Demographic history mediates the effect of stratification on polygenic scores

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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.

Data availability

The data used in this study were generated through simulations. The code for these simulations is freely available at https://github.com/Arslan-Zaidi/popstructure and can be used to reproduce all simulations and carry out all analyses in the manuscript.

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Arslan A Zaidi

Genetics, University of Pennsylvania, Philadelphia, United States

For correspondence
aazaidi@pennmedicine.upenn.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2155-8367
Iain Mathieson

Department of Genetics, University of Pennsylvania, Philadelphia, United States

For correspondence
mathi@pennmedicine.upenn.edu

Competing interests
The authors declare that no competing interests exist.

Funding

National Institute of General Medical Sciences (R35GM133708)

Iain Mathieson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.