Genetic architectures of brain-related traits are shaped by strong selective constraints

Abstract

Significance A central goal of human genetics is to understand how genetic variation shapes complex traits, including height and susceptibility to diseases. Over the past two decades, genome-wide association studies (GWAS) have identified numerous trait-associated genetic variants, but the findings can differ widely across traits. Notably, psychiatric disorders such as schizophrenia—and brain-related traits more broadly—share unusual patterns that lack a formal explanation. Using a population genetics framework, we showed that brain-related traits have large mutational target sizes, with underlying variants shaped by strong selective constraints. Our findings are of both practical and foundational significance, informing the interpretation of past and future GWAS results and contributing to a general understanding of how evolutionary forces shape heritable variation in human populations.