Demographic history mediates the effect of stratification on polygenic scores

Arslan A. Zaidi, Iain Mathieson

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Population stratification continues to bias the results of genome-wide association studies (GWAS). When these results are used to construct polygenic scores, even subtle biases can cumulatively lead to large errors. To study the effect of residual stratification, we simulated GWAS under realistic models of demographic history. We show that when population structure is recent, it cannot be corrected using principal components of common variants because they are uninformative about recent history. Consequently, polygenic scores are biased in that they recapitulate environmental structure. Principal components calculated from rare variants or identity-by-descent segments can correct this stratification for some types of environmental effects. While family-based studies are immune to stratification, the hybrid approach of ascertaining variants in GWAS but re-estimating effect sizes in siblings reduces but does not eliminate stratification. We show that the effect of population stratification depends not only on allele frequencies and environmental structure but also on demographic history.

Original languageEnglish (US)
Article numbere61548
Pages (from-to)1-30
Number of pages30
JournaleLife
Volume9
DOIs
StatePublished - Oct 2020
Externally publishedYes

Bibliographical note

Funding Information:
406 This research was supported by NIGMS award number R35GM133708. The content is solely the 407 responsibility of the authors and does not necessarily represent the official views of the National 408 Institutes of Health. The UK Biobank Resource was used under Application 33923.

Funding Information:
This research was supported by NIGMS award number R35GM133708. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The UK Biobank Resource was used under Application 33923.

Publisher Copyright:
© 2020, eLife Sciences Publications Ltd. All rights reserved.

Fingerprint

Dive into the research topics of 'Demographic history mediates the effect of stratification on polygenic scores'. Together they form a unique fingerprint.

Cite this