Current State and Future of Polygenic Risk Scores in Cardiometabolic Disease: A Scoping Review

Abstract

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.

A proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study)

“…Adding PRSs to established clinical risk models is a growing trend in cardiometabolic research, with reported AUC/ c -statistic values ranging from 0.61 to 0.82. 12 , 62 Our study also demonstrates the potential of PRSs as predictors for disease incidence, although their feasibility to clinical application remains an open question. 62 The differential separation achieved by AF-PRSs across studies might be in part due to differences in recruitment strategy, age of cohort at baseline, or the size of the base GWAS providing the estimates used to construct the AF-PRS.…”

“… 12 , 62 Our study also demonstrates the potential of PRSs as predictors for disease incidence, although their feasibility to clinical application remains an open question. 62 The differential separation achieved by AF-PRSs across studies might be in part due to differences in recruitment strategy, age of cohort at baseline, or the size of the base GWAS providing the estimates used to construct the AF-PRS. In our study, we additionally cannot exclude a potential influence of unknown sample overlap between the AGES-RS cohort and the AF GWAS.…”

The Inclusion of Underrepresented Populations in Cardiovascular Genetics and Epidemiology

“…A polygenic risk score (PRS) is one such method for aggregation-formulated using the sum of risk alleles identified in GWASs for a given phenotype-that has widespread and clinically relevant use [7][8][9]. In cardiovascular epidemiology, PRS development is improving risk prediction and shaping clinical management in atrial fibrillation [10,11], CAD [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30], cerebrovascular disease [31][32][33][34][35][36][37], hypertension [38][39][40][41][42][43][44][45], and heart failure [46][47][48][49].…”

Genetics-based risk scores for prediction of premature coronary artery disease

“…It may not be very useful in other populations such as South Asians, East Asians, other Asians, Africans and native populations in the Americas and Europe. 69 , 70 , 71 , 72 …”