Polygenic Risk Score Improves the Accuracy of a Clinical Risk Score for Coronary Artery Disease

Abstract

Background: The value of polygenic risk scores (PRS) towards improving guideline-recommended clinical risk models for coronary artery disease (CAD) prediction is controversial. Here we examine whether an integrated polygenic risk score improves prediction of CAD beyond pooled cohort equations. Methods: An observation study of 291,305 unrelated White British UK Biobank participants en-rolled from 2006 to 2010 was conducted. A case-control sample of 9,499 prevalent CAD cases and an equal number of randomly selected controls was used for tuning and integrating of the polygen-ic risk scores. A separate cohort of 272,307 individuals (with follow-up to 2020) was used to exam-ine the risk prediction performance of pooled cohort equations, integrated polygenic risk score, and PRS-enhanced pooled cohort equation for incident CAD cases. Performance of each model was analyzed by discrimination and risk reclassification using a 7.5% threshold. Results: In the cohort of 272,307 individuals (mean age, 56.7 years) used to analyze predictive ac-curacy, there were 7,036 incident CAD cases over a 12-year follow-up period. Model discrimination was tested for integrated polygenic risk score, pooled cohort equation, and PRS-enhanced pooled cohort equation with reported C-statistics of 0.640 (95% CI, 0.634-0.646), 0.718 (95% CI, 0.713-0.723), and 0.753 (95% CI, 0.748-0.758), respectively. Risk reclassification for the addition of the integrated polygenic risk score to the pooled cohort equation at a 7.5% risk threshold resulted in a net reclassification improvement of 0.117 (95% CI, 0.102 to 0.129) for cases and -0.023 (95% CI, -0.025 to -0.022) for noncases [overall: 0.093 (95% CI, 0.08 to 0.104)]. For incident CAD cases, this represented 14.2% correctly reclassified to the higher-risk category and 2.6% incorrectly reclassi-fied to the lower-risk category. Conclusions and Relevance: Addition of the integrated polygenic risk score for CAD to the pooled cohort questions improves the predictive accuracy for incident CAD and clinical risk classification in the White British from the UK biobank. These findings suggest that an integrated polygenic risk score may enhance CAD risk prediction and screening in the White British population.