An integrated polygenic and clinical risk tool enhances coronary artery disease prediction

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 This research has been conducted using the UK Biobank (UKB) resource. We developed our own polygenic risk score (PRS) for coronary artery disease (CAD), using novel and established methods to combine published genomewide association study (GWAS) data with data from 114,196 UK Biobank individuals, also leveraging a large resource of other GWAS datasets along with functional information, to aid in the identification of causal variants, and thence define weights for > 8M genetic variants. We utilised a further 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 the UK’s QRISK3) which was then tested in an additional, independent, set of 212,563 UKB individuals. We evaluated prediction performance in individuals of European ancestry, both as a whole and stratified by age and sex. Findings The novel CAD PRS showed superior predictive power for CAD events, compared to other published PRSs. As an individual risk factor, it has similar predictive power to each of systolic blood pressure, HDL cholesterol, and LDL cholesterol, but is more predictive than total cholesterol and smoking history. Our novel CAD PRS is largely uncorrelated with PCE, QRISK3, and family history, and, when combined with PCE into an integrated risk tool, had superior predictive accuracy. In individuals reclassified as high risk, CAD event rates were markedly and significantly higher compared to those reclassified as low risk. Overall, 9.7% of incident CAD cases were misclassified as low risk by PCE and correctly classified as high risk by the IRT, in contrast to 3.7% misclassified by the IRT and correctly classified by PCE. The overall net reclassification improvement for the IRT was 5.7% (95% CI 4.4−7.0), but when individuals were stratified into four age-by-sex subgroups the improvement was larger for all subgroups (range 7.7%−17.3%), with best performance in younger middle-aged men aged 40–54yo (17.3%, 95% CI 13.0–21.5). Broadly similar results were found using a different risk tool (QRISK3), and also for cardiovascular disease events defined more broadly. Interpretation An integrated risk tool that includes polygenic risk outperforms current, clinical 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. Funding Genomics plc ### Competing Interest Statement FRM, MEW, RM, SS, EK, RMS, WAT, PS, ASL, JAG, AS, CCAS, VP and PD are employees and PD is a Director of Genomics plc, a genomics healthcare company with an interest in the application of genetics to precision health. Funding for this study was provided by Genomics plc. PD is also a partner in Peptide Groove LLP. ### Funding Statement Funding for this study was provided by Genomics plc. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This research has been conducted using the UK Biobank (UKB) resource. The REC reference for UK Biobank is 16/NW/0274. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The values of the polygenic risk scores using our novel CAD PRS for the 212,563 individuals on whom they were evaluated in the paper will be returned to UK Biobank so that they can be made available to approved UK Biobank researchers. The UKB Group I GWAS summary statistics will be shared by Genomics plc on a public data repository. Please contact author VP for details.