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Background - There is considerable interest in whether genetic data can be used to improve standard cardiovascular disease risk calculators, as the latter are routinely used in clinical practice to manage preventative treatment. Methods - Using the UK Biobank (UKB) resource, we developed our own polygenic risk score (PRS) for coronary artery disease (CAD). We used an additional 60,000 UKB individuals to develop an integrated risk tool (IRT) that combined our PRS with established risk tools (either the American Heart Association/American College of Cardiology's Pooled Cohort Equations (PCE) or UK's QRISK3), and we tested our IRT in an additional, independent, set of 186,451 UKB individuals. Results - The novel CAD PRS shows superior predictive power for CAD events, compared to other published PRSs and is largely uncorrelated with PCE and QRISK3. When combined with PCE into an integrated risk tool, it has superior predictive accuracy. Overall, 10.4% of incident CAD cases were misclassified as low risk by PCE and correctly classified as high risk by the IRT, compared to 4.4% misclassified by the IRT and correctly classified by PCE. The overall net reclassification improvement for the IRT was 5.9% (95% CI 4.7-7.0). When individuals were stratified into age-by-sex subgroups the improvement was larger for all subgroups (range 8.3%-15.4%), with best performance in 40-54yo men (15.4%, 95% CI 11.6-19.3). Comparable results were found using a different risk tool (QRISK3), and also a broader definition of cardiovascular disease. Use of the IRT is estimated to avoid up to 12,000 deaths in the USA over a 5-year period. Conclusions - An integrated risk tool that includes polygenic risk outperforms current risk stratification tools and offers greater opportunity for early interventions. Given the plummeting costs of genetic tests, future iterations of CAD risk tools would be enhanced with the addition of a person's polygenic risk.

Original publication




Journal article


Circulation. Genomic and precision medicine

Publication Date



Genomics plc, Oxford, United Kingdom.