Allele frequency differentiation at height-associated SNPs among continental human populations.

Abstract

Methods to detect polygenic adaptation have recently been shown to be sensitive to uncorrected stratification in GWAS, thereby casting doubts on whether polygenic adaptation is prevalent among humans. Consistent with a signal of adaptationat human height loci, the mean FST among African, East Asian, and European populations was shown to be significantly higher at height-associated SNPs than that at non-associated SNPs. This conclusion was reached, however, using height-associated SNPs ascertained from a GWAS design impacted by residual confounding due to uncorrected stratification. Specifically, we show here that the estimated effect sizes are significantly correlated with population structure across continents, potentially explaining the elevated differentiation previously reported. We alleviated these concerns of confounding by ascertaining height-associated SNPs from two biobank GWAS (UK Biobank, UKB, and Biobank Japan, BBJ), where measures to control for confounding in GWAS are more effective. Consistent with a global signature of polygenic adaptation, we found that compared to non-associated SNPs, frequencies of height-associated SNPs are indeed significantly more differentiated among continental populations from both the 1000 Genomes Project (p = 0.0012 for UKB and p = 0.0265 for BBJ), and the Human Genome Diversity Project (p = 0.0225 for UKB and p = 0.0032 for BBJ). However, we found no significant difference among continental populations in polygenic height scores. Through simulations, we found that polygenic score-based statistics could lose power in detecting polygenic adaptation in presence of independent converging selections, thereby potentially explaining the inconsistent results based on FST and polygenic scores.