Disentangling selection on genetically correlated polygenic traits via whole-genome genealogies

We present a full-likelihood method to infer polygenic adaptation from DNA sequence variation and GWAS summary statistics to quantify recent transient directional selection acting on a complex trait. Through simulations of polygenic trait architecture evolution and GWASs, we show the method substantially improves power over current methods. We examine the robustness of the method under stratification, uncertainty and bias in marginal effects, uncertainty in the causal SNPs, allelic heterogeneity, negative selection, and low GWAS sample size. The method can quantify selection acting on correlated traits, controlling for pleiotropy even among traits with strong genetic correlation (vertical bar r(g)vertical bar = 80%) while retaining high power to attribute selection to the causal trait. When the causal trait is excluded from analysis, selection is attributed to its closest proxy. We discuss limitations of the method, cautioning against strongly causal interpretations of the results, and the possibility of undetectable gene-by-environment (GxE) interactions. We apply the method to 56 human polygenic traits, revealing signals of directional selection on pigmentation, life history, glycated hemoglobin (HbA1c), and other traits. We also conduct joint testing of 137 pairs of genetically correlated traits, revealing widespread correlated response acting on these traits (2.6-fold enrichment, p = 1.5 x 10(-7)). Signs of selection on some traits previously reported as adaptive (e.g., educational attainment and hair color) are largely attributable to correlated response (p = 2.9 x 10(-6) and 1.7 x 10(-4), respectively). Lastly, our joint test shows antagonistic selection has increased type 2 diabetes risk and decrease HbA1c (p = 1.5 x 10(-5)).

Automated summary

The study presents a method to infer polygenic adaptation and quantify transient selection on complex traits, showing improved power compared to current methods. The method is robust under various conditions and can control for correlated traits, attributing selection to causal traits with high power. Results from 56 human polygenic traits show signals of directional selection and widespread correlated response, with signs of selection on some traits previously reported as adaptive largely attributable to correlated response. The joint test reveals antagonistic selection increasing type 2 diabetes risk and decreasing HbA1c.