Circ Genom Precis Med. 2026 Jun 8:e005382. doi: 10.1161/CIRCGEN.125.005382. Online ahead of print.
ABSTRACT
BACKGROUND: Performance and transferability of contemporary polygenic risk scores (PRS) for atherosclerotic cardiovascular disease phenotypes may vary across PRS methods, training data, and trait ascertainment.
METHODS: 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 multitrait 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 multitrait.
RESULTS: PRS for CHD and AAA performed better than IS and PAD. For CHD, CHD 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 being best for admixed American (1.91 [1.70-2.15]), and CHD for other (1.75 [1.58-1.95]). The best performing PRS for AAA was AAA 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 for African (1.39 [1.19-1.63]). For IS, IS performed best for other and European (1.49 [1.17-1.89], 1.33 [1.25-1.42]), and IS performed best in admixed American and African (1.17 [1.07-1.27], 1.09 [1.04-1.15]). For PAD, PAD 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]).
CONCLUSIONS: Multitrait and multiancestry 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.
PMID:42253048 | DOI:10.1161/CIRCGEN.125.005382