Polygenic adaptation on height is overestimated due to uncorrected stratification in genome-wide association studies.

TitlePolygenic adaptation on height is overestimated due to uncorrected stratification in genome-wide association studies.
Publication TypeJournal Article
Year of Publication2019
AuthorsSohail, M, Maier, RM, Ganna, A, Bloemendal, A, Martin, AR, Turchin, MC, Chiang, CWk, Hirschhorn, J, Daly, MJ, Patterson, N, Neale, B, Mathieson, I, Reich, D, Sunyaev, SR
Date Published2019 Mar 21

Genetic predictions of height differ among human populations and these differences have been interpreted as evidence of polygenic adaptation. These differences were first detected using SNPs genome-wide significantly associated with height, and shown to grow stronger when large numbers of sub-significant SNPs were included, leading to excitement about the prospect of analyzing large fractions of the genome to detect polygenic adaptation for multiple traits. Previous studies of height have been based on SNP effect size measurements in the GIANT Consortium meta-analysis. Here we repeat the analyses in the UK Biobank, a much more homogeneously designed study. We show that polygenic adaptation signals based on large numbers of SNPs below genome-wide significance are extremely sensitive to biases due to uncorrected population stratification. More generally, our results imply that typical constructions of polygenic scores are sensitive to population stratification and that population-level differences should be interpreted with caution.

Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Alternate JournalElife
PubMed ID30895926
PubMed Central IDPMC6428571
Grant ListGM100233 / / National Institutes of Health /
Investigator / / Howard Hughes Medical Institute / United States
Sloan Research Fellowship / / Alfred P. Sloan Foundation /
R01 GM100233 / GM / NIGMS NIH HHS / United States
New Investigator Research Grant / / Charles E Kaufman Foundation /
R01 HG006399 / HG / NHGRI NIH HHS / United States
Allen Discovery Center / / Paul Allen Foundation /
R01 DK075787 / DK / NIDDK NIH HHS / United States
R35 GM127131 / GM / NIGMS NIH HHS / United States
MH101244 / / National Institutes of Health /
GM127131 / / National Institutes of Health /
R01 MH101244 / MH / NIMH NIH HHS / United States
U01 HG009088 / HG / NHGRI NIH HHS / United States
HG009088 / / National Institutes of Health /
HG006399 / / National Institutes of Health /