A Population Genetic Signal of Polygenic Adaptation

Adaptation in response to selection on polygenic phenotypes may occur via subtle allele frequencies shifts at many loci. Current population genomic techniques are not well posed to identify such signals. In the past decade, detailed knowledge about the specific loci underlying polygenic traits has begun to emerge from genome-wide association studies (GWAS). Here we combine this knowledge from GWAS with robust population genetic modeling to identify traits that may have been influenced by local adaptation. We exploit the fact that GWAS provide an estimate of the additive effect size of many loci to estimate the mean additive genetic value for a given phenotype across many populations as simple weighted sums of allele frequencies. We use a general model of neutral genetic value drift for an arbitrary number of populations with an arbitrary relatedness structure. Based on this model, we develop methods for detecting unusually strong correlations between genetic values and specific environmental variables, as well as a generalization of comparisons to test for over-dispersion of genetic values among populations. Finally we lay out a framework to identify the individual populations or groups of populations that contribute to the signal of overdispersion. These tests have considerably greater power than their single locus equivalents due to the fact that they look for positive covariance between like effect alleles, and also significantly outperform methods that do not account for population structure. We apply our tests to the Human Genome Diversity Panel (HGDP) dataset using GWAS data for height, skin pigmentation, type 2 diabetes, body mass index, and two inflammatory bowel disease datasets. This analysis uncovers a number of putative signals of local adaptation, and we discuss the biological interpretation and caveats of these results.Author Summary: The process of adaptation is of fundamental importance in evolutionary biology. Within the last few decades, genotyping technologies and new statistical methods have given evolutionary biologists the ability to identify individual regions of the genome that are likely to have been important in this process. When adaptation occurs in traits that are underwritten by many genes, however, the genetic signals left behind are more diffuse, and no individual region of the genome is likely to show strong signatures of selection. Identifying this signature therefore requires a detailed annotation of sites associated with a particular phenotype. Here we develop and implement a suite of statistical methods to integrate this sort of annotation from genome wide association studies with allele frequency data from many populations, providing a powerful way to identify the signal of adaptation in polygenic traits. We apply our methods to test for the impact of selection on human height, skin pigmentation, body mass index, type 2 diabetes risk, and inflammatory bowel disease risk. We find relatively strong signals for height and skin pigmentation, moderate signals for inflammatory bowel disease, and comparatively little evidence for body mass index and type 2 diabetes risk.