.I don't think this is anything too different from what I said in my post.
All genes are genes for something. Therefore, all genetic conditions will be conditions where the genes cause something that cause the disorder.
The two examples I gave were that cystic fibrosis, a classic genetic disease, is also a disease of lung mucus. And that if there were some virus where likelihood of getting it was 100% genetic, it would look like a 100% genetic condition.
I described this a bit in Argument 6B, "Genes could just be a proxy for some more satisfying cause of schizophrenia", and partly in the subsequent Open Thread, where I said that "part of my argument is that there may never be a satisfying unitary story of schizophrenia (any more than there will be a satisfying unitary story of what causes kidney disease), so instead of treating genes as the IOU for the satisfying story downstream of the genes, we should just go with the genes."
In terms of the schizotypy connection, the paper you cite finds many detrimental facets of negative schizotypy, but beneficial aspects of positive schizotypy (some of which I'm not impressed by; they seem to be things like "if they're in a cult, they're happier with the cult" and "sometimes the hallucinations say nice things to them"). But my impression is that in general, negative schizotypy is genetically correlated with schizophrenia, but positive schizotypy mostly isn't. See eg https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2015.00143/full
"While positive schizotypy is the underlying dimension explaining psychotic features, it is not necessarily related to Krankheitswert. Negative schizotypy, however, appears closely related to schizophrenia regarding its heritability"
"These results provide genetic evidence in support of the spectrum model of schizophrenia, and support the view that negative and disorganised symptoms may have greater genetic basis than positive symptoms, making them better indices of familial liability to schizophrenia"...We further note that the association of SCZ PRS with only the negative dimension of schizotypy is in agreement with previous epidemiological findings that show familial predisposition to SCZ in the relatives of probands without a history of a psychotic episode is likely to be better indexed by the negative symptoms."
A simpler test of your thesis is whether schizophrenia risk is associated with creativity directly. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4590283/ looks at this and finds yes, but weakly. Given the polygenic scoring ability we actually have, someone in the 99.9th percentile of schizophrenia risk is about 0.2 percentage points more likely to have a creative job than someone at the median. Given hypothetical perfect scoring ability, it's 1.75 pp (these look larger as relative effects, 20% and 175% respectively). I'm not sure how much this actually reflects increased creativity compared to less suitability for other jobs and/or more interest in creative ones. I think profession in this study was something like self-rated; there are lots of schizophrenic-seeming people who think they're musicians, artists, and writers; but fewer who have convinced others.
It's implausible that any substantial portion of the population will be selected for low schizophrenia risk, because even if everyone in the population opts for polygenic selection, most people will be selecting for other things like low diabetes risk or whatever. The people most likely to select for low schizophrenia risk would be people in families with high likelihood of schizophrenia, or people who incidentally notice that one of their eggs has very high schizophrenia risk.
So the way I would think about this is that now when polygenic scores are weak, given the weak schizophrenia->creativity correlation, nothing we do to imputed schizophrenia risk can affect creativity much. Later, when polygenic scores are strong, we'll be able to identify embryos at very high risk to actually get schizophrenia, without lowering overall risk significantly on a population-wide level (and in fact we won't want to, since if the kid probably won't get schizophrenia we'd rather use that selection ability to prevent heart attacks or whatever).
"But my impression is that in general, negative schizotypy is genetically correlated with schizophrenia, but positive schizotypy mostly isn't."
The big problem for most of this stuff, including both linked studies, is it has a "negative/disorganised" dimension. That doesn't seem to be what schizotypy looks like (i.e. disorganised is a third axis from positive/negative). Now, what disorganised schizotypy *is* is a bigger question. It's probably not something very common in the general population, compared to the other two. Attempts at constructing disorganized-ST axises pull up all sorts of probably-different things, including oddness, low conscientiousness, and anxiety.
If we take the best possible definition of disorganised schizotypy, we probably end up with something like "subclinical thought disorder", or maybe "thought disorder in the absence of clear psychosis" (subtle distinctions). This is importantly different to negative schizotypy! I'm skeptical that if you perfectly separate the "negative" and "disorganised" signals, you end up with the strong negative-PRS connection reported when conflating them. Negative schizotypy is agonizingly nonspecific in ways everyone complains about constantly. It also seems to be genuinely-not-good, but at times in a way that shades into "that's perfectly acceptable population variance and you shouldn't select against it" ("do you prefer to be alone?").
Is disorganised schizotypy associated with anything interesting/good/positive? Well, it remains super-hard to measure, but arguably. https://peerj.com/articles/5615/ discusses how the O-LIFE's cognitive disorganisation (not great, but the most popular one we have) relates to multiple forms of creativity and accomplishment, particularly when controlling for sleep disorders (which are common in schizospec populations and impair all those things). Anecdotally, "mild thought disorder is associated with beneficial/interesting things when harnessed properly" checks out. "When harnessed properly" is doing *some work there*.
So, I don't think the "positive/negative" dichotomy as presented by these studies works (I intentionally stepped around it in this piece). Note in particular what the second study you linked (Ahangari et al., 2023) uses for its "negative/disorganised" dimension -- it seems to be using the exact STPD criteria in a yes/no sense, and it categorizes all the "oddness" things as "negative", as well as "suspiciousness and paranoid ideation"! ("Excessive social anxiety", meanwhile, got labelled "positive".) I think the oddness and suspiciousness domains *will* uniquely predict schizophrenia PRS, no matter what you call them. I don't think affect or isolation will, because those (like all negative schizotypy) load on So Many Things.
"It's implausible that any substantial portion of the population will be selected for low schizophrenia risk, because even if everyone in the population opts for polygenic selection, most people will be selecting for other things like low diabetes risk or whatever."
I agree this is hopefully true in a real-world environment, but I'm concerned about what real-world environments actually look like. People seem to say pretty absurd things when you ask them what they want to screen for (there's this one I encountered once and have constantly tried to find again where, supposedly, preventing alcohol flush is self-reported high-priority for Chinese parents). People seem scared of potential cognitive-broadly-construed problems in a somewhat unique way, especially when they're presented terribly by practitioners, which is...a very serious risk. (An interesting rabbit hole here is sex chromosome aneuploidies, which are strikingly common, almost never diagnosed, and increasingly-often found by coincidence in prenatal testing. The abortion rates for Turner's and Klinefelter's are "majority". For trisomy X and XYY, which are sex-concordant/don't involve the scary-sounding-to-people-who-don't-understand-chromosomes component of an "extra-X male" or "missing-X female", they're somewhere around a significant minority. Much of the research we have on this, for the trisomies (which lack the Turner's miscarriage risk), implies this is largely from practitioners who barely understand SCAs and tell the parents horror stories. People are not good at *not* telling horror stories about the schizospec.)
"Given the polygenic scoring ability we actually have, someone in the 99.9th percentile of schizophrenia risk is about 0.2 percentage points more likely to have a creative job than someone at the median"
I agree these are pretty weak *absolute* effects (not many people are in creative jobs)/that there are a lot more complicated elements involved. I think this loads in a large part on the heterogeneity of what we call "schizophrenia genes", i.e. they include schizotypy genes/intelligence genes/"true schizophrenia genes"/200 other things. (I wish we had more "schizotypal PD PRS"-type stuff.) I'm intentionally trying not to say too hard that the benefit is "schizotypy = creativity" -- I think it's a more complex group of things that include many things we think of as creativity, and many other things. One big handicap here is we don't have great ways of measuring personality (I think you've talked about this before re. Openness) -- a lot of the colloquial connection seems to be mediated through Openness or facets of it, and there's an apparent correlation between positive non-psychotic schizotypy and Openness, but we don't have anything like a true OQ test normed as well as e.g. IQ tests.
"All genes are genes for something. Therefore, all genetic conditions will be conditions where the genes cause something that cause the disorder."
I agree, but I think there are important subtle distinctions here. This might be a gap between "what people read when they understand the subtext of something" and "what people in the general, or even slightly-broader-than-absolute-core, population read". There are tricky detailed implications to things "being genetic". TBI is clearly, in an important sense, genetic. Autism is also clearly so. There are...differences...between TBI and autism. "Which is schizophrenia more like?" is an important question, and people will tend to parse "schizophrenia is a genetic disorder", without context, as "schizophrenia is like autism in this sense". (We are ignoring for simplicity purposes "ah, so it's caused by vaccines!" et al.)
But what I don't agree with is the "IOU for a more satisfying cause" thing. I agree there's probably no "more satisfying cause", in any simple sense. We clearly aren't dealing with a TBI-equivalent, where some magickal blinding is missing a blatant environmental cause for all cases (well, could we tell if we were?). I think the truth is schizotypy + other genetic vulnerabilities (intelligence, ?other?) + true-environment, in some complex and inequal mix where you can never and will never predict the "cause" of an individual, and that this is the unsatisfying cause we'll have to deal with. I think going with "it's a genetic disorder, or caused by genes, or mostly genetic" is itself part of that retreating-to-a-satisfying-cause issue. It provides particular solutions that seem beneficial, until you see a control group for what it means to have "genes for something". I think this distinction is lost on most people until they actively compare the control group. The distinctions are real subtle, but a lot turns on them.
(Can you tell how much I wish we studied schizotypy-for-its-own-sake more?)
Of these, I think the first is most important to schizophrenia PRS itself -- the ways we study schizotypy-for-its-own-sake tend to sideline disorganisation a lot, and lump it vaguely into negativity even when there's something very wrong there (like considering oddness and suspiciousness "negative schizotypy"). This is understandable in the context that mild thought disorder is probably not very common in a truly "control" sample (of all three axises, it's probably the most likely to get someone saying "huh, this guy is weird, diagnose him with something"). There are...things to say here about healthy-volunteer-bias type problems. The last is most important re. the complex world that is Science Communication. I don't think there are actually large disagreements on the *facts* between any given person talking about this -- well, except Torrey, but Torrey is sui generis. The devil is in the details.
As a clinician who does a lot of work with folks with first episode psychosis, I feel the need to second the sentiment about the disorganized axis of schizotypy being quite distinctive. It's quite striking when I meet the first degree relative of one of my more thought-disordered patients and it becomes clear very quickly that although they are just never, ever going to be able to give me a linear narrative about anything.
.I don't think this is anything too different from what I said in my post.
All genes are genes for something. Therefore, all genetic conditions will be conditions where the genes cause something that cause the disorder.
The two examples I gave were that cystic fibrosis, a classic genetic disease, is also a disease of lung mucus. And that if there were some virus where likelihood of getting it was 100% genetic, it would look like a 100% genetic condition.
I described this a bit in Argument 6B, "Genes could just be a proxy for some more satisfying cause of schizophrenia", and partly in the subsequent Open Thread, where I said that "part of my argument is that there may never be a satisfying unitary story of schizophrenia (any more than there will be a satisfying unitary story of what causes kidney disease), so instead of treating genes as the IOU for the satisfying story downstream of the genes, we should just go with the genes."
In terms of the schizotypy connection, the paper you cite finds many detrimental facets of negative schizotypy, but beneficial aspects of positive schizotypy (some of which I'm not impressed by; they seem to be things like "if they're in a cult, they're happier with the cult" and "sometimes the hallucinations say nice things to them"). But my impression is that in general, negative schizotypy is genetically correlated with schizophrenia, but positive schizotypy mostly isn't. See eg https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2015.00143/full
"While positive schizotypy is the underlying dimension explaining psychotic features, it is not necessarily related to Krankheitswert. Negative schizotypy, however, appears closely related to schizophrenia regarding its heritability"
...and https://www.cambridge.org/core/services/aop-cambridge-core/content/view/47381AEC2205356A81390D3D214CF4B9/S0007125022001799a.pdf/relationship_between_polygenic_risk_scores_and_symptom_dimensions_of_schizophrenia_and_schizotypy_in_multiplex_families_with_schizophrenia.pdf
"These results provide genetic evidence in support of the spectrum model of schizophrenia, and support the view that negative and disorganised symptoms may have greater genetic basis than positive symptoms, making them better indices of familial liability to schizophrenia"...We further note that the association of SCZ PRS with only the negative dimension of schizotypy is in agreement with previous epidemiological findings that show familial predisposition to SCZ in the relatives of probands without a history of a psychotic episode is likely to be better indexed by the negative symptoms."
A simpler test of your thesis is whether schizophrenia risk is associated with creativity directly. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4590283/ looks at this and finds yes, but weakly. Given the polygenic scoring ability we actually have, someone in the 99.9th percentile of schizophrenia risk is about 0.2 percentage points more likely to have a creative job than someone at the median. Given hypothetical perfect scoring ability, it's 1.75 pp (these look larger as relative effects, 20% and 175% respectively). I'm not sure how much this actually reflects increased creativity compared to less suitability for other jobs and/or more interest in creative ones. I think profession in this study was something like self-rated; there are lots of schizophrenic-seeming people who think they're musicians, artists, and writers; but fewer who have convinced others.
It's implausible that any substantial portion of the population will be selected for low schizophrenia risk, because even if everyone in the population opts for polygenic selection, most people will be selecting for other things like low diabetes risk or whatever. The people most likely to select for low schizophrenia risk would be people in families with high likelihood of schizophrenia, or people who incidentally notice that one of their eggs has very high schizophrenia risk.
So the way I would think about this is that now when polygenic scores are weak, given the weak schizophrenia->creativity correlation, nothing we do to imputed schizophrenia risk can affect creativity much. Later, when polygenic scores are strong, we'll be able to identify embryos at very high risk to actually get schizophrenia, without lowering overall risk significantly on a population-wide level (and in fact we won't want to, since if the kid probably won't get schizophrenia we'd rather use that selection ability to prevent heart attacks or whatever).
(no particular order)
"But my impression is that in general, negative schizotypy is genetically correlated with schizophrenia, but positive schizotypy mostly isn't."
The big problem for most of this stuff, including both linked studies, is it has a "negative/disorganised" dimension. That doesn't seem to be what schizotypy looks like (i.e. disorganised is a third axis from positive/negative). Now, what disorganised schizotypy *is* is a bigger question. It's probably not something very common in the general population, compared to the other two. Attempts at constructing disorganized-ST axises pull up all sorts of probably-different things, including oddness, low conscientiousness, and anxiety.
If we take the best possible definition of disorganised schizotypy, we probably end up with something like "subclinical thought disorder", or maybe "thought disorder in the absence of clear psychosis" (subtle distinctions). This is importantly different to negative schizotypy! I'm skeptical that if you perfectly separate the "negative" and "disorganised" signals, you end up with the strong negative-PRS connection reported when conflating them. Negative schizotypy is agonizingly nonspecific in ways everyone complains about constantly. It also seems to be genuinely-not-good, but at times in a way that shades into "that's perfectly acceptable population variance and you shouldn't select against it" ("do you prefer to be alone?").
Is disorganised schizotypy associated with anything interesting/good/positive? Well, it remains super-hard to measure, but arguably. https://peerj.com/articles/5615/ discusses how the O-LIFE's cognitive disorganisation (not great, but the most popular one we have) relates to multiple forms of creativity and accomplishment, particularly when controlling for sleep disorders (which are common in schizospec populations and impair all those things). Anecdotally, "mild thought disorder is associated with beneficial/interesting things when harnessed properly" checks out. "When harnessed properly" is doing *some work there*.
So, I don't think the "positive/negative" dichotomy as presented by these studies works (I intentionally stepped around it in this piece). Note in particular what the second study you linked (Ahangari et al., 2023) uses for its "negative/disorganised" dimension -- it seems to be using the exact STPD criteria in a yes/no sense, and it categorizes all the "oddness" things as "negative", as well as "suspiciousness and paranoid ideation"! ("Excessive social anxiety", meanwhile, got labelled "positive".) I think the oddness and suspiciousness domains *will* uniquely predict schizophrenia PRS, no matter what you call them. I don't think affect or isolation will, because those (like all negative schizotypy) load on So Many Things.
"It's implausible that any substantial portion of the population will be selected for low schizophrenia risk, because even if everyone in the population opts for polygenic selection, most people will be selecting for other things like low diabetes risk or whatever."
I agree this is hopefully true in a real-world environment, but I'm concerned about what real-world environments actually look like. People seem to say pretty absurd things when you ask them what they want to screen for (there's this one I encountered once and have constantly tried to find again where, supposedly, preventing alcohol flush is self-reported high-priority for Chinese parents). People seem scared of potential cognitive-broadly-construed problems in a somewhat unique way, especially when they're presented terribly by practitioners, which is...a very serious risk. (An interesting rabbit hole here is sex chromosome aneuploidies, which are strikingly common, almost never diagnosed, and increasingly-often found by coincidence in prenatal testing. The abortion rates for Turner's and Klinefelter's are "majority". For trisomy X and XYY, which are sex-concordant/don't involve the scary-sounding-to-people-who-don't-understand-chromosomes component of an "extra-X male" or "missing-X female", they're somewhere around a significant minority. Much of the research we have on this, for the trisomies (which lack the Turner's miscarriage risk), implies this is largely from practitioners who barely understand SCAs and tell the parents horror stories. People are not good at *not* telling horror stories about the schizospec.)
"Given the polygenic scoring ability we actually have, someone in the 99.9th percentile of schizophrenia risk is about 0.2 percentage points more likely to have a creative job than someone at the median"
I agree these are pretty weak *absolute* effects (not many people are in creative jobs)/that there are a lot more complicated elements involved. I think this loads in a large part on the heterogeneity of what we call "schizophrenia genes", i.e. they include schizotypy genes/intelligence genes/"true schizophrenia genes"/200 other things. (I wish we had more "schizotypal PD PRS"-type stuff.) I'm intentionally trying not to say too hard that the benefit is "schizotypy = creativity" -- I think it's a more complex group of things that include many things we think of as creativity, and many other things. One big handicap here is we don't have great ways of measuring personality (I think you've talked about this before re. Openness) -- a lot of the colloquial connection seems to be mediated through Openness or facets of it, and there's an apparent correlation between positive non-psychotic schizotypy and Openness, but we don't have anything like a true OQ test normed as well as e.g. IQ tests.
"All genes are genes for something. Therefore, all genetic conditions will be conditions where the genes cause something that cause the disorder."
I agree, but I think there are important subtle distinctions here. This might be a gap between "what people read when they understand the subtext of something" and "what people in the general, or even slightly-broader-than-absolute-core, population read". There are tricky detailed implications to things "being genetic". TBI is clearly, in an important sense, genetic. Autism is also clearly so. There are...differences...between TBI and autism. "Which is schizophrenia more like?" is an important question, and people will tend to parse "schizophrenia is a genetic disorder", without context, as "schizophrenia is like autism in this sense". (We are ignoring for simplicity purposes "ah, so it's caused by vaccines!" et al.)
But what I don't agree with is the "IOU for a more satisfying cause" thing. I agree there's probably no "more satisfying cause", in any simple sense. We clearly aren't dealing with a TBI-equivalent, where some magickal blinding is missing a blatant environmental cause for all cases (well, could we tell if we were?). I think the truth is schizotypy + other genetic vulnerabilities (intelligence, ?other?) + true-environment, in some complex and inequal mix where you can never and will never predict the "cause" of an individual, and that this is the unsatisfying cause we'll have to deal with. I think going with "it's a genetic disorder, or caused by genes, or mostly genetic" is itself part of that retreating-to-a-satisfying-cause issue. It provides particular solutions that seem beneficial, until you see a control group for what it means to have "genes for something". I think this distinction is lost on most people until they actively compare the control group. The distinctions are real subtle, but a lot turns on them.
(Can you tell how much I wish we studied schizotypy-for-its-own-sake more?)
Of these, I think the first is most important to schizophrenia PRS itself -- the ways we study schizotypy-for-its-own-sake tend to sideline disorganisation a lot, and lump it vaguely into negativity even when there's something very wrong there (like considering oddness and suspiciousness "negative schizotypy"). This is understandable in the context that mild thought disorder is probably not very common in a truly "control" sample (of all three axises, it's probably the most likely to get someone saying "huh, this guy is weird, diagnose him with something"). There are...things to say here about healthy-volunteer-bias type problems. The last is most important re. the complex world that is Science Communication. I don't think there are actually large disagreements on the *facts* between any given person talking about this -- well, except Torrey, but Torrey is sui generis. The devil is in the details.
As a clinician who does a lot of work with folks with first episode psychosis, I feel the need to second the sentiment about the disorganized axis of schizotypy being quite distinctive. It's quite striking when I meet the first degree relative of one of my more thought-disordered patients and it becomes clear very quickly that although they are just never, ever going to be able to give me a linear narrative about anything.