Demographic history mediates the effect of stratification on polygenic scores
- University of Pennsylvania, United States
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.
Article and author information
Author details
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.
Reviewing Editor
- George H Perry, Pennsylvania State University, United States
Version history
- Received: July 29, 2020
- Accepted: November 16, 2020
- Accepted Manuscript published: November 17, 2020 (version 1)
- Version of Record published: December 23, 2020 (version 2)
Copyright
© 2020, Zaidi & Mathieson
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.
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Demographic history mediates the effect of stratification on polygenic scores
eLife 9:e61548.
https://doi.org/10.7554/eLife.61548
Further reading
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- Epidemiology and Global Health
Background:
Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been associated with various chronic diseases and mortality, but results are conflicting. Few studies examined the role of omega-6/omega-3 ratio in mortality.
Methods:
We investigated plasma omega-3 and omega-6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort, the UK Biobank. Of 85,425 participants who had complete information on circulating PUFAs, 6461 died during follow-up, including 2794 from cancer and 1668 from cardiovascular disease (CVD). Associations were estimated by multivariable Cox proportional hazards regression with adjustment for relevant risk factors.
Results:
Risk for all three mortality outcomes increased as the ratio of omega-6/omega-3 PUFAs increased (all Ptrend <0.05). Comparing the highest to the lowest quintiles, individuals had 26% (95% CI, 15–38%) higher total mortality, 14% (95% CI, 0–31%) higher cancer mortality, and 31% (95% CI, 10–55%) higher CVD mortality. Moreover, omega-3 and omega-6 PUFAs in plasma were all inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects.
Conclusions:
Using a population-based cohort in UK Biobank, our study revealed a strong association between the ratio of circulating omega-6/omega-3 PUFAs and the risk of all-cause, cancer, and CVD mortality.
Funding:
Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institute of Health under the award number R35GM143060 (KY). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
