I can't read the full Torrey article, but I'm confused by this and think it might reflect a misunderstanding of genetics.
It sounds like it's expecting there to be one gene which causes schizophrenia, which is no longer how people conceive of genetic conditions working (except a few very simple ones like sickle cell). Rather, there's some portion of the risk which is genetic (in schizophrenia, ~80%), distributed across hundreds or thousands of different genes (including the 300 Torrey mentions and others that we haven't found yet because their effect size is too small).
It's not correct to say that risk genes "play a role in the clinical expression of most diseases but do not cause the disease in the absence of other factors" , except insofar as no single risk gene causes it because you need many of them together.
Maybe Torrey addresses this in his article, but we don't need to speculate about whether schizophrenia is genetic or not - we can just use twin studies, which find that it mostly is. This doesn't mean there's no other factors that affect it, but it puts it firmly in the category of other mostly genetic things like height, which depends primarily on your parents' heights but can be affected by nutritional deficiencies, bone injuries and random embryological events.
Torrey's been pushing various weird infectious theories of schizophrenia for a long time, and confusing "there's no single gene that causes 100% of conditions" with "it's not mostly genetic" is a classic tactic for people who want to do this kind of thing - but although there's a little bit of residual variance for infections to explain, I honestly expected better of him and I'm surprised this argument made it into a journal in 2024.
Torrey does discuss heritability studies. I can email you the pdf if you like.
I think “heritability” gets misleading pretty fast. It’s an abstraction at the population level. Heritability is neither genetic causation nor is it proportion of risk applicable to an individual. Many conditions we don’t usually think of as “genetically caused” can show high heritability. Heritability estimates of COPD, eg, often reach 60%.
While 80% heritability sounds impressive, it’s sobering to look at actual numbers. Take Hilker et al, 2018 (https://www.sciencedirect.com/science/article/pii/S0006322317319054 ), a recent well-designed twin study of SZ using nationwide Danish register. They calculate a heritability of 79%, matching older estimates; they have a total of 81 monozygotic twin pairs in which someone has SZ: in 12 pairs both have SZ and in 69 pairs only one has SZ. If you are a monozygotic twin and you have SZ, there is only a 15% chance that both of you have SZ. The probandwise concordance rate of SZ is 33% in monozygotic twins and 7% in dizygotic twins. There is no way to explain this if SZ is 80% “caused by genetics.”
It gets trickier if we say that SZ is caused by thousands of genes of very tiny effect each. The more common variants there are, the greater the proportion of the population that will have them, but only 1% develop SZ and majority of them don’t have a family history of SZ. It’s clear that SZ is highly polygenic but the hundreds/thousands of genes involved appear to represent some sort of nonspecific vulnerability to psychopathology, rather than a causative link to SZ (a vulnerability that is neither necessary nor sufficient).
My impression is that most studies find twin concordance rates for SZ to be 40 - 50%.
I'm not sure of this, but I think in rare conditions, twin concordance rate should always be lower than heritability because of regression to the mean. That is, since schizophrenia is rare, we should expect the average person who gets it to have both a very poor roll of the genetic dice *and* a very poor roll of the environmental dice. That means that even if the genetic dice are more important, the average person who gets exactly the same roll of the genetic dice of a schizophrenic, but a random roll of the environmental dice, won't have schizophrenia.
You could do the same thing with environment - the average person who gets the exact same environment as a schizophrenic (whatever that means - not actually study-able) won't get schizophrenia, because they're genetically different. This wouldn't mean "it's not really environment, it's truly genetic and environment is only a 'risk factor'". It's just how variance works.
My impression is that the heritability of COPD is more like 30 - 40%, and that this is unsurprising - partly because everything is partly genetic, and partly because COPD is often caused by smoking and smoking status is partly genetic.
I agree that there's no clear distinction between "genetic disease" and "non-genetic disease" given that almost every disease has both sets of risk factors (including "purely genetic" diseases like sickle cell which have variable penetrance), but I think Torrey is doing an unfair thing of saying "So we all agree that means we can call the category all diseases are in 'non-genetic', and focus on the environmental factors", which we definitely can't.
40-50% concordance rate is the usual textbook figure, based on older studies with some methodological limitations (such as a selection bias towards twin pairs in which both have SZ); nationwide registries overcome some of those limitations.
What should count as a “genetic disorder” is not well defined. If you think any disorder with high heritability is a genetic disorder, sure, we can consider SZ a genetic disorder in that particular sense. But it remains the case that aside from rare variants, there are no common variants of large effect, most of these variants are nonspecific, and that these variants are not essential to develop SZ. They are more like risk factors. For any given person with SZ, they may have none or very few of these common variants or they may have a lot of them.
I don’t agree with Torrey about the infectious/environmental etiology part.
I don't know if we actually disagree or are just using different words, but I don't agree if by "risk factor" you mean something that "isn't the real cause".
Suppose someone got obese because they ate ten donuts a day for 5 years. If they'd only eaten donut #5000, and nothing else, they would not have gotten obese. So is donut #5000 a "cause" or a "risk factor" for their obesity? Is their donut-eating overall a"cause" or a "risk factor"? This is how I would think of arguments about whether X gene is a "cause" or a "risk factor" vs. whether the disease is genetic or not.
I think genetics (the aggregate genetic makeup) are a cause of schizophrenia in the same sense as cannabis use or childhood adversity are causes of schizophrenia. If by cause, we simply mean a shifting of probabilities, then these are all causes, but we don’t usually say that “schizophrenia is a disorder of cannabis use” or “schizophrenia is disorder of childhood adversity.” We can, if we want to, but I think whatever we choose, we should be consistent. The question is, is there something that privileges genetics as a factor to such a degree that we are justified in calling it a genetic disorder but not a disorder of adversity?
If someone has a family history of schizophrenia or if they have rare variants/CNVs with large effect, their risk is substantially increased. Even in such cases, the risk conferred to the individual is a small part of the causal story (less than 10% risk if you have a sibling with schizophrenia).
And that’s when we are talking about genetic influences in aggregate. If we start trying to pin down genes themselves, the degree of influence is less and less. SNP-heritability of Schizophrenia (SNP-h2), the heritability attributable to common variants in total (including unidentified) in most GWAS studies is estimated to be 0.20-0.30. (The gap between SNP-h2 and h2 based on twin studies, “the heritability gap” is common for behavioral phenotypes & there is a lot of fierce discussion of why the gap exists.)
When we look at the individual genes that we have identified, most of them are not specific to schizophrenia, which means we lose the specificity component of causality as well, and we have something more like a nonspecific vulnerability to psychopathology.
If we select an average person with schizophrenia in the population, someone without a family history of schizophrenia, we have no basis to tell them, “the bulk of your risk of schizophrenia comes from your genetics.” It’s just not true.
> "I think genetics (the aggregate genetic makeup) are a cause of schizophrenia in the same sense as cannabis use or childhood adversity are causes of schizophrenia. "
I think the difference between cannabis and genes is that cannabis probably explains ~1% of the variance, and genes explain ~80%. I agree this isn't a qualitative difference, it's just a very big quantitative one. I think a reasonable answer to "what causes schizophrenia?" is "it's mostly genetic, but other factors are also involved".
> "Even in such cases, the risk conferred to the individual is a small part of the causal story (less than 10% risk if you have a sibling with schizophrenia)."
Again, this is exactly what you would predict from a condition which is 80% genetic with a 1% prevalence. I'm trying to run some simulations of this which I can post if a friend confirms that I didn't massively screw them up.
> "And that’s when we are talking about genetic influences in aggregate. If we start trying to pin down genes themselves, the degree of influence is less and less. SNP-heritability of Schizophrenia (SNP-h2), the heritability attributable to common variants in total (including unidentified) in most GWAS studies is estimated to be 0.20-0.30. (The gap between SNP-h2 and h2 based on twin studies, “the heritability gap” is common for behavioral phenotypes & there is a lot of fierce discussion of why the gap exists.) "
My impression is that the gap is in exact proportion to how good a genetic analysis you do and how big your sample sizes are. We previously were only able to detect the few genes with huge effects, and the gap seemed huge. Now we're able to also detect the genes with medium effects, and the gap seems medium sized. I see no reason not to think that when we can detect all relevant genes, the gap will disappear entirely. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611648/ has done some clever work that closes most of the gap, although he thinks a little bit might still remain, but for some of the reasons discussed at https://www.reddit.com/r/heredity/comments/97hmji/relatedness_disequilibrium_regression_estimates/ I think probably there is no remaining gap once your techniques are good enough. Either way, I think even if Young's skepticism is right there's no way schizophrenia ends up < 50% genetic.
> "When we look at the individual genes that we have identified, most of them are not specific to schizophrenia, which means we lose the specificity component of causality as well, and we have something more like a nonspecific vulnerability to psychopathology."
Most of the contribution to psych diseases, both genetic and environmental (eg trauma, low SES, etc) comes via the general factor of psychopathology. It's not even clear that there's a real-world distinction between the different psychoses, so it's not surprising that it's hard to find this genetically. My guess is that almost all variance (both genetic and environmental) will contribute to general psychopathology, with a small amount of it determining which specific kind of psychopathology it gets expressed as. I don't find specificity too philosophically interesting - eating donuts causes not just obesity, but also diabetes, heart disease, strokes, cancer, etc - I don't think that makes it any less of a real cause of obesity. Smoking causes dozens of different problems but is reasonably considered a cause of all of them.
> "If we select an average person with schizophrenia in the population, someone without a family history of schizophrenia, we have no basis to tell them, 'the bulk of your risk of schizophrenia comes from your genetics.' It’s just not true."
I'm not sure what you're basing this on, given the high heritability estimates and lack of any reason to think anything else is higher.
Some people in the mental health field really get so hung up on the long game that they become positively hostile to doing what we can here and now. Like, people who are totally opposed to offering any kind of medication-free treatment. They're all like psychosis is in the brain, pure talk therapies were a failed nineteen sixties experiment that we shouldn't repeat, we just gotta do more brain research and make better meds.
Ok. But here and now, there are a substantial portion of people who are "non-responders", or who can't find any medication with tolerable side-effects. So what should we do with that group here and now? Try to find alternative approaches that at least HELPS, even if no one believes anymore that you can sit down and talk about your mother for a hundred hours and then you turn normal? Or should we just tell them to be patient and wait for some future scientific breakthrough that may or may not come?
I can't read the full Torrey article, but I'm confused by this and think it might reflect a misunderstanding of genetics.
It sounds like it's expecting there to be one gene which causes schizophrenia, which is no longer how people conceive of genetic conditions working (except a few very simple ones like sickle cell). Rather, there's some portion of the risk which is genetic (in schizophrenia, ~80%), distributed across hundreds or thousands of different genes (including the 300 Torrey mentions and others that we haven't found yet because their effect size is too small).
It's not correct to say that risk genes "play a role in the clinical expression of most diseases but do not cause the disease in the absence of other factors" , except insofar as no single risk gene causes it because you need many of them together.
Maybe Torrey addresses this in his article, but we don't need to speculate about whether schizophrenia is genetic or not - we can just use twin studies, which find that it mostly is. This doesn't mean there's no other factors that affect it, but it puts it firmly in the category of other mostly genetic things like height, which depends primarily on your parents' heights but can be affected by nutritional deficiencies, bone injuries and random embryological events.
Torrey's been pushing various weird infectious theories of schizophrenia for a long time, and confusing "there's no single gene that causes 100% of conditions" with "it's not mostly genetic" is a classic tactic for people who want to do this kind of thing - but although there's a little bit of residual variance for infections to explain, I honestly expected better of him and I'm surprised this argument made it into a journal in 2024.
Torrey does discuss heritability studies. I can email you the pdf if you like.
I think “heritability” gets misleading pretty fast. It’s an abstraction at the population level. Heritability is neither genetic causation nor is it proportion of risk applicable to an individual. Many conditions we don’t usually think of as “genetically caused” can show high heritability. Heritability estimates of COPD, eg, often reach 60%.
While 80% heritability sounds impressive, it’s sobering to look at actual numbers. Take Hilker et al, 2018 (https://www.sciencedirect.com/science/article/pii/S0006322317319054 ), a recent well-designed twin study of SZ using nationwide Danish register. They calculate a heritability of 79%, matching older estimates; they have a total of 81 monozygotic twin pairs in which someone has SZ: in 12 pairs both have SZ and in 69 pairs only one has SZ. If you are a monozygotic twin and you have SZ, there is only a 15% chance that both of you have SZ. The probandwise concordance rate of SZ is 33% in monozygotic twins and 7% in dizygotic twins. There is no way to explain this if SZ is 80% “caused by genetics.”
It gets trickier if we say that SZ is caused by thousands of genes of very tiny effect each. The more common variants there are, the greater the proportion of the population that will have them, but only 1% develop SZ and majority of them don’t have a family history of SZ. It’s clear that SZ is highly polygenic but the hundreds/thousands of genes involved appear to represent some sort of nonspecific vulnerability to psychopathology, rather than a causative link to SZ (a vulnerability that is neither necessary nor sufficient).
My impression is that most studies find twin concordance rates for SZ to be 40 - 50%.
I'm not sure of this, but I think in rare conditions, twin concordance rate should always be lower than heritability because of regression to the mean. That is, since schizophrenia is rare, we should expect the average person who gets it to have both a very poor roll of the genetic dice *and* a very poor roll of the environmental dice. That means that even if the genetic dice are more important, the average person who gets exactly the same roll of the genetic dice of a schizophrenic, but a random roll of the environmental dice, won't have schizophrenia.
You could do the same thing with environment - the average person who gets the exact same environment as a schizophrenic (whatever that means - not actually study-able) won't get schizophrenia, because they're genetically different. This wouldn't mean "it's not really environment, it's truly genetic and environment is only a 'risk factor'". It's just how variance works.
My impression is that the heritability of COPD is more like 30 - 40%, and that this is unsurprising - partly because everything is partly genetic, and partly because COPD is often caused by smoking and smoking status is partly genetic.
I agree that there's no clear distinction between "genetic disease" and "non-genetic disease" given that almost every disease has both sets of risk factors (including "purely genetic" diseases like sickle cell which have variable penetrance), but I think Torrey is doing an unfair thing of saying "So we all agree that means we can call the category all diseases are in 'non-genetic', and focus on the environmental factors", which we definitely can't.
40-50% concordance rate is the usual textbook figure, based on older studies with some methodological limitations (such as a selection bias towards twin pairs in which both have SZ); nationwide registries overcome some of those limitations.
What should count as a “genetic disorder” is not well defined. If you think any disorder with high heritability is a genetic disorder, sure, we can consider SZ a genetic disorder in that particular sense. But it remains the case that aside from rare variants, there are no common variants of large effect, most of these variants are nonspecific, and that these variants are not essential to develop SZ. They are more like risk factors. For any given person with SZ, they may have none or very few of these common variants or they may have a lot of them.
I don’t agree with Torrey about the infectious/environmental etiology part.
I don't know if we actually disagree or are just using different words, but I don't agree if by "risk factor" you mean something that "isn't the real cause".
Suppose someone got obese because they ate ten donuts a day for 5 years. If they'd only eaten donut #5000, and nothing else, they would not have gotten obese. So is donut #5000 a "cause" or a "risk factor" for their obesity? Is their donut-eating overall a"cause" or a "risk factor"? This is how I would think of arguments about whether X gene is a "cause" or a "risk factor" vs. whether the disease is genetic or not.
I think genetics (the aggregate genetic makeup) are a cause of schizophrenia in the same sense as cannabis use or childhood adversity are causes of schizophrenia. If by cause, we simply mean a shifting of probabilities, then these are all causes, but we don’t usually say that “schizophrenia is a disorder of cannabis use” or “schizophrenia is disorder of childhood adversity.” We can, if we want to, but I think whatever we choose, we should be consistent. The question is, is there something that privileges genetics as a factor to such a degree that we are justified in calling it a genetic disorder but not a disorder of adversity?
If someone has a family history of schizophrenia or if they have rare variants/CNVs with large effect, their risk is substantially increased. Even in such cases, the risk conferred to the individual is a small part of the causal story (less than 10% risk if you have a sibling with schizophrenia).
And that’s when we are talking about genetic influences in aggregate. If we start trying to pin down genes themselves, the degree of influence is less and less. SNP-heritability of Schizophrenia (SNP-h2), the heritability attributable to common variants in total (including unidentified) in most GWAS studies is estimated to be 0.20-0.30. (The gap between SNP-h2 and h2 based on twin studies, “the heritability gap” is common for behavioral phenotypes & there is a lot of fierce discussion of why the gap exists.)
When we look at the individual genes that we have identified, most of them are not specific to schizophrenia, which means we lose the specificity component of causality as well, and we have something more like a nonspecific vulnerability to psychopathology.
If we select an average person with schizophrenia in the population, someone without a family history of schizophrenia, we have no basis to tell them, “the bulk of your risk of schizophrenia comes from your genetics.” It’s just not true.
> "I think genetics (the aggregate genetic makeup) are a cause of schizophrenia in the same sense as cannabis use or childhood adversity are causes of schizophrenia. "
I think the difference between cannabis and genes is that cannabis probably explains ~1% of the variance, and genes explain ~80%. I agree this isn't a qualitative difference, it's just a very big quantitative one. I think a reasonable answer to "what causes schizophrenia?" is "it's mostly genetic, but other factors are also involved".
> "Even in such cases, the risk conferred to the individual is a small part of the causal story (less than 10% risk if you have a sibling with schizophrenia)."
Again, this is exactly what you would predict from a condition which is 80% genetic with a 1% prevalence. I'm trying to run some simulations of this which I can post if a friend confirms that I didn't massively screw them up.
> "And that’s when we are talking about genetic influences in aggregate. If we start trying to pin down genes themselves, the degree of influence is less and less. SNP-heritability of Schizophrenia (SNP-h2), the heritability attributable to common variants in total (including unidentified) in most GWAS studies is estimated to be 0.20-0.30. (The gap between SNP-h2 and h2 based on twin studies, “the heritability gap” is common for behavioral phenotypes & there is a lot of fierce discussion of why the gap exists.) "
My impression is that the gap is in exact proportion to how good a genetic analysis you do and how big your sample sizes are. We previously were only able to detect the few genes with huge effects, and the gap seemed huge. Now we're able to also detect the genes with medium effects, and the gap seems medium sized. I see no reason not to think that when we can detect all relevant genes, the gap will disappear entirely. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611648/ has done some clever work that closes most of the gap, although he thinks a little bit might still remain, but for some of the reasons discussed at https://www.reddit.com/r/heredity/comments/97hmji/relatedness_disequilibrium_regression_estimates/ I think probably there is no remaining gap once your techniques are good enough. Either way, I think even if Young's skepticism is right there's no way schizophrenia ends up < 50% genetic.
> "When we look at the individual genes that we have identified, most of them are not specific to schizophrenia, which means we lose the specificity component of causality as well, and we have something more like a nonspecific vulnerability to psychopathology."
Most of the contribution to psych diseases, both genetic and environmental (eg trauma, low SES, etc) comes via the general factor of psychopathology. It's not even clear that there's a real-world distinction between the different psychoses, so it's not surprising that it's hard to find this genetically. My guess is that almost all variance (both genetic and environmental) will contribute to general psychopathology, with a small amount of it determining which specific kind of psychopathology it gets expressed as. I don't find specificity too philosophically interesting - eating donuts causes not just obesity, but also diabetes, heart disease, strokes, cancer, etc - I don't think that makes it any less of a real cause of obesity. Smoking causes dozens of different problems but is reasonably considered a cause of all of them.
> "If we select an average person with schizophrenia in the population, someone without a family history of schizophrenia, we have no basis to tell them, 'the bulk of your risk of schizophrenia comes from your genetics.' It’s just not true."
I'm not sure what you're basing this on, given the high heritability estimates and lack of any reason to think anything else is higher.
Some people in the mental health field really get so hung up on the long game that they become positively hostile to doing what we can here and now. Like, people who are totally opposed to offering any kind of medication-free treatment. They're all like psychosis is in the brain, pure talk therapies were a failed nineteen sixties experiment that we shouldn't repeat, we just gotta do more brain research and make better meds.
Ok. But here and now, there are a substantial portion of people who are "non-responders", or who can't find any medication with tolerable side-effects. So what should we do with that group here and now? Try to find alternative approaches that at least HELPS, even if no one believes anymore that you can sit down and talk about your mother for a hundred hours and then you turn normal? Or should we just tell them to be patient and wait for some future scientific breakthrough that may or may not come?