Complex human phenotypes are mainly polygenic in nature and are not likely to undergo selection in the form of major selective sweeps, but rather in subtle shifts in allele frequencies. These shifts are often hard to detect using traditional statistical methods. Our recently developed false discovery rate (FDR) framework exploits ancillary information to improve the power of genome-wide association studies (GWAS). This method can assess enrichment of polygenic effects on various phenotypes in specific genic annotation categories. We applied this method to study the effect of evolutionary metrics using data from GWASs of psychiatric and cognitive phenotypes.
We used different evolutionary proxies representing various time periods of human evolution. The Neanderthal selective sweep score, which measures positive selection in humans after the human-Neanderthal split some 50,000 years ago, was used to test the hypothesis that the schizophrenia is related to the development of the complex human brain and concurrently, language skills and creative reasoning. We show that regions that underwent positive selection in humans after divergence from Neanderthals are more likely to be associated with schizophrenia.
We investigated traces of schizophrenia association in less recently evolved regions like the human accelerated regions (HAR), segmental duplication regions (SD), and ohnologous regions (Ohno). These represent time periods before 200,000 years ago when hominid and chimpanzee branches split (HAR), 35-40 million years ago during the great ape-hominid split (SD), and the period of separation of vertebrate and invertebrate lineages 500 million years ago (Ohno). We could not detect significant enrichment for any of these evolutionary markers.
We investigated GWAS of education attainment, college completion, and cognitive function, after the Neanderthal split. Our results indicate that SNPs in the swept regions are more likely to be associated with education attainment, college completion, and to some extent to general cognitive function.
These findings help us understand the evolutionary history of mental and cognitive phenotypes. As humans evolved, their ability to think in the abstract, communicate with one another and organize in complex rule-based societies improved, but such development probably exposed them to mental pathologies like schizophrenia.
