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Thank you for another educational and thought-provoking article. Dr. Gusev notes, “for schizophrenia, which was thought to be largely genetic, the most we can expect from a common variant polygenic score is an accuracy (R-squared) of ~0.24, with the current score reaching about a third of that (Trubetskoy et al. 2022).” But if the phenotype we call schizophrenia is really a wide spectrum of disorders with similar symptoms, might the R-squared be higher if we identify the different conditions that we today broadly call schizophrenia and look at them separately?

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Yes, absolutely, and there are major efforts to identify disease "subtypes" that are individually more heritable than the whole.

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Dec 15
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Examples would be addressing substance use (eg avoiding cannabis), optimising psychosocial functioning (eg employment/educational support), monitoring of mental state for development of frank psychosis (so treatment can be initiated promptly). This is the current model of managing at risk mental state for psychosis.

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Dec 15
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In my experience, the psychiatric genetics organizations take unintended consequences very seriously. See (https://pgc.unc.edu/for-the-public/genetic-testing/) on genetic testing / prediction, (https://pgc.unc.edu/for-the-public/stigma/) on stigma, (https://www.youtube.com/watch?v=yltzRp6hX-E) on gene-environment interplay and complexity, etc.

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Valid concerns! I’ve written critically about early intervention in psychosis https://rationalpsychiatry.substack.com/p/early-intervention-in-psychosis

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Our child’s psychosis became apparent to us when she was merely 6 years old. She* told me about an event in her first-grade classroom where she saw skulls floating near the ceiling, and then a dragon swinging its tail at the homes of villagers who lived on a mountain. She said she wanted to help, but could not reach them. Soon she tapped and scratched on her bedroom wall while we read to her at night, saying she was communicating with her friends who lived inside the wall. Later, a preschool teacher told us our daughter spoke of hearing whispers and bells in preschool when she was 4 years old. Her psychiatrist thought she had a vivid imagination and did not prescribe an antipsychotic until she was 7 years old. Who rushes to put a young child on an antipsychotic? Many people don’t believe me when I tell them about our daughter’s early-onset psychosis.

*She is biologically male, but now identifies as a transgender woman.

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Because this is a predictive definition, it can include the contribution of non-causal genetic variables, for example, genetic variation that influenced traits in prior generations and was then passed down culturally through families (I’ll refer to this as “cultural transmission”). For some traits, the proportion of “heritability” that is actually operating through environment or cultural transmission rather than genes can be substantial, complicating the interpretation.

Does this imply a biological/genetic "start" that over time, transforms into a non material or less biological cause for a particular behavioral trait of interest? Hopefully that question makes sense. What would be an example of this?

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Absolutely, this is sometimes referred to as "active gene-environment correlation" or an environmental matching model. For instance, say someone has a very mild genetic propensity to extroversion, so they start going to more parties / social events, where they meet other extroverted people, who encourage them to go to more social events, etc. An initially small genetic difference gets amplified over time. This type of active amplification/matching would be included in the within-family/direct estimates of heritability, and this heritability would increase over ones lifetime as individuals match into more correlated environments.

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Thank you for that explanation! I have so many questions but not the vocabulary or expertise to ask them, so apologies for the over simplistic questions. In this example, would we/should we expect that the very mild genetic propensity to extroversion in the initial individual, to be/have been biologically mechanistic?

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No problem at all. For traits like personality it is still too early to say as we do not have clear, large-effect genetic mechanisms like the smoking example I mentioned. It seems plausible to me that there will be some genes that lead to increased anxiety in certain social situations and contribute to what we think of extroversion/introversion. But even these genes will still very likely be interacting with the environment in complex ways.

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I've been wanting to learn more about genetics and heritability studies for some time so this was so interesting and I learned a lot, thank you! It's also a tough topic to communicate well and you made it so understandable. New subscriber!

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Thank you!

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Wouldn't the leading hypothesis accounting for most of the missing heritability be that traits are influenced by a smatteringly high number of genes, for the most part making the detection of a single gene's influence impossible?

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We have methods to estimate "SNP-based heritability," which is the proportion of phenotypic variance that can be attributed to all common genetic variants, including genetic variants that we have not yet identified as associated with the condition (at a certain threshold of statistical significance). It was the gap between SNP heritability and traditional heritability estimates based on twin/family studies that raised the issue of "missing heritability." It was initially thought that rare genetic variants in the community may account for this gap, but as Sasha explained, this is looking less likely now.

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Yes, thank you! I did some further reading after asking and it got me to understand the issue better.

I'll have to re-read the interview more in depth now that I actually have understood this.

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I am a fan of looking for genetic links to behavioral tendencies and characteristics. But it seems to me that the scope of the potential link is often too broad. It's like trying to find a genetic link to being a good basketball player. There are many genetic and environmental factors to becoming a good basketball player, on the other hand being tall is highly correlated to being a good basketball player. It is not too difficult to study the genetics involved with being tall. In this same way behavioral tendencies, such as susceptibility to depression, should be broken down into component parts. What behavioral tendencies typically lead to depression? Then the genetic component parts could be studied more accurately.

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Yes I think that's right. The initial assumption was that genetic analyses would identify a handful of very clear "brain genes" and the mechanisms could then be understood from the ground up. Given that did not pan out and most traits are driven by thousands of variants, it would make sense to try to partition the genetic effects into more coherent underlying sub-phenotypes.

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