADHD?
Most pop science about "epigenetics" is bogus. That would be my guess about the group you attended.
This sounds like a conflation between epigenetics and any old gene x environment interaction. Epigenetics is concerned with changes in the regulation of the expression of genes. These are changes that aren't hard coded into the genome but are achieved through modifications like DNA methylation, that influence whether and how much of the downstream product is produced. The environment as we tend to think about it can be involved in epigenetic regulation but isn't necessarily.
Gene x environment interactions can take many more casual pathways. Let's say there's something about the way the frontal cortex develops (genetically influenced) that makes it more or less vulnerable to lead exposure. That would be a gene x environment interaction that isn't epigenetic.
I also think the story you were told about ADHD is ahead of our current understanding. As far as I know, there are both genetic and environmental risk factors, and someone with ADHD is likely to have both, but I'm not aware of any established universal casual pathways that involve environmental triggers of gene regulation, or evidence that such pathways are necessary. It's more of a "we think this is how it must work because this is our operating hypothesis for most things with genetic and environmental contributions," but that's at the gene x environment level generally. I'm curious now and I'll look into it but adding specificity and certainty to causes of disease hypotheses for popular consumption is common.
> Would we really? If schizophrenia was caused by an omnipresent virus, but the only people who got it, got it entirely because of genetic differences from the rest of the population, why would we call the virus “the cause” rather than the genes? Is it just because we’re used to calling pathogens the causes of things from our long history with infectious disease? It might be equally reasonable in this case to think of schizophrenia as a genetic immunodeficiency. I don’t know exactly how to think about things like this.
I mean, it kind of sounds like you do know how to think about things like this, but you don't want to do it.
Suppose there were oxygen lying around everywhere (as in fact there is!), and some people had genes that caused them, when exposed to oxygen, to harness it to cells in their circulatory system and generate energy in specific areas through controlled chemical reactions, while other people had genes that caused them, when exposed to oxygen, to catch fire and burn to death.
Would that be a genetic problem? Could we fairly attribute it to the genes?
Of course; everything you ever do is caused by your genes, because there is no theoretical alternative. The range of possible reactions of an organism to different environments is one more thing that is fully specified by its genes.
>schizophrenia is so famously hard to define that we’re not even sure it exists
This was news to me! You kind of just dropped a bombshell there and kept walking.
Well, considering that DSM-5 basically defines schizophrenia as having positive (delusions, hallucinations, etc) and negative (apathy, anhedonia, etc) symptoms while also being fairly sure that those things aren't being caused by something else... There's probably multiple, distinct conditions getting lumped together here.
> even though smoking causes 80% of lung cancer, if Alice gets lung cancer and Bob smokes exactly the same as Alice, Bob will have a much lower than 80% chance of getting lung cancer. The solution isn’t to stop describing smoking as causing lung cancer, it’s to get better intuitions.
This example makes me queasy; the two 80%s do not refer to related numbers, and neither of them is related to the problem you're discussing in the post. I want to think about the link between smoking and lung cancer in terms of risk increase, something along the lines of "in these two otherwise comparable groups of nonsmokers and habitual smokers, the smokers get five times as much lung cancer". It's never relevant how much of lung cancer is caused by smoking; you'd need to normalize that against the number of people who smoke. This is just the confusion between P(smoker | lung cancer), which in the example is at least 80% (though actually more†), and P(lung cancer | smoker), which is Bob's chance of getting lung cancer from being a smoker.
But while confusing the two directions of a conditional probability is a common problem that occurs when people try to think about probability, it is not the same as what is otherwise the focus of this post, which is the meaning of claims like "80% of the variance in random variable X is explained by random variable Y, a component of X".
This makes the thesis "this is equally true of everything else" a bit weird. The smoking / cancer example provided in support isn't analogous to the schizophrenia / heritability claim and doesn't transfer. It could be an example illustrating that we need to get better intuitions about everything, and, sure, I guess that would be nice...
† Why more? By assumption, 80% of lung cancer patients developed their cancer by smoking, and they are all, by definition, smokers. This gives us a lower bound of 80%. But there will be some smokers who developed lung cancer even though their smoking didn't contribute to it, the same way nonsmokers develop lung cancer without any contribution from smoking, and those smokers-with-lung-cancer-unrelated-to-smoking will raise the rate above 80%.
Addendum: I think it's about as likely that we can train people to have good probability-related intuitions as that we can train them to have good four-dimensional mental visualization abilities. Or in other words, it will never happen.
Logic is sort of a liminal case. There are many people who can process basic logical relationships in their minds without difficulty. And there are many other people who aren't capable of processing logical relationships and can't be trained to do so. 3D visualization is similar: some people are very good at it, and others can't do it at all.
Probability and 4D visualization are like that, except without the population that is able to do it.
Is age a risk factor for the flu? It's a risk factor for *dying from* the flu, but is it one for getting it?
None of those arguments make up the true rejection. Instead, like you say, if genetics could be admitted as the cause, then it would likely be possible to describe any workable solution as EUGENICS, which is obviously far too horrible to contemplate.
This comment here is the only one a ctrl-f for "eugenic" turns up. Top comment, imo.
This really is the whole story ('story' on purpose, like 'narrative'). It's socially undesirable to think about genetics for somet hings, and in some contexts. We've over-updated in response to those guys in Germany that one time .If they'd had a single-use genie that could only eliminate genetic causes of diseases, and they'd chosen to eliminate schizophrenia, we'd note in history books that there used to be this weird thing that went wrong with people but it stopped happening in 1942 for some reason -- and we'd be glad.
I don’t think it’s that thought-through; to most people, “eugenics” is just some Nazi thing that was also in Moonraker. It’s more a concern that most people view “genetic” to mean “fundamentally part of who you are,” and “environmental” to mean “randomness/luck.” If it’s environmental, then someone who’s fundamentally healthy just caught schizophrenia the way you’d catch a cold. If it’s genetic, there’s no non-schizophrenic person underneath; it’s part of their soul.
Sure, but most people don't set the agenda. The so-called intellectual elite does it, and it's not short on awareness about "Nazi things", given the steady stream of proclamations that fascism is about the most pressing threat to civilization, until we all drown due to global warming of course.
> Fine. Epilepsy is also genetic.
I don’t see any particular issues with this statement. Many forms of epilepsy are highly heritable. I’m currently trying to solve my husband’s and sister-in-law’s epilepsy and there’s a ton of data that indicate that at least propensity for seizures is highly genetically determined.
"This is possible, but I think it’s false. We know many apparent risk factors for schizophrenia: cannabis use, birth canal asphyxia, social defeat, toxoplasma infection, poor prenatal nutrition. If you try to combine these into one big picture, it doesn’t work."
What the - cocial defeat causes schizophrenia! How? Why? Is this another case of X is not about X, it's about signalling?
That appears to just be a hypothesis rather than something firmly established.
Thanks! Even so, I find it kind of suprising. Though perhaps the supposed mechanism applies to more than just schizophrenia? Somehow that sounds more plausible to me.
> The only thing that makes sense to me (and I’m definitely not an expert, and E. Fuller Torrey is, so take this with a grain of salt) is thinking of schizophrenia as cumulative damage to some abstract computational organ.
My pet theory is that schizophrenia arises more specifically from a deficiency in long-range cortex-to-cortex communication. I wrote about it (poorly) at https://www.lesswrong.com/posts/H2epKysvFgPcTwC2f/schizophrenia-as-a-deficiency-in-long-range-cortex-to-cortex and then later https://www.lesswrong.com/posts/tgaD4YnpGBhGGbAy5/model-of-psychosis-take-2
If that's on the right track, then lots and lots of genes would presumably be relevant, including glutamate receptors, myelination, dendrite structure, synapse structure, neuron resting potential, and on and on.
well-argued as usual. You address only briefly our weird reluctance to acknowledge that schizophrenia in fact does have a large genetic component. This reflects something about current society... in past eras, genetic contributions to behavior were taken for granted and often exaggerated. What's the deal here?
Schizophrenia is one of the many, many examples given in 𝘛𝘩𝘦 𝘉𝘭𝘢𝘯𝘬 𝘚𝘭𝘢𝘵𝘦 of things that are denied to be genetically influenced despite mountains of evidence to the contrary. The controversy was old by then.
Current society is ideologically committed to the position that nothing has a genetic component. That's the reason it's unacceptable to admit that schizophrenia has one. Think of schizophrenia as analogous to the Galilean moons.
I haven't read the book, but I find this example of cultural disconnection with reality striking. I suspect this particular disconnection (denying a relationship between genes and mental processes) dwells predominantly in the Tribe of the Left, perhaps because of perceived historical resonances?
No, it's definitely on the right too. They idiotically insist that free will exists and that everyone "deserves" what they get. No one deserves anything. All we can do is try to make things a little better for the people who are alive.
Much of what you say about the comparison with smoking causes cancer seems obviously right. But I guess the meat (or perhaps, heat) of this argument is about what happens downstream of the statement, "schizophrenia is caused by X": where money for researching therapies ought to go, or what advice to (potential) sufferers should be.
The statement "schizophrenia is mostly genetic" is, on the face of it, a suggestion to direct research dollars to genetics research; for sufferers it is perhaps perceived by Fuller as a counsel of despair. (I wonder if that is a motivator for him making the argument?)
Two things in your post leapt out at me as worthy of comment:
(1) "Kidney disease is just a catch-all term for “anything causing your kidney to work less well than it should”. If you examined its heritability, it would probably be substantially genetic."
Assuming this is true, this seems like an argument against saying "schizophrenia is mainly genetic," because that's not something we commonly say about kidney disease (is it?).
(2) "schizophrenia is caused by some extremely common virus...everybody has all the time...immune system controls the virus...genes for bad immune systems...virus causes schizophrenia."
I just wanted to raise the obvious analogy of HPV here. Once it was discovered that HPV was a key factor in cervical cancer, research moved to HPV prevention, culminating with the HPV vaccine, which as far as I know is now doing an admirable job of reducing infections and the downstream cancers. This seems to me to illustrate what I was saying above: the argument about what we should *say* causes condition X is really an argument about how we should go about researching and treating condition X.
Back on a more general level, the issue you point up of different common medical terms for diseases/conditions/syndromes being on completely different levels of the symptom-condition-cause spectrum just makes any generalisation hard to do. Particularly for something like schizophrenia, where it's still unknown whether that word refers to a causally disparate collection of different symptoms; a single, fairly well-defined syndrome; or a monocausal disease. Any conclusion you might draw about how to talk about particular kinds of diseases may or may not apply to schizophrenia...
I am sad to see this bunch of non-arguments that neither grasp the philosophical question, the science communication problem or the scientific problem.
The philosophical question is, when multiple prerequisites are necessary, but neither is on their own sufficient, what do we consider the cause of something? This is a persistent problem in medicine. When an old person dies of a rhinovirus infection, what is the cause of death? The rhinovirus or old age? A young person would have surived the virus without any problem whatsoever, so it is reasonable to say old age, but then again, without the virus, the person might still be alive, so it would be equally reasonable to say the virus. The sad fact is that there is no scientific way of assigning what amounts to moral blame. Scott would like to use the numbers™, but heritability is a statistical expression of variance, not quantitative causal contribution or population attributable fraction, it rests mostly on outdated evidence and is misleading regarding the preventative effects environmental interventions may have. Neither of these points is adressed in the post.
The science communication question is whether we should advertise heritability estimates as relevant. The original article claims we should not, and nothing Scott argues changes that very much. Environmental interventions still can have large effects on incidence in diseases with high heritability. Scott ignores this for some reason.
Lastly, the scientific problem involves the high heritability estimates of twin studies, which were not replicated by GWAS. It is yet unclear whether they will be replicated by whole-genome sequencing studies, but the likelihood is low in my opinion (WGS studies claim better sensitivity to rare variants, but this is unlikely a major contributor do disease burden due to selection pressure). Polygenic scores do not explain much more than the GWAS estimates, either. The missing heritability problem is easily resolved when assuming twin studies simply give overestimates due to GIGO. This has been argued for a decade now (doi: http://dx.doi.org/10.2190/HS.43.2.f). So what are we left with here, exactly? An isolated demand to strongly believe in outdated results based on poor methodology. This is motivated reasoning at its finest.
Which brings me to the last point, "if you are already doing IVF" - no, most people are not "already doing IVF". If you need IVF you either missed the on-ramp to having kids or there is something biologically wrong to begin with (some might argue that the former is an expression of the latter, but I digress). IVF is a disagreeable procedure for women to go through. It likely leads to inferior pergnancy outcomes compared to, oh, just having sex. Preimplantation genetic testing is an experimental procedure with little long term data that barely passes ethical muster in obvious cases of monogenetic diseases. Recommending PID to a patient willy-nilly based on an abstract desire to improve their offspring might (at least ought to) get your clinical license yanked.
Polygenic screening was never proven effecntive in a clincal trial. The 50% reduction in risk you were sold is not based on RCT evidence. Selecting against schizophrenia might select for something else, for better or worse. Your mileage may still vary overwhelmingly.
I used to appreciate this blog because of the thoughtful discussion of medical evidence it offered on psychiatric treatments and diseases. Reading this series of articles both suggests that these skills do not translate well to other fields of medicine and casts doubt on the quality of previous discussions.
no, most people are not "already doing IVF".
Good thing nobody ever said that then.
"Lastly, the scientific problem involves the high heritability estimates of twin studies, which were not replicated by GWAS. It is yet unclear whether they will be replicated by whole-genome sequencing studies, but the likelihood is low in my opinion." Based on what exactly? Our intuition that there should be selection against rare variants? Although you sound confident about the solution to the missing heritability problem, I don't believe that your view is shared by a majority of the geneticists who are working on this issue. From one recent study: "Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease." https://pubmed.ncbi.nlm.nih.gov/35256806/
It's possible that twin studies are biased, but I think the jury is still very much out on this question.
Shower thoughts:
1. Gene X is highly correlated with Bad Thing A
2. Everyone starts screening for Gene X
3. It turns out Gene X basically makes people more in touch with reality
4. Being in touch with reality causes Stress Type 1 because our society sucks
5. Stress Type 1 causes Bad Thing A
6. Much fewer people now experience Stress Type 1, since they're delusional enough to ignore how much society sucks
7. Bad Thing A has been virtually eradicated
8. Success?
> if we knew for sure that all of the genes involved in schizophrenia were for an autoimmune condition, we might say “schizophrenia is an autoimmune disease”.
My understanding of polygenic scores is that it is a statistical method.
My reluctance for a (voluntary) eugenic solution depending on these scoring is, that we don't understand these genes and if there is a side effect? It is like deleting programming code without knowing if it maybe also had beneficial effects? Maybe in this autoimmune genes are also supergood for surviving covid or preventing allergies. Maybe they are involved in creativity and erradicating slightly crazy genes would lead to a boring dystopia of bureaucrats out of tune with the spirit world?
"Maybe they are involved in creativity and eradicating slightly crazy genes would lead to a boring dystopia of bureaucrats out of tune with the spirit world?"
I'd categorize this as something like "unambiguously true" -- the positive schizotypy/creativity relationship is clear enough at this point, and if you distinguish "disorganized schizotypy" (a weird cluster-space of "not clearly positive and not clearly negative", loading on some combination of eccentricity and thought disorder) it seems to be so as well. Even without focusing on a schizotypy-creativity connection, high schizotypy is a thing many people self-report liking about themselves (whether they describe it in those terms or otherwise) and find helps them get to self-actualization and fulfillment. Schizotypal PD is famously one of those PDs that gets diagnosed by coincidence in people who report with other concerns, who consider the PD diagnosis a weird consequence of "I went to therapy for depression and they told me all my best characteristics are this instead for some reason".
"PRS discrimination against schizophrenia" should, without evidence that schizophrenia-genes and schizotypy-genes come apart (I think they might at the tails, i.e. that there are additional genetic factors in whether schizotypal people develop schizophrenia and what it looks like if they do, but I think this would be a minority of what we currently consider "schizophrenia genes"), be read as "PRS discrimination against schizotypy". When you *actually look at* schizotypal screening questionnaires or diagnostic criteria, it becomes apparent this isn't something you need to throw everything away to Prevent. If anything, it starts sounding parodically dystopian -- "we need to eradicate people who are eccentric and suspicious!".
It's very puzzling. Here we have claims that it's
A) the same prevalence in nearly every society studied
B) higher in African-Americans
What? How could both be simultaneously true?
Possibilities ...
- African-Americans are subject to higher stress due to being discriminated against (environmental effect)?
- Some sort of local parasite that people of European ancestry have evolved resistance to ? (Difficulty: we're talking about America here...)
- Desire to emigrate being influenced by same alleles as schizophrenia?
- Discriminatory diagnosis by psychiatrists ? (E.g. marginal cases more likely to be diagnosed if patient is both (a) black and (b) in America)?
Did you miss that the entire discussion is about *genetics*?
My point here is that here is we have two pieces of evidence about what that genetics might be that are hard to reconcile. Between them, they would appear to rule out quite a few things.
E.g. on some plausible models...
- African-Americans would have similar risk to people in Africa (nope)
- genetically different populations would have different frequencies of the risk alleles, and hence different disease rates (nope)
Urbanicity is a risk factor.
Yes, that's one of the risk factors.
(Thinks for a moment) but immigrants more often move to big cities than the rural countryside, so if whatever's causing schizophrenia is some toxin or pathogen encountered in cities, immigrants will encounter it more often.
Yes, this is weird. I feel like a lot of this discussion is dancing around the central point that saying "schizophrenia is 80% genetic" will be treated by the media as equivalent to "black brains are genetically worse than white brains." (And will definitely be treated that way by /pol/, etc...) Researchers' hesitation to claim this does not surprise me at all.
My favourite example is that wearing earrings is very heritable in modern human population. Based on whether person has two X chromosomes or not, one can predict quite well whether they are wearing earrings or not.
More specifically, identical twins will be more similar in the earrings trait than fraternal twins (who have a 50% chance of being different sex).
>You also can’t point to any individual lung cancer patient and say “smoking caused this person’s lung cancer”.
Actually we can! Tobacco smoke causes characteristic types of mutations in cells, and if we see those mutations in someone's cancer, it's pretty certain that it was caused by smoking.
See https://pubmed.ncbi.nlm.nih.gov/27811275/ "Mutational signatures associated with tobacco smoking in human cancer"
Re: footnote 3 (ubiquitous virus plus genes):
The natural way to describe such a situation would be: the virus causes schizophrenia, and certain people's genes cause them to get schizophrenia.
Does that distinction help for the issue at hand? I think it does help clarify what we mean by causation. As for what we mean by "genetic", not directly, but it does point toward a more precise way of describing the situation: "genetically mediated". Would we be having this argument if the question was about schizophrenia being genetically mediated? I don't think so.
I'll note that the vast majority of smokers don't get lung cancer (LC), so even the perfectly reasonable sounding "smoking causes lung cancer" is suspect. It's true that smoking massively increases the odds of LC (i've seen ORs from 20x-40x), the base rate is so low that even for smokers the lifetime risk of LC is less than 1% (at least by my quick and sloppy estimates from CDC/NIH numbers. My hope is that by being wrong on the internet I can get someone else to do this, and even if I'm off by 50x I'm still right.)
The only use I've gotten out of calling things 'causal' is to indicate that modifying one variable will meaningfully affect another variable. It's about actions one can take that are expected to do the thing you think they should. I'm okay with saying "smoking causes lung cancer" because I believe that modifying smoking habits will clearly and directly decrease LC risk, whatever mechanisms or moderators or whatever are "actually" responsible.
Scott, if you haven’t already seen the reply I got from Steven Hyman to my posts, that will interest you: https://www.psychiatrymargins.com/p/a-note-from-hyman-on-the-genetic
From my perspective, we are in this odd position where we know that a substantial aggregate genetic influence on schizophrenia exists (and that such substantial aggregate influences exist for nearly all complex disorders, even if not to the same extent), but we seem unable to make it tangible. The influence dissolves into genes of tinier & tinier effects, and this seriously limits what we can practically do with all this. It’s obvious that hundreds and thousands of gene influence the risk of developing schizophrenia.
We need to distinguish between several different strands of the debate here. “Are genetic influences in aggregate a cause of schizophrenia?” is one question (and I’d say yes, in the same sense of cause as smoking causes lung cancer) but that is a different question from whether “Is the etiology of schizophrenia 80% genetic?” The latter question is rather ambiguous but that’s how many ppl talk about schizophrenia. My view is that it is 80% genetic only in the strict sense of the heritability statistic for a population, and that the heritability statistic becomes kinda meaningless if you try to turn it into a statement about what component of “etiology” (etiology ≠ phenotype variation) is genetic.
A second thing we need to distinguish is that we mean different things by the term “genetic disorder.” It could mean something very general, like any disorder where a substantial portion of the risk/vulnerability comes from aggregate genetic influences. A second more specific sense is where identification of causal genetic variants provides a coherent way to understand the mechanisms or pathophysiology of a condition. Schizophrenia genetics program was kinda based on the hope that we could move from the former sense to the latter sense, and it has become rather clear by now that this is not likely to happen. The influence of any particular gene is too small & current polygenic scores explain like 6-7% of risk. What people are hoping now is that genetic associations can provide clues to understanding what pathways are involved, like disruption of synapses or immune dysregulation. I don’t mind if we consider schizophrenia as a genetic disorder in the first sense (which means many other complex disorders are also genetic) but we shouldn’t simply assume that because it is genetic, the latter sense is also true.
Scott thinks the evidence suggests that it's possible to halve the risk of schizophrenia by polygenic selection - do you disagree? It doesn't seem compatible with your statement that polygenic scores explain 6-7% of the risk of schizophrenia
I misremembered the actual figure; it is a bit higher than 6-7%. It’s 7-9%.
“For schizophrenia, which possesses the most well powered GWAS to date, the best-performing PRS (polygenetic risk score) method explained just 8.5 % of the variance in liability for the disease, falling to 7.3 % when non-European ancestry cohorts were included” (Andreassen et al., 2023) https://onlinelibrary.wiley.com/doi/10.1002/wps.21034
In the context of polygenic embryo screening, we are talking about relative reduction.
With regards to using polygenic embyro screening, under certain conditions, there could possibly be a 50% reduction of relative risk of schizophrenia, but this would amount to an absolute reduction in risk of about 0.5% for a random embryo (i.e. not someone with a biological relatives). For someone with a first-degree relative with schizophrenia a 50% relative reduction could be quite meaningful though.
"Our model shows that a 52% RRR is attainable using the LRP strategy with n=5 embryos. However, this translates to only ≈0.5 percentage points reduction on the absolute scale: a randomly-selected embryo would have a 99% chance of not developing schizophrenia, compared to a 99.5% chance for an embryo selected according to LRP." Lencz, 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510582/
Thank you, this is great. Though I think I'd disagree that a relative risk reduction could only be meaningful if there's an absolutely high risk. Reducing the risk of my child developing schizophrenia from 1% to 0.5% is something that I would (personally, ymmv, etc) find meaningful.
Couldn’t you use this exact reasoning to say that a perfect test for schizophrenia, that reduced your absolute risk to 0%, would be also unimpressive?
Correction: Polygenic risk score explains 7-9% of variance in risk.
“For schizophrenia, which possesses the most well powered GWAS to date, the best-performing PRS (polygenetic risk score) method explained just 8.5 % of the variance in liability for the disease, falling to 7.3 % when non-European ancestry cohorts were included” (Andreassen et al., 2023) https://onlinelibrary.wiley.com/doi/10.1002/wps.21034
Awais, I am curious to hear your thoughts about the high prevalence of schizophrenia/psychotic disorders in 22q11.2 deletion syndrome, which has been well-established for a number of decades now. This is the strongest known single genetic risk factor for schizophrenia, to the extent where ~25% of individuals with 22q are diagnosed with schizophrenia by adulthood (this was referenced briefly in Torrey's original commentary). Between the different Substack posts on this topic amongst Scott, yourself, and Dr. Hyman's editorial, there has been no further discussion about the link between 22q and schizophrenia, which to me seems an important omission when are are talking about whether schizophrenia is genetic or not.
References:
https://link.springer.com/article/10.1007/s11920-021-01225-z
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780289/
Hi Anthony. I mentioned 22q11.2 deletion syndrome as an example of a rare genetic alteration with a large effect. It's certainly important, and it reveals that genetic effects can be large, and it provides a scientific opportunity to study what pathways are disrupted as a result of 22q11.2 deletion. As I wrote in the heritability post, "Clearly, only a very small subset of people with schizophrenia have a genetic etiology *in this sense*. 22q11.2 deletion syndrome would be one contender. Other CNVs and rare variants with larger effects could be candidates as well, etc." Since most cases of schizophrenia are not associated with genetic variants/alterations of large effects, we are limited in what can be inferred from 22q11.2 deletion syndrome.
Agree that preventing SCZ is good, and polygenic screening probably helps more than other known interventions, and most of the arguments you reject ought to be rejected, except #7. Violating assumptions of heritability estimates is not a small point.
First, the limitations of adoption studies are not just the importance of the intrauterine environment. An adoptee's adult behavior is caused by a combination of 1. intrauterine environment, 2. early-life experiences before adoption, 3. post-adoption environment, 4. direct genetic causal effects on behavior, and 5. indirect genetic causes on behavior (e.g. gene → physical appearance → another trait). I would not confidently rule out any of these factors without experimental evidence directly controlling for them, which in the case of gene-by-environment interactions (#5) is essentially impossible.
For twin studies, it feels extremely implausible that the equal environment assumption is even close to true. Glancing at the paper you cited, they seem to find that the ways in which identical twins' environments are more similar only have small relationships with behavior. However, the value of this analysis depends on accurately identifying how identical twin's environments are similar. It seems this paper neglected some plausible ways in which identical twin's environments are more similar than fraternal twins (genes → attractiveness → people being nice to you, genes → athleticism → being on a sports team, genes → disease susceptibility → feeling sick). If some of these mechanistic explanations are correct (likely in combination or for particular sub-groups), it wouldn’t be reasonable to say that genes cause schizophrenia.
If you want to say X causes Y, a randomized controlled trial is a nearly universally accepted way to do so. With smoking, we have controlled trials in animals and some limited smoking-cessation interventions in humans. Also as you say, we have mechanistic evidence about mutations & that adds confidence. Sure, this is an example of imperfect evidence that most people accept and act upon, but it also feels like much stronger evidence than the purely genetic basis of schizophrenia.
The reason I feel strongly about this is that a blanket acceptance of heritability estimates leads to assertions about the innate intellectual ability of races. In this case, the arguments for the violation of heritability estimates are extremely plausible (e.g. in an adoption study, black kid gets adopted into a white family, but is still treated as black by society, and consequently his environment comes with him).
PS I love this blog & massively respect what you do.
“But as we often discuss here, this is backwards - society is fixed and biology is mutable.”
…the examples in the 2014 piece are fine, but come on – “society is fixed while biology is mutable” is just as wrong as the opposite statement.
The boring but truer statement is: both society and biology are mutable to some extent, but it varies to which extent. The variation is partly based on which society we are talking about, partly based on which biological factor/s we are talking about, and partly based on what kind of problem/s we are talking about.
I'll never forget how startled I was when I learned in college that no one with congenital or early blindness has ever been diagnosed as schizophrenic. A quick search just now confirmed that this is still believed to be true. Are we any closer to understanding why? Has investigation of this oddity yielded any progress toward understanding the cause(s) of schizophrenia?
See mistake #50 here:
https://www.astralcodexten.com/p/mistakes
Thanks!
> We know many apparent risk factors for schizophrenia: [...] social defeat
"Social defeat" struck me as the odd one out in that list. I clicked on the link, which was just to the wikipedia article on the concept, and it in turn had this in its list of sources:
https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/social-defeat-risk-factor-for-schizophrenia/ABB536863ACE99B8B4D7D1CCE18B49C5
That merely proposed the hypothesis that social defeat can increase the risk, and presented data in support. It didn't claim that we "know" it's a risk factor. Instead, it ends with suggestions for how to test the hypothesis in the face of the ethical problem of subjecting humans to social defeat and the inability to test for schizophrenia in other species of animals it is permitted to experiment on.
You seem to be completely right, but you make it a hard read. Why not start with "People in schizophrenia research are adamantly opposed to saying it's a largely genetic disease, even though the evidence says it is. Why is that?" You probably do want to put the long-winded analysis at the bottom as a massive footnote to the first sentence, but the interesting part is the psycho-politics of why people resist considering schizophrenia a largely genetic condition. And indeed, you barely scratch the surface of that. I'd think that if you did as much careful sniffing of how people talked about schizophrenia as you did dissecting the analysis of the data, you'd get a pretty good idea.
I came across something recently called the "eggshell skull rule" in Law which I feel is relevant to describing human intuitions about causation that other comments have mentioned. The idea behind the rule as described by wikipedia is:
"If a person had a skull as delicate as that of the shell of an egg, and a tortfeasor who was unaware of the condition injured that person's head, causing the skull unexpectedly to break, the defendant would be held liable for all damages resulting from the wrongful contact, even if the tortfeasor did not intend to cause such a severe injury. "
So if the genetic correlates of schizophrenia are ultimately best described as vulnerabilities -- things that do require one or more other significant factors to result in schizophrenia -- then I suspect that many people would intuitively find it much more comfortable to just describe them as genetic vulnerabilities rather than as genetic causes. And that's even if the most straightforward path to preventing schizophrenia were still to prevent or correct the genes somehow.
Second, anecdotally, I narrowly avoided a schizophrenia diagnosis a couple years ago (and did get a schizotypal plus transient psychosis diagnosis) despite having symptoms that, based on most descriptions I've read, do not fit schizophrenia well at all in my opinion: chronic pain, chronic headaches, fatigue, pins-and-needles, dizziness, difficulty thinking, and involuntary muscle contraction, all of which are weirdly exacerbated by common allergens. I specifically did not at the time have visual or auditory hallucinations, delusions, or disorganized thinking (by my estimate still, years later, though the psychiatrists considered my pain to be hallucinatory and my belief that it was associated with common allergens to be delusional) And based on that experience of how easily schizophrenia can be "read into" various symptoms as well as stories I've come across like this one: https://www.washingtonpost.com/wellness/2023/06/01/schizophrenia-autoimmune-lupus-psychiatry/ where a woman spent twenty years with a schizophrenia diagnosis when all her symptoms were caused by lupus and enormously improved for the first time by finally, y'know, treating the lupus, I've come to doubt the usefulness of schizophrenia as a label.
When schizophrenia is in practice reduced to "What might be interpreted as psychosis plus general impairment," as seems to be the case to me, while at the same time being thought of as something basically genetic, then there seems to be enormous potential for it to act as a diagnostic thought-stopping cliche. Maybe at a high level "what might be interpreted as psychosis plus general impaiment" is best correlated with genetics, but if it's actually the case that there are dozens of specific genetic conditions or genetic vulnerabilities each of which manifests apparent psychosis plus general impairment under certain conditions, in response to certain things, or in the absence of certain treatments, then wouldn't it be better to not treat schizophrenia as a monolithic "thing" with a "cause" at all, but rather as characteristic presentation of many things, most of which are ultimately genetically-based?
So I guess I'm on the side of: "The studies are probably right, but in a philosophical sense we shouldn’t describe it as mostly genetic."
I assume the real issue is that “genetic” is ambiguous between things like sickle cell or Tays-Sachs where there is a very specific gene variant whose presence or absence is definitive, and things that involve complex interactions between many genetic variants and the environment. It’s not like the former. And we don’t have good use to make of the latter category yet, so it isn’t one that we have broadly developed useful vocabulary for describing.
If people need a low tech method, not reproducing with people who have a family history of schizophrenia should help. On the other hand, if the percentage of schizophrenia is the same worldwide, it doesn't seem to help much, or is harder than it sounds, or helps the same amount everywhere.
I'm still worried about the eugenics thing.
I really do understand why you're so defensive of polygenic screening. I wouldn't judge any individual parents for choosing the option, and obviously in 2024 you are in no meaningful sense affecting the genetic fabric of society by doing so. But all the same, I worry about what it does to humanity in the long term if it becomes normalised, and I think you're wrong not to.
To get it out of the way there's the obvious thing where if it becomes possible, bigots might select against having (non-cripplingly) autistic, or gay, or etc. children in sufficient numbers to endanger the long-term survival of those traits. But that's not even what I'm most worried about. I'm worried that trying to do polygenic screening with our current half-baked understanding of genetics is the equivalent of doing advanced chemistry with a kitchen blender.
That is to say: can we reliably select against schizophrenia without selecting against various non-harmful forms of neurodiversity? Or indeed, random unrelated benign traits which happen to be genetically correlated with schizophrenia but have to do with the shape of your nose or left-handedness or something? On a societal level I worry about this a lot. I find it *most* concerning with people selecting against severe autism than against schizophrenia, because severe autism is more clearly on the same directly-related spectrum as personality types which humanity would be immeasurably poorer for not having. But A) I'm not sure schizophrenia isn't also correlated with positive /benign traits, and B) I don't think I trust society to be responsible with these tools if they get normalised, and *only* use them to screen out "safe" conditions.
People with the mentioned mental illnesses don't reproduce a lot, so selecting someone in the 90th percentile of autism instead of 99th may well lead to more autism genes in the generations afterwards.
My family has a history of schizophrenia, including members of both my immediate and extended family. We also have a history of high academic achievement, which includes advanced degrees in hard sciences and at least one department head at a major US university. I have noticed other families of high academic achievers with schizophrenic children.
Is there any data that links schizophrenia and high academic achievement within a family? I feel like I have seen this mentioned before. If so, is there any possibility that selecting against schizophrenia would select against gifted people as well?
You are ignoring the massive role that psychological injuries play in people later developing symptoms of psychosis. People with 5 Adverse Childhood Experiences are anywhere from 60 to 150 times more likely to have these symptoms, than people with no ACE's. https://pubmed.ncbi.nlm.nih.gov/17586579/ Schizophrenia is hugely influenced by being emotionally neglected, sexually abused, having a raging alcoholic as a parent, and other emotional wounds. It is not fundamentally in the genes.
I find it plausible that ACES play a causative role, but surely such estimates (60x - 150x) are inflated by confounding? Especially considering some of the heritable liability for SCZ is shared with other psychiatric disorders. I'd love to see some methodologically tight work on the subject, if you have any good refs.
I suppose one argument for not saying schizophrenia is genetic is to prevent that from becoming a dogma that can't easily be displaced? Like suppose some researcher has a theory about the cause or a treatment for schizophrenia but it's not linked to genes in any clear way and so when she goes to apply for funding she gets rejected because "everybody knows it's genetic".
You probably aren't arguing that schizophrenia should be specifically and always described as a genetic disease you just don't want people to be in denial about the role of genetics but perhaps (and to be clear I haven't read them) they are arguing against a more extreme version of your position.
Is it fair to say that genes do not cause two-leggedness? The heritability is near zero, on the same meaning of heritability. For bonus-points, y'all obviously agree accent is more heritable and therefore more genetic than two-leggedness, right?
Can't have any isolated demands for rigor here, and in certain communities any demand for statistical rigor is isolated, so please everybody get with the program.
I'm a public health professional. I think there is no difference between cause and risk-factor for scientists or professionals, but there is a big difference when creating public messages. Many people interpret "cause" to mean 100% correlation, as in, smoking 100% always causes cancer. When you say "risk-factor" people are better at understanding that there is some amount of probability around the factor. So generally you see a preference for saying risk-factor.
> "more satisfying cause of schizophrenia"
I think this is the core of the failure in communication. The human mind does not seek truth, it seeks satisfaction.
For a person not affected by schizophrenia, it's perfectly normal to think that "Schizophrenia is a disease that crazy* people have, and runs in the family" (*I'm not endorsing that word, but it is in common usage)
If you are affected, or work on it, that's not nearly good enough. A satisfying definition would include the idea that it's a bucket of conditions, not just one thing, and that it can cause a range of symptoms of varying degree.
When you work on a problem, you want to be able to work backwards and forwards with different suppositions to see what works.
Cause is like Proof - it's a place where you can stop thinking about something. If you say "I have evidence of something", that means you may have to keep looking. If you say "I have PROOF", then you can stop looking.
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I wonder how the various parties would engage with the terms Major Contributing Factor vs Minor Contributing Factor.
It is unfortunate there is no special word like "causes" in English that means "always causes but is not always the cause of." Successfully feeding someone into a wood-chipper always causes death, but death is not always caused by being fed into a wood-chipper. You could say genes cause schizophrenia, but don't wood-chipper cause schizophrenia.
Are there are other languages that concisely communicate that?
"sufficient but not necessary?"
How does “the prevalence of schizophrenia is the same across societies” square with the large differences in schizophrenia rates by race?
>it’s a million times more than the drug abuse and social defeat issues
A million is a lot, this is meant rhetorically, like "a bazillion"...right? After the "Unintuitive Properties" post, I don't totally trust my surprise at seeing 10^6 mixed in with the other numbers.
Risk factors are not consistently defined. Here's a real science article making the point in a fun way: https://www.bmj.com/content/355/bmj.i6536
The tldr is that there's four common meanings for risk factor.
- diagnosis: something that can tell us if you have a disease
- prognosis: something that can predict later development of a disease
- treatment effect: something that will casually change whether you develop a disease
- aetiology: something involved biologically in the disease pathway
Great post, Scott!
typo: reminds of them of
Not directly relevant, but thank you for at least mentioning COPD. Everybody thinks tobacco will give you cancer, and it totally can, but it's way more likely to give you the other thing which will also kill you but in a very different (still horrible) way. We stress cancer way more, probably because cancer is an easier and more familiar thing to understand than an umbrella category for two overlapping disease states.
I think that the resistance to genetics as a cause for diseases is because it is very unsatisfying to blame genetics.
If the cause of your disease is environmental and beyond your control, you can always blame society. You are the victim of systemic injustice because society did not protect you well enough.
If the cause is environmental and thought to be within your control, you can always be blamed yourself. You should have known better than to smoke.
If the cause is genetic, that does not make for a very satisfying narrative outside of Nazi circles. Blaming your parents for not using screening or CRISPR is frowned upon, so you can just call it bad luck.
To the degree genetics as a cause is actionable, it would proscribe actions (gene screenings, selective abortions, DNA edits) which would make huge parts of society uncomfortable.
But we all accept genetic causes for certain diseases (e.g. Down Syndrome), and indeed screenings and selective abortions are common (if not without some controversy).
Well said.
Didn't you write an article about how mainstream media rarely lies and apply a standard of "lying" under which one could claim the national enquirer rarely lies? (In that they didn't lie if they accurately reported what it was their source said to them without comment on the accuracy of that source)
There’s a disease that occurs only in people with a known, single gene (actually one allele). Because we know that gene, we know exactly what’s happening when it kills someone.
And yet it doesn’t kill everyone it could; people with the bum gene are still alive. Though if it did wipe them all out, we’d probably *still* blame the vector, not the victims’ genes.
The disease is mad cow, and the cause is ingesting misfolded prions. We are so impressed by a concrete explanation that most people don’t even know every victim (save one, IIRC) was genetically identical in one spot. If that’s not a genetic disease, how is schizophrenia?
Nobody wants a GWAS disease. It’s too fuzzy and it smacks of either missing something on the causal side or the definition being too broad. Like other unsatisfactorily explained diseases (MS, chronic fatigue, etc.), it’s better to admit ignorance than blame a thousand insignificant genes in the victim affecting an entirely hypothetical no-voices system in his brain.
Genetic screening for dominant genes whose pathological effects appear in adulthood reduces the frequency of those genes. That is an unalloyed good only if we certain than any possible beneficial effect of those genes is outweighed by its pathological effects. But we can't be certain of that.
Imagine a future ultracontagious virus that kills everybody who doesn't have the gene for Huntington's Chorea (WIV is working on that right now -- maybe...). With 100% screening of embryos for the gene for Huntington's Chorea, human beings go extinct.
"health care should be about treating schizophrenia, not preventing it"
I was trying to figure out why anyone would oppose polygenic screening and this sounds like the real reason. A doctor or therapist can't make a career transition to genetic screening tech, so they correctly see "we could cure schizophrenia" as a threat to their employment.
Providers would absolutely love to “cure” mental illness in all its forms because of the great suffering they see. The idea that they want to see people ill is quite frank insane.
"PGC objects to such uses because its goal is to improve the lives of people with mental illness, not stop them from being born, says University of North Carolina at Chapel Hill psychiatrist Patrick Sullivan, PGC’s founder"
How do most of these arguments not also apply to IQ being genetic?
...Why do you think they shouldn't? Do you think intelligence isn't affected by genetics?
Genetics has nothing to do with schizophrenia, save for growing up among the deviations from “society’ as it is accepted and wanting to be ‘someone else’. Some young actors have been diagnosed schizophrenic after taking on a role and keeping it. You can pretend to be someone else and end up really believing it. To someone who craves attention, they can create as many different “voices” as they want. Not being accepted in society is what keeps them so sad and hides away in the group they created for themselves. When someone is sick or not all there as with drugs, some sayings can stay with the person. I have helped a person see where there voices originally came from. A friend kept telling her she never listens so she wasn’t. They have to be active in their life and at least able to laugh once in a while to be able to even talk to them about it.
Ash Clif_high. He says he has the ‘schizophrenic gene’. But he is not schizophrenic . Basically if you cannot get them to create their life, they will just stay apathetic and reactionary. The medication for psychotics is a tranquilizer,......this keeps them quiet and depressed unless they can form some life while on them. Drugs is definitely not the answer. They need acceptance and confidence and acknowledgement. Cal mag and B vitamins really help.
Once argued with someone who said it was "reductive" to say that "genes are among the causes of risk of skin cancer." And at that point I gave up because at a certain point demands for further nuance just become a reason not to have thoughts.
Is there really a clear definition of "schizophrenia"? This was all very interesting -- no irony -- but without a clear definition of the supposed disease, talking about its "causes" seems somewhat beside the point.
I have a question: if schizophrenia is mostly genetic, then why is there so little evidence of it in ancient texts? (Whereas other mental illnesses are described in Greek and Roman sources etc.) Doesn't that suggest that there are factors new in the environment that cause it (perhaps in interactions with genes or recent gene mutations). As well, all twin studies are compromised by the shared womb and in the case of adoption, by shared adoption trauma, and while genes run in families, so do environmental factors, stress levels, nutritional factors, parenting styles, and intergenerational traumas.
From Iain McGilchrist (The Master and His Emissary, page 404):
"... schizophrenia has in fact increased in tandem with industrialization and modernity. In England, schizophrenia was rare indeed, if it existed at all, before the eighteenth century, but increased dramatically in prevalence with industrialization. Similar trends can be observed in Ireland, Italy, and the United States, and elsewhere ... What is beyond reasonable doubt, however, since it has been established by repeated research over at least half a century, is that schizophrenia increased pari passu with industrialization; that the form in which schizophrenia exists is more severe and has a clearly worse outcome in Western countries; and that, as recent research confirms, prevalence by country increases in proportion to the degree that the country is "developed", which in practice means Westernized. Descriptions of melancholia, or of manic-depressive (now called bipolar), are immediately recognizable in accounts from ancient Egypt, Greece and Rome, yet there are no descriptions of schizophrenia ... The relative risk of developing schizophrenia in an urban rather than a rural setting is nearly double, and the evidence suggests that is it more likely that the urban environment causes psychosis than that high-risk individuals migrate to urban areas."
I can't believe that you would reduce THE Ronald Fisher to a tobacco statistician. Back in the day it might have been a reasonable position to say that the causation hasn't been proven to a high degree of confidence. Just because it turned out to be true, doesn't mean it was wrong to caution against premature regulation!
> But age is certainly more than correlational with flu
Minor but: but your example is wrong. If you changed age and held everything else equal then you wouldn’t get the flu less. It’s because age is correlated with other health properties (like a weaker immune system) and you’re assuming these change too when you change age.
I haven’t read the Aftab post or Torrey paper, but it seems that something is being assumed at the outset of the arguments you’re responding to—and your responses to them—that hasn’t been established yet, as far as I’m aware; namely, that there are “genes that cause schizophrenia” (as stated in Argument 3). Has this actually been established?
I’m reading Chris Palmer’s book, Brain Energy and he has a chapter on genetics in which he claims that since the human genome project, we haven’t been able to find specific genes related to mental disorders, though researchers have tried very hard to do so. My understanding based on my reading of Palmer’s theory is that epigenetics—the turning on or off of genes that are mostly common in all of us—are what produce psychiatric symptoms when epigenetic regulators like mitochondria are defective. Interested in your (or anyone’s) thoughts on this, as well as the whole “mental illnesses are metabolic disorders of the brain” idea promoted by Palmer. After all, the satisfying nexus, or the thing that “all schizophrenia causes have in common” might be, according to this idea, mitochondrial dysregulation—which happens to be treatable by various methods, including (but not limited to) medication.
Thanks, from a schizoaffective with his illness in remission for 5 years!
You say "If cannabis really is involved in schizophrenia, it’s probably 1-3% of the variance - but nobody is entirely sure it’s involved"; Do you think that the risk of psychosis from cannabis use is currently exaggerated by the media? (E.g. perhaps https://www.usatoday.com/story/life/health-wellness/2024/01/31/what-is-cannabis-induced-psychosis-california-stabbing-reveals-dangers/72411293007/).
In my opinion, this all comes back to the irresponsible shirking of physical brain scans which we have the technology and enough information to do. It's frankly bureaucratic stupidity from my seat.
But if you want my wild stab, I think it's environment poisoning. Some persons are more inclined to sensitivity writ large. It's not necessarily a weakness toward anything, but all things. You can really see this in autism more clearly which is highly related to schizophrenia.
So causal things more apt to create disability would include, in no particular order, metal poisoning, mother stress, mother drugs, father age, heavy toxins/molds, toxin history of mother and father, nutrition, lack of natural sunlight, lack of functional digestion, metabolism dysregulation, working your body (mostly mother) in regularwork performance .. and yes, I'll risk it potentially even up to and including getting poked with a needle up to around age 2 or 3 in particular.
I think the second part to this that's even less understood is general resonance (sounds, light etc.) & DNA template creating thought patterns that work something not too disimilar but definitely unlike a motor bike dirt track. It's for this same reason children pick up on language and behavior they didn't explicitly learn, it's for the same reason we cannot pinpoint on a DNA chart where the pain is. for the same reason a person can have anomic aphasia and still 'mostly get it' though confusing the language interplay variables, for the same reason we aren't assigned implicit sexual interest, but 'tune in to it.' The same reason we can look at a composed work of music for instance created by an autistic and a non-autistic and can recognize the patterned thinking differences more clearly in some ways than with direct language interplay.
while I won't go so far as to say we 'feel everything' or just as silly 'we are our attitude' I will suggest these things play out, our genetic baseline of prerecorded bits of sequenced thinking jumbled from both parents, and our ability to react heathily over time.
"This is possible, but I think it’s false. We know many apparent risk factors for schizophrenia: cannabis use, birth canal asphyxia, social defeat, toxoplasma infection, poor prenatal nutrition. If you try to combine these into one big picture, it doesn’t work."
There's a theory that does: Cell Danger Response Theory by Robert Naviaux. All the above are related to over/under-engagement of the healing process in response to stress/trauma. He even lists toxo as a possible disorder from the CDR malfunctions. In short: When you have a chronic stressor in your life for over 6 months or of sufficient magnitude your body cannot complete the healing process and it gets stuck at one of 3 sequential stages. 1 Cell shutdown and hardening, 2 cell replication , 3 cell differentiation and establishment of connections to other cells.
As the 334th comment I expect this to get buried, but in any case there is a literature you may find helpful regarding the erotetic nature of explanation: We generally aren't explaining things in extreme specificity and/or extreme universality (a God's eye view). Instead, we are evidentially-limited beings with goals, and we choose the scope and granularity to explain something to a situated human for a specific purpose.
That provides a framework to understand the fact that the same question may have more than one answer. It also allows one to make systematic sense of why some causally-relevant factors are placed in the background rather than called "causes," and why the background and foreground can change.
We take the background for granted. Those conditions are "normal" while the thing we call the cause is the intrusion on the normal state, or a violation of the state we prefer (in other words "normal" can refer to frequency of occurrence or normative preference). The distinction between cause and background condition is often NOT in the modal logic of implication. It is rather based on our own interests and preferences about where to intervene to change things, or our preference for assigning responsibility/blame as agents.
Van Fraassen is typically presented as the classic argument for erotetic explanation. But I found Hart and Honore to be more eye-opening. If you've never read their work on causation and the law, I highly recommend it. A place to start: https://scholarship.law.vanderbilt.edu/cgi/viewcontent.cgi?article=3749&context=vlr
It had never occured to me that biology was sometimes easier to fix than environment...
Now it see it everywhere.
For example obesity is both a stigma and a medical condition surrounded by truckload of environmental (if not moral) advice and one a someone invents a drug that just fixes obesity and it is not a problem anymore
Are drugs not environmental?
I don’t think the cause | risk factor distinction is explained well using the language of necessary and sufficient conditions, but here’s an alternative:
Causes are events which lead to the dice rolling (for a given outcome to happen). A given cause doesn’t have to be the *only* way for the event to happen.
Risk factors influence the odds of the roll. Alternatively, risk factors can also refer to any change in the success criteria. Smoking causes lung cancer, but being a heavy smoker is also a risk factor for lung cancer because repeated rolling of the dice increases the probability that one will hit.
My gut says this definition is pretty close, but I’m concerned that (e.g.) smoking would, given a deep enough understanding of the underlying biomechanics, only be a risk factor. Maybe the more expert commenters can evaluate better.
I stumbled onto this Substack just today. I perceive many readers/commentators are way smarter than me. I only want to say, I had a terrible schizophrenic sister as well as a brother with bipolar disorder. None of this information was around forty years ago. My grandfather committed suicide (in his younger life he had electroshock therapy for severe depression). My dad wasn’t right but it was the 50’s and 60’s. I have considered these disorders hereditary based on my personal experience (and some reading). As a mom, I made sure my kids (now fine adults) knew what to look for if they felt/believed such and such. I wanted them to know our family history and be aware because it seems to me once the disease is in full swing, the patient becomes the proverbial ‘I’m not mentally ill’ person who is very hard to help. It’s a terrible burden I would advise for genetic testing when available.
“ You can never 100% prove a number with no assumptions.”
This is borderline Liars Paradox.