Key result
Multi-ancestry PRS improve diverse prediction, with top scores linked to ~72% greater CHD risk per SD.
Why the study?
Performance and portability of contemporary polygenic risk scores for ASCVD phenotypes vary based on different methods, training data, and trait ascertainment.
Do multi-trait and multi-ancestry polygenic risk scores improve the prediction of ASCVD subtypes across diverse genetic ancestries?
Observational (n=245,388)
Yes
Do multi-trait and multi-ancestry polygenic risk scores improve the prediction of ASCVD subtypes across diverse genetic ancestries?
Multi-trait and multi-ancestry polygenic risk scores for ASCVD subtypes perform better across diverse populations, though predictive performance remains lower in individuals of African ancestry compared to European ancestry.
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.
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Smith et al. (2024) conducted an observational in Atherosclerotic cardiovascular disease (ASCVD) subtypes (n=245,388). Polygenic risk scores for ASCVD subtypes vs. Per standard deviation increase was evaluated on Incident coronary heart disease (CHD) risk per 1 SD increase in CHDPGS003725 score in European ancestry (HR 1.72, 95% CI 1.67-1.78). Polygenic risk scores for ASCVD developed from multi-ancestry cohorts and multiple related traits performed best across ancestrally diverse individuals, with the best CHD score yielding a HR of 1.72 per SD increase in European ancestry.
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