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

Abstract

Polygenic adaptation is thought to be an important mechanism of phenotypic evolution in humans, although recent evidence of confounding due to residual stratification in consortium GWAS made studies of polygenic adaptation more difficult to interpret. Using FST as a measure of allele frequency differentiation, a previous study has shown that the mean FST among African, East Asian, and European populations is significantly higher at height-associated SNPs than that found at matched non-associated SNPs, suggesting that polygenic adaptation is one of the reasons for differences in human height among these continental populations. However, we showed here even though the height-associated SNPs were identified using only European ancestry individuals, the estimated effect sizes are significantly associated with structures across continental populations, potentially explaining the elevated level of differentiation previously reported. To alleviate concerns of biased ascertainment of SNPs, we re-examined the distribution of FST at height-associated alleles ascertained from two biobank level GWAS (UK Biobank, UKB, and Biobank Japan, BBJ). We showed that when compared to non-associated SNPs, height-associated SNPs remain significantly differentiated among African, East Asian, and European populations from both 1000 Genomes (p = 0.0012 and p = 0.0265 when height SNPs were ascertained from UKB and BBJ, respectively), and Human Genome Diversity Panels (p = 0.0225 for UKB and p = 0.0032 for BBJ analyses). In contrast to FST-based analyses, we found no significant difference or consistent ranked order among continental populations in polygenic height scores constructed from SNPs ascertained from UKB and BBJ. In summary, our results suggest that, consistent with previous reports, height-associated SNPs are significantly differentiated in frequencies among continental populations after removing concerns of confounding by uncorrected stratification. Polygenic score-based analysis in this context appears to be susceptible to the choice of SNPs and, as we compared to FST-based statistics in simulations, would lose power in detecting polygenic adaptation if there are independent converging selections in more than one population.