Polygenic risk scores: pleiotropy and the effect of environment.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Loika, Y; Irincheeva, I; Culminskaya, I; Nazarian, A; Kulminski, AM

Published Date

  • December 2020

Published In

Volume / Issue

  • 42 / 6

Start / End Page

  • 1635 - 1647

PubMed ID

  • 32488673

Pubmed Central ID

  • 32488673

Electronic International Standard Serial Number (EISSN)

  • 2509-2723

International Standard Serial Number (ISSN)

  • 2509-2715

Digital Object Identifier (DOI)

  • 10.1007/s11357-020-00203-2


  • eng