Scott, if you haven’t already seen the reply I got from Steven Hyman to my posts, that will interest you: psychiatrymargins.com/p/a-note-from-hym…

From my perspective, we are in this odd position where we know that a substantial aggregate genetic influence on schizophrenia exists (and that such substantial aggregate influences exist for nearly all complex disorders, even if not to the same extent), but we seem unable to make it tangible. The influence dissolves into genes of tinier & tinier effects, and this seriously limits what we can practically do with all this. It’s obvious that hundreds and thousands of gene influence the risk of developing schizophrenia.

We need to distinguish between several different strands of the debate here. “Are genetic influences in aggregate a cause of schizophrenia?” is one question (and I’d say yes, in the same sense of cause as smoking causes lung cancer) but that is a different question from whether “Is the etiology of schizophrenia 80% genetic?” The latter question is rather ambiguous but that’s how many ppl talk about schizophrenia. My view is that it is 80% genetic only in the strict sense of the heritability statistic for a population, and that the heritability statistic becomes kinda meaningless if you try to turn it into a statement about what component of “etiology” (etiology ≠ phenotype variation) is genetic.

A second thing we need to distinguish is that we mean different things by the term “genetic disorder.” It could mean something very general, like any disorder where a substantial portion of the risk/vulnerability comes from aggregate genetic influences. A second more specific sense is where identification of causal genetic variants provides a coherent way to understand the mechanisms or pathophysiology of a condition. Schizophrenia genetics program was kinda based on the hope that we could move from the former sense to the latter sense, and it has become rather clear by now that this is not likely to happen. The influence of any particular gene is too small & current polygenic scores explain like 6-7% of risk. What people are hoping now is that genetic associations can provide clues to understanding what pathways are involved, like disruption of synapses or immune dysregulation. I don’t mind if we consider schizophrenia as a genetic disorder in the first sense (which means many other complex disorders are also genetic) but we shouldn’t simply assume that because it is genetic, the latter sense is also true.