Comparative Performance of Polygenic Risk Scores for Atherosclerotic Cardiovascular Disease Subtypes in the All of Us Research Program
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Performance and portability of contemporary polygenic risk scores (PRS) for atherosclerotic cardiovascular disease (ASCVD) phenotypes vary based on different methods, training data, and trait ascertainment.
Objectives
We aimed to investigate performance and portability of contemporary PRS for ASCVD subtypes: coronary heart disease (CHD), abdominal aortic aneurysm (AAA), ischemic stroke (IS), and peripheral artery disease (PAD), using the All of Us Workbench which provides access to a large diverse cohort with phenotype and whole genome sequence data. We also developed and evaluated a multi-trait PRS for each subtype.
Methods
Performance of PRS for 4 ASCVD traits and related risk factors was compared across genetic ancestry groups in 245,388 All of Us participants. Genetic EUR, African (AFR), Admixed American (AMR), and remaining ancestry groups (combined as Other, OTH) were defined by All of Us based on principal components. PRS for CHD, IS, AAA, PAD, and multi-trait (combining PRS for the 4 traits as well as PRS for ASCVD risk factors) were assessed for portability across genetic ancestry groups using hazard ratios (HR) per SD increase.
Results
For CHD, CHD PGS003725 performed the best (HR for 1 SD increase [95% CI]), across 4 genetic ancestry groups (EUR: 1.72[1.67-1.78], AFR: 1.24[1.18-1.31], AMR: 1.48[1.37-1.59], OTH: 1.65[1.52-1.79]). The best performing PRS for AAA was AAA PGS003972 (EUR: 1.68[1.59-1.78], AFR: 1.29[1.13-1.48], AMR: 1.30[1.06-1.60], OTH: 1.45[1.20-1.75]). The best performing IS PRS was IS PGS000039 in AFR (1.12[1.06-1.17]), AMR (1.11[1.04-1.19]), and OTH (1.23[1.09-1.38]), and IS PGS004939 in EUR (1.16[1.12-1.20]). For PAD, PAD PGS004940 performed best in EUR (1.26[1.22-1.30]), AFR (1.11[1.05-1.18]), AMR (1.08[1.01-1.16]), and OTH (1.13[1.04-1.22]). Multi-trait PRS performed better than individual trait PRS for each ASCVD phenotype. Also, PRS derived from multi-ancestry cohorts performed better than those derived from single ancestry.
Conclusions
PRS for ASCVD developed from multi-ancestry cohorts and multiple related traits performed best across ancestrally diverse and admixed individuals. PRS for CHD and AAA performed better than those for IS and PAD.
