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.

多基因风险评分 (PRS) 比单一遗传标记更能区分性状风险，因为它们聚合了来自多个基因位点的风险等位基因的影响。构建多效性 PRS 并了解异质性，以及 PRS 性状关联的复制可以加强其应用。通过使用变分贝叶斯多元高维回归，我们在来自三个独立队列的 18,108 名白种人样本中构建了与体重指数、收缩压和舒张压、总和高密度脂蛋白胆固醇联合相关的多效 PRS。我们发现，剖析与出生年份相关的异质性，这是外源暴露的代表，改善了从 37 个显着 PRS 性状关联的复制。