Abstract P879: Differences in Statistical Performance of Polygenic Risk Scores for Cardiovascular Disease Across Different Race/Ethnicities

Abstract

Introduction: Genome-wide association studies have identified numerous genetic risk variants for stroke and myocardial infarction (MI) in Europeans. However, the limited applicability of these results to non-Europeans due to racial/ethnic differences in the genetic architecture of cardiovascular disease (CVD), coupled with the limited availability of genomic data in non-Europeans, may create significant health disparities now that genomic-based precision medicine is a reality. We tested the hypothesis that the performance of polygenic risk scores (PRS) for CVD differ in Europeans versus non-Europeans. Methods: We conducted a nested study within the UK Biobank, a prospective, population-based study that enrolled ~500,000 participants across the UK. For this study, we identified self-reported black participants and randomly matched them 1:1 by age and sex with white participants. We created a PRS using previously discovered loci for stroke and MI. We then tested whether this PRS representing the aggregate polygenic susceptibility to CVD yielded similar precision in black versus white participants in logistic regression models. Results: Of the 502,536 participants enrolled in the UK Biobank, 8,061 were self-reported blacks, with 7,644 having available data for our analyses. We randomly matched these participants with white individuals, leading to a total sample size of 15,288 (mean age 51.9 [SD 8.1], female 8,722 [57%]). The total number of events was 741 overall, with 363 happening in blacks and 378 happening in whites. In logistic regression models including age, sex, and 5 principal components, the statistical precision (e.g. narrower confidence intervals) for the PRS was substantially higher for whites (OR 1.22, 95%CI 1.08 - 1.37; p<0.0001) compared to blacks (OR 1.24, 95%CI 1.05-1.47; p=0.01). Secondary analyses using genetically-determined ancestry yielded similar results. Conclusion: Because CVD-related PRSs are derived mainly using genetic risk factors identified in populations of European ancestry, their statistical performance is lower in non-European populations. This asymmetry can lead to significant health disparities now that these tools are being evaluated in multiple precision medicine approaches.