A polygenic risk score (PRS) is derived from a genome-wide association study and represents an aggregate of thousands of single-nucleotide polymorphisms that provide a baseline estimate of an individual’s genetic risk for a specific disease or trait at birth. However, it remains unclear how PRSs can be used in clinical practice. We provide an overview of the PRSs related to cardiometabolic disease and discuss the evidence supporting their clinical applications and limitations. The Preferred Reporting Items For Systematic Reviews and Meta-Analysis Extension for Scoping Reviews protocol was used to conduct a scoping review of the MEDLINE, EMBASE, and CENTRAL databases. Across the 4863 studies screened, 82 articles met the inclusion criteria. The most common PRS related to coronary artery disease, followed by hypertension and cerebrovascular disease. Limited ancestral diversity was observed in the study sample populations. Most studies included only individuals of European ancestry. The predictive performance of most PRSs was similar to or superior to traditional risk factors. More than half of the included studies reported an integrated risk model combining a derived PRS and clinical risk tools such as the Framingham Risk Score and Pooled Cohort Equations. The inclusion of a PRS into a clinical risk model tended to improve predictive accuracy consistently. This scoping review is the first of its kind and reports strong evidence for the clinical utility of PRSs in coronary artery disease, hypertension, cerebrovascular disease, and atrial fibrillation. However, most PRSs are generated in cohorts of European ancestry, which likely contributes to a lack of PRS transferability across different ancestral groups. Future prospective studies should focus on further establishing the clinical utility of PRSs and ensuring diversity is incorporated into genome-wide association study cohorts.

Introduction: A polygenic risk score (PRS) is derived from a genome-wide association study (GWAS) and represents an aggregate of thousands of single-nucleotide polymorphisms (SNPs) that provide a baseline estimate of an individual’s genetic risk for a specific disease or trait at birth. Cardiometabolic disease represents a set of disease processes that historically have disproportionally affected underrepresented racial and minority groups. Furthermore, these groups represent a population generally not well captured by traditional risk scores compared to European cohorts. Since the first GWAS studying myocardial infarction was published, PRSs have increasingly been seen as a promising tool to improve risk stratification of non-European populations. However, how PRSs can be best used in clinical practice remains unclear. Hypothesis: We provide an overview of the PRSs related to cardiometabolic disease, analyze the ancestral diversity of GWAS cohorts, and discuss the evidence supporting their clinical applications. Methods: The Preferred Reporting Items For Systematic Reviews and Meta-analysis extension for Scoping Reviews protocol was used to conduct a scoping review of the MEDLINE, EMBASE, and CENTRAL databases. English studies that published a PRS related to atrial fibrillation (AF), cerebrovascular disease (CVD), coronary artery disease (CAD), dyslipidemia, heart failure, heritable cardiomyopathy, hypertension, and type 2 diabetes were reviewed. Results: Across the 4,863 studies screened, 82 articles met the inclusion criteria. The most common PRS related to CAD, followed by hypertension and CVD. Limited ancestral diversity was observed as most studies (56) included only individuals of European ancestry. A smaller proportion of studies (16) published PRSs derived in multi-ancestry cohorts. Only ten studies published a PRS derived solely from a sample population of non-European ancestry (Chinese, East Asian, Japanese, and Korean). The predictive performance of most PRSs was similar to or superior to traditional risk factors. More than half of the included studies (42) reported an integrated risk model combining a PRS with traditional risk factors or a clinical risk tool (FRS, PCE, CHADS2). The integrated risk model consistently improved predictive accuracy, but few studies investigated the performance in a non-European population. Conclusion: In conclusion, this scoping review reports strong evidence for the clinical use of PRSs in AF, CAD, CVD, and hypertension. However, most PRSs are derived in cohorts of European ancestry, which contributes to a lack of PRS transferability across different ancestral groups, likely exacerbating health inequities. Future prospective studies should focus on further establishing the clinical utility of PRSs. Additionally, diversity in future GWAS cohorts is essential to ensure that PRSs reflect the multi-ancestry society at large.