Abstract
Polygenic risk scores (PRSs) discriminate trait risks better than single genetic markers because they aggregate the effects of risk alleles from multiple genetic loci. Constructing pleiotropic PRSs and understanding heterogeneity, and the replication of PRS-trait associations can strengthen its applications. By using variational Bayesian multivariate high-dimensional regression, we constructed pleiotropic PRSs jointly associated with body mass index, systolic and diastolic blood pressure, total and high-density lipoprotein cholesterol in a sample of 18,108 Caucasians from three independent cohorts. We found that dissecting heterogeneity associated with birth year, which is a proxy of exogenous exposures, improved the replication of significant PRS-trait associations from 37.5% (6 of 16) in the entire sample to 90% (18 of 20) in the more homogeneous sample of individuals born before the year 1925. Our findings suggest that secular changes in exogenous exposures may substantially modify pleiotropic risk profiles affecting translation of genetic discoveries into health care.
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Data availability
This manuscript was prepared using a limited access datasets obtained through dbGaP, accession numbers: phs000287.v5.p1 (CHS), phs000007.v28.p10 (FHS), and phs000428.v1.p1 (HRS). Phenotypic HRS data are available publicly and through restricted access from http://hrsonline.isr.umich.edu/index.php?p=data.
Correspondence and requests for materials should be addressed to Yury Loika (yury.loika@duke.edu), Irina Irincheeva (iirincheeva@gmail.com), and Alexander M. Kulminski (alexander.kulminski@duke.edu).
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Funding
This research was supported by Grants No P01 AG043352, R01 AG065477, and R01 AG047310 from the National Institute on Aging. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. See also Supporting Acknowledgment Text in Online Resource 15.
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AMK conceived and designed the experiment, planned the analyses, and wrote the paper; YL prepared data, designed the experiment, planned and performed statistical analyses, and wrote the paper; II designed the experiment, planned and performed statistical analyses, and wrote the paper; IK performed bioinformatic analysis and wrote the paper; AN prepared and imputed genetic data.
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Loika, Y., Irincheeva, I., Culminskaya, I. et al. Polygenic risk scores: pleiotropy and the effect of environment. GeroScience 42, 1635–1647 (2020). https://doi.org/10.1007/s11357-020-00203-2
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DOI: https://doi.org/10.1007/s11357-020-00203-2