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

TitleDisentangling selection on genetically correlated polygenic traits via whole-genome genealogies.
Publication TypeJournal Article
Year of Publication2021
AuthorsStern, AJ, Speidel, L, Zaitlen, NA, Nielsen, R
JournalAm J Hum Genet
Date Published2021 02 04
KeywordsComputer Simulation, Diabetes Mellitus, Type 2, Evolution, Molecular, Gene-Environment Interaction, Genetic Heterogeneity, Genetic Pleiotropy, Genome, Human, Genome-Wide Association Study, Glycated Hemoglobin A, Humans, Models, Genetic, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Sample Size, Selection, Genetic

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 (|r|=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 × 10). 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 × 10 and 1.7 × 10, respectively). Lastly, our joint test shows antagonistic selection has increased type 2 diabetes risk and decrease HbA1c (p = 1.5 × 10).

Alternate JournalAm J Hum Genet
PubMed ID33440170
PubMed Central IDPMC7895848
Grant ListR01 CA227466 / CA / NCI NIH HHS / United States
R01 CA227237 / CA / NCI NIH HHS / United States
R01 HG006399 / HG / NHGRI NIH HHS / United States
U01 HG009080 / HG / NHGRI NIH HHS / United States
R01 MH122688 / MH / NIMH NIH HHS / United States
R01 GM138634 / GM / NIGMS NIH HHS / United States
R01 ES029929 / ES / NIEHS NIH HHS / United States
R56 MD013312 / MD / NIMHD NIH HHS / United States