Open AccessPolygenic risk scores: pleiotropy and the effect of environment
Author(s) -
Yury Loika,
Irina Irincheeva,
Irina Culminskaya,
Alireza Nazarian,
Alexander M. Kulminski
Publication year - 2020
Publication title -
geroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.883
H-Index - 63
eISSN - 2509-2715
pISSN - 2509-2723
DOI - 10.1007/s11357-020-00203-2
Subject(s) - pleiotropy , trait , quantitative trait locus , multivariate statistics , proxy (statistics) , biology , body mass index , allele , medicine , demography , genetics , statistics , computer science , gene , mathematics , sociology , phenotype , programming language
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.