We’ve been gradually working our way through the conversation around E. Fuller Torrey’s concerns about schizophrenia genetics - last week we had It’s Fair To Describe Schizophrenia As Probably Mostly Genetic, the week before Unintuitive Properties Of Polygenic Disorders. Here are two more arguments Torrey makes that we haven’t gotten to:

  1. Studies have failed to find any schizophrenia genes of large effect. If schizophrenia is genetic, it must be caused of thousands of genes, hidden in the most obscure corners of the genome, each with effects too small to detect with current technology. This seems less like the sort of thing that happens naturally, and more like the sort of thing you would claim if you wanted to make your theory untestable.

  2. Schizophrenia is bad for fitness, so if it were genetic, evolution would have eliminated those genes.

In the comments of the Unintuitive Properties post, Michael Roe points out that one of these mysteries solves the other:

If there were single gene polymorphisms with large negative effect, they would get selected out of the population … eventually. Which suggests that there can’t be high-frequency mutations with large negative effect, unless there is some compensating advantage (like, e.g. giving you resistance to malaria).

Which leaves us with multiple mutations, each of which individually has a small effect, adding up to a large total effect. And mutation-selection balance, where random mutations are introducing harmful mutations at about the same rate the natural selection is removing them.

If there were genes of large effect, evolution would have removed them. So all that can be left is genes of small effect.

And the only way genes of small effect can cause a common and severe condition is if there are so many of them that they add up to a large effect.

(Dr. Steven Hyman of NIMH made the same point recently on Psychiatry at the Margins)

So many of the traits we’re most interested in - intelligence, strength, schizophrenia, etc - are necessarily massively polygenic, because one side of them is better for fitness than the other. If they were monogenic, evolution would have already selected for the good side, and there would be no remaining genetic variance.

The remaining question is: why are there still even these genes of very small effect? Here are three possible answers:

  1. Evolution hasn’t had time to remove all of them yet. Because a gene that increases schizophrenia risk 0.001% barely changes fitness at all, it takes evolution forever to get rid of it. And by that time, maybe some new mildly-deleterious mutations have cropped up that need to be selected out.

  2. Schizophrenia genes have a counterbalancing advantage in some legible, schizophrenia-related way. For example, they all make people more creative.

  3. Each particular schizophrenia gene has a counterbalancing advantage in a different way. One gene might increase schizophrenia risk 0.001%, but also improve kidney function a little. Another might increase schizophrenia risk 0.02%, but also decrease risk of heart attacks. And so on.

Studies seem to mostly support (1), for example this study of ancient hominid genomes finds that schizophrenia genes are getting less common over time, suggesting that evolution is trying to get rid of them and it’s just taking a few tens of thousands of years.

It should be relatively easy to disprove (2) - just use genetic testing to find the people with the lowest schizophrenia genetic risk, and see if they all have some problem (eg low creativity). I don’t think genetic testing is good enough to do this yet, but based on the evolutionary argument above, I doubt this one.

I’ve never heard anyone discuss (3), but it sort of makes sense, doesn’t it? It sounds hard to test, but you might be able to look at all-cause mortality in the people with the lowest schizophrenia genetic risk and see if it’s unusually high. I would be shocked if this turned out to be true, but it’s theoretically possible.

Why does this matter? We’re getting to the point where we can select embryos for low schizophrenia risk (we’re not at the point where we can engineer low schizophrenia risk yet, but someday we might be). If schizophrenia genes are good in some way, we might want to hold back until we understand why1. If they’re just evolutionary mistakes, we could move forward with less concern.

So far the evolutionary mistake theory seems most plausible.

The clearest way to resolve these questions would be to genetically engineer someone to zero schizophrenia risk and see what happened (this is beyond current technology). I predict they would be not only less schizophrenic, but healthier in lots of other ways too, since it would eliminate random mutations and most random mutations that do anything at all are deleterious.

  1. The scare-mongering here has to be false - that is, it can’t be bad to choose an embryo at the 50th percentile of schizophrenia risk rather than the 99.9th, because half of people are at the 50th percentile of schizophrenia risk and nothing bad happens to them. Schizophrenia genes can be at best fitness-neutral; otherwise evolution would be selecting for them. The worst you could say is that this would be depriving some people of exceptional creativity (as in 2) or exceptional organ effectiveness (as in 3), instead pushing them towards the average of these traits. But there’s no reason to think this is true, and plenty of reasons to think it isn’t.