Performance of Polygenic Risk Scores for Atherosclerotic Cardiovascular Disease in the All of Us Program

Performance and transferability of contemporary polygenic risk scores (PRS) for atherosclerotic cardiovascular disease phenotypes may vary across PRS methods, training data, and trait ascertainment.

We aimed to investigate the performance and transferability of contemporary PRS for atherosclerotic cardiovascular disease subtypes: coronary heart disease (CHD), abdominal aortic aneurysm (AAA), ischemic stroke (IS), and peripheral artery disease (PAD), using the All of Us Workbench, which consists of a large, diverse cohort with whole-genome sequence data. We also developed and evaluated a multi-trait PRS for each subtype. Performance of PRS for 4 atherosclerotic cardiovascular disease subtypes was compared across genetic similarity groups in 245 388 All of Us participants. Groups genetically similar to European, African, admixed American, and remaining groups (combined as other) were used to assess PRS for CHD, IS, AAA, PAD, and multi-trait.

PRS for CHD and AAA performed better than IS and PAD. For CHD, CHD_PGS003725 performed the best (hazard ratio per SD increase [95% CI]), across genetic ancestry groups, European, and African (1.72 [1.67-1.78], 1.23 [1.17-1.29]), with CHD_PGS004696 being best for admixed American (1.91 [1.70-2.15]), and CHD_PGS003356 for other (1.75 [1.58-1.95]). The best performing PRS for AAA was AAA_Multi for European, other, and admixed American (1.71 [1.52-1.92], 1.59 [1.07-2.37], 1.50 [0.90-2.52]) and AAA_PGS003972 for African (1.39 [1.19-1.63]). For IS, IS_Multi performed best for other and European (1.49 [1.17-1.89], 1.33 [1.25-1.42]), and IS_PGS000039 performed best in admixed American and African (1.17 [1.07-1.27], 1.09 [1.04-1.15]). For PAD, PAD_Multi performed best for all groups (other, 1.51 [1.19-1.92]; European, 1.32 [1.24-1.41]; admixed American, 1.23 [1.05-1.45]; and African, 1.18 [1.04-1.34]).

Multi-trait and multi-ancestry PRS performed better than individual trait and/or single ancestry PRS for each atherosclerotic cardiovascular disease phenotype across ancestrally diverse and admixed individuals, with minimal change including adjustment for conventional risk factors.