Genetic association data are broadly consistent with stabilizing selection shaping human common diseases and traits

Abstract

Results from genome-wide association studies (GWAS) enable inferences about the balance of evolutionary forces maintaining genetic variation underlying common diseases and other genetically complex traits. Natural selection is a major force shaping variation, and understanding it is necessary to explain the genetic architecture and prevalence of heritable diseases. Here, we analyze data for 27 traits, including anthropometric traits, metabolic traits, and binary diseases--both early-onset and post-reproductive. We develop an inference framework to test existing population genetics models based on the joint distribution of allelic effect sizes and frequencies of trait-associated variants. A majority of traits have GWAS results that are inconsistent with neutral evolution or long-term directional selection (selection against a trait or against disease risk). Instead, we find that most traits show consistency with stabilizing selection, which acts to preserve an intermediate trait value or disease risk. Our observations also suggest that selection may reflect pleiotropy, with each variant influenced by associations with multiple selected traits.