Tuesday, January 31, 2023

Comments by Scotoma

Showing 3 of 3 comments.

  • I guess I am making the argument that you say sounds unlikely, that one person has a lot of “schizophrenia genes”, many (or most) of which may be rare. I’m definitely not making the claim that schizophrenia is Mendelian, though looking at what I initially said, I can see how it could be construed that way, so I think it’s fair that you brought it up. I think the easiest way to make this more clear is to explain just how many rare variants an individual has. Each person has around 20,000 differences from the reference genome just in their genes, and they have around 2,000,000 differences when looking at the whole genome. If you just look at rare variants [present in <0.5% of the population], there are "130–400 non-synonymous variants per individual[protein coding changes], 10–20 LOF[loss-of-function] variants, and 2–5 damaging mutations"[ref 1]. Again, that's just in the coding sequence of genes and there could be many more functionally important changes in regulatory regions of the genome outside of genes. In fact, each person has 2000-10000 rare–less than 0.5 percent–changes at evolutionarily conserved positions throughout the genome, and GWAS only looks at variants present in 5 percent of the population. Which is missing a lot of rare genetic variation, some of which likely has functional effect. Now combine this with the very likely possibility that many genes contribute to schizophrenia, and you can see how these variants might be present in one person or family (or at least be rare) but still not be amenable to the family studies that are used for Mendialian disorders (like Cystic Fibrosis). Your parents could pass on several of these rare variants, but any given variant won’t necessarily track perfectly with the phenotype as it would for a Mendialian disorder. A related problem with GWAS is that you need a LOT of people to find variants with small effect sizes. We’re good at finding common variants with large effect sizes (with GWAS), and rare variants with huge effect sizes (Family studies for Mendialian traits), but we still have a lot of trouble finding rare variants with medium effect sizes. This is a huge, unexplored part of human genetic variation, so I think it’s premature (especially when taking into account twin studies) to say that these disorders are “fundamentally environmental conditions”. And if you think about it, why would a detrimental variant (one that contributes to schizophrenia) be present in more than 5% of the population? Of course the worst and likely causative variants will be at least somewhat rare. They aren’t great for fitness.

    Maybe there are a lot of schizophrenia genes, but they interact with each other and cluster in the same pathways. These pathways would still potentially be druggable. Current drugs do work much of the time for the positive symptoms of schizophrenia, but they usually don’t work for the negative symptoms and they have pretty bad side effects, so they are far from ideal. Regardless, I agree that pyschotherapy, social support, and open dialogue are very very important. I just don’t think the failures of GWAS should mean we stop looking for the genetic contributions to schizophrenia (as argued in this post).

    1 http://www.nature.com/nature/journal/v491/n7422/full/nature11632.html

  • Thanks for the link! I thought the article was interesting and well-written, and I think I agree that Twins Reared Apart (TRA) studies aren’t the best for assessing phenotypic heritability, precisely because they rely heavily on the assumption that all similarities between separated twins are due to genetics (isn’t that what we’re trying to measure? :D). The studies I mentioned are not TRA studies, and so this article does not apply to them. When the twins are raised together (not apart), the excess concordance rate in identical twins over fraternal twins is very likely due to genetics, as shared environment should contibute equally to the phenotypic variation in both identical and fraternal twin groups. The only caveat I can think of is if there were major socioeconomic differences between the group of identical twins and the group of fraternal twins (in which case the shared environment might preferentially affect one group over another). This can be controlled for. I’d be interested in seeing a similar critique for studies of twins reared together if you remember seeing one. Thanks!

  • I’m a little concerned that you’re taking the small amount of explained variation from GWAS as proof that genetics plays a small role in the disease. You should really, really read about twin studies. Looking at fraternal vs. identical twins, we can get very good estimates of how much of a disease is caused by genetics. Both fraternal and identical twins grow up in similar environments, so much of the environmental component in the comparison cancels out, but fraternal twins share 50% of their genes and identical twins share 100% of their genes. If identical twins share disease status more than fraternal twins, then at least some of it has to be genetic. The concordance rate in schizophrenia is higher in identical twins (40-60%) than in fraternal twins (10-20%) (Gottesman and Shields, 1982; Gottesman, 1991). This is how we know that roughly 80% of the risk of schizophrenia is genetic (NOT from GWAS, but from twin studies). That said, GWAS has been a disappointment. My guess is that this is because GWAS looks at common genetic variants. Probably most of the genetic variants that cause schizophrenia are super rare (like just in one family or one person even). GWAS studies don’t look for rare variants, so they haven’t found them. I’m not saying we don’t have free will, but messing with genes (deleting them, changing their sequence) WILL have an effect on you, and I don’t think it’s surprising that some genes are important for brain function.