Ten years ago, most of us paying attention were exhilarated about the prospects for psychiatric genetics. Heritability is high for many disorders-80% of the variation in vulnerability to bipolar disorder and schizophrenia can be attributed to genetic variations. We thought we would soon find the responsible abnormal genes, and this would quickly reveal the biochemical defects that cause these disorders, and this would quickly lead to ways to cure, or at least dramatically alleviate, these terrible scourges.

Candidate genes were examined by the best researchers using larger and larger samples and sophisticated statistics; a few were identified as prime suspects. Most results could not be replicated, but a few loci were very suspicious based on multiple studies.

Now, in an article by in this month’s American Journal of Psychiatry, Saunders et al. report on 433 SNPs associated with 14 candidate genes that were prime suspects for schizophrenia in about 1900 cases and 2000 controls of European ancestry. The results? Not one of the genes was significantly associated with schizophrenia prevalence. Even a 25% increase would have been detected with high probability.

An editorial by Steven Hamilton tries to put the best possible face on the results by noting that studies of tens of thousands of subjects were required to find genes that contribute to real but small (<25%) increases in risk for Type II diabetes. But that is not the point. Sanders, et al. deserve commendation for stating their conclusion clearly:

Our results suggest that, taken together, common DNA variants in these 14 genes are unlikely to explain a large proportion of the genetic risk for schizophrenia in populations of European ancestry. More robust findings are likely to be discovered using genome-wide association methods and, as our knowledge of the biology of mental illness continues to improve, focused studies of genes based on more precise mechanistic hypotheses. Nevertheless, although larger samples could possibly detect small genetic effects that were missed in this experiment, our findings suggest it is unlikely that true associations exist at the population level for the alleles that have formed the basis for the large candidate gene literature for these 14 postulated schizophrenia candidate genes.

Now what? Should we just do larger and larger studies with fancier and fancier bioinformatics? We have been looking for abnormal genes-mutations that cause diseases. But what if that is not the right model? That presumes that there is a normal genome and if all is in order all works fine, but when a part breaks, disease results.

A clue comes from Craig Ventner’s genome. The human genome project provided sequences for haploid genomes. But the chromosomes from both Ventner’s father and mother have now been sequenced. The results, in a recent Science article, are a big surprise. Variation between human individuals is five times higher than we thought: 0.5% instead of 0.1%. Much of the difference is in the number of copies of a gene, and their locations.

Copy number variations look likely to explain a lot. They are invisible to genetic testing that just looks for the presence of certain sequences. But they are important. Especially for mental disorders.

Even more recently, in this week’s Science,Walsh, et al. report big differences in CNVs in people with schizophrenia: “Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases” DOI: 10.1126/science.1155174 In previous work they have found similar differences in autism.

This may well explain why we have not been able to find the genes for schizophrenia-schizophrenics don’t have different genes from other people, just different numbers of certain genes. This also fits with paternal age effects on schizophrenia – the risk of schizophrenia increases as the father’s -but not the mother’s-age increases. (Male gametes keep dividing throughout out life, increasing the risk of errors, while the eggs of females are all formed by birth)

So, myriads of different genetic variations may contribute to schizophrenia, many involving micro insertions, and deletions. This tells us where to look.

What does evolution have to do with all of this?  Many have asked why genes that cause such a serious disease persist, and a number of evolutionary hypotheses have been inspired by the kind of balancing selection that explains the persistence of genes that cause sickle cell disease. A new article by Adriaens debunks such hypotheses. He offers a nice review of studies about the reproductive success of people with schizophrenia, although I think he discounts excessively the evolutionary significance of a 50% fitness decrease for male schizophrenics.

It seems to me that he is absolutely right, however, to point out data that undermine hypotheses based on covert benefits of schizophrenia genes. He generalizes about evolutionary psychiatrists as if they are not only all in one category, but as if they all think the same things. This is especially surprizing given his emphasis on the mistake of assuming that schizophrenia is a natural category. It is so important to criticize hypotheses, not people or groups.

There is much additional useful in his paper, especially his outline of evolutionary reasons why the genetic factors in schizophrenia will be much more complex than we have imagined. This all fits very nicely with other reports this week about the genetics of schizophrenia I do think, however, that we do need to ask why such a highly heritable devastating disorder persists. Balancing selection is not likely. It could be just that new mutations happen. But I think that the high heritability has kept attention focused on the level of the gene, when the problem may well be in constraints and trade-offs at a higher level.