Ancestry-specific polygenic risk scores are risk enhancers for clinical cardiovascular disease assessments

Clinical implementation of new prediction models requires evaluation of their utility in a broad range of intended use populations. Here we develop and validate ancestry-specific Polygenic Risk Scores (PRSs) for Coronary Artery Disease (CAD) using 29,389 individuals from diverse cohorts and genetic ancestry groups. The CAD PRSs outperform published scores with an average Odds Ratio per Standard Deviation of 1.57 (SD = 0.14) and identify between 12% and 24% of individuals with high genetic risk. Using this risk factor to reclassify borderline or intermediate 10 year Atherosclerotic Cardiovascular Disease (ASCVD) risk improves assessments for both CAD (Net Reclassification Improvement (NRI) = 13.14% (95% CI 9.23–17.06%)) and ASCVD (NRI = 10.70 (95% CI 7.35-14.05)) in an independent cohort of 9,691 individuals. Our analyses demonstrate that using PRSs as Risk Enhancers improves ASCVD risk assessments outlining an approach for guiding ASCVD prevention with genetic information.