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 …
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.
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.