Polygenicity of complex traits is explained by negative selection

Abstract

Complex traits and common disease are highly polygenic: thousands of common variants are causal, and their effect sizes are almost always small. Polygenicity could be explained by negative selection, which constrains common-variant effect sizes and may reshape their distribution across the genome. We refer to this phenomenon as flattening, as genetic signal is flattened relative to the underlying biology. We introduce a mathematical definition of polygenicity, the effective number of associated SNPs, and a robust statistical method to estimate it. This definition of polygenicity differs from the number of causal SNPs, a standard definition; it depends strongly on SNPs with large effects. In analyses of 33 complex traits (average N=361k), we determined that common variants are ∼4x more polygenic than low-frequency variants, consistent with pervasive flattening. Moreover, functionally important regions of the genome have increased polygenicity in proportion to their increased heritability, implying that heritability enrichment reflects differences in the number of associations rather than their magnitude (which is constrained by selection). We conclude that negative selection constrains the genetic signal of biologically important regions and genes, reshaping genetic architecture.