Top Things to Know: Polygenic Risk Scores for CVD

Published: July 18, 2022

  1. Cardiovascular (CV) disease is the leading cause of global death and disability, yet current risk prediction methods are imprecise and based on broad clinical and cohort-related factors, limiting risk mitigation. Advances in understanding of the genetics of disease are enabling the inclusion of genetic information in disease-predictive risk factors.
  2. Monogenic risk variants that contribute to some CV diseases such as familial hypercholesterolemia arise from a variation in a single gene, are typically rare and confer a large risk of disease. Observations of complex and less severe forms of CVD clustering in families supports the idea of multiple genes or other factors contributing to disease development.
  3. The availability of large genome-wide association studies (GWAS) has increasingly shown that many SNVs in the genome contribute to CVD risk, confirming the polygenic basis of cardiometabolic disease. Polygenic risk scores (PRS) are calculated as weighted summations of risk conferred by multiple disease associated SNVs across the genome.
  4. Although PRS information is becoming more widely available, their interpretation and clinical considerations are not well understood. The current science, the benefits and cost of implementation for patients, clinicians and administrators, and gaps in understanding about clinical use of PRS for CVD are discussed.
  5. Specific focus is placed on the considerations of implementing PRS for five cardiometabolic diseases; coronary artery disease, hypercholesterolemia, type 2 diabetes mellitus, atrial fibrillation, and venous thromboembolic disease, providing provisional guidance to clinician, researchers, policy makers and patients on the use of PRS in CVD risk assessment and reduction.
  6. In accordance with the NHLBI 2020 guidelines on the use and reporting of race, ethnicity, and ancestry, and the AHA 2020 Presidential Advisory on structural racism as a fundamental driver of health disparities, the term ‘ethnicity’ is used to refer to social categories including both race and ethnicity, while the term ‘ancestry’ is used for inferences from genetic data. While these terms may be correlated, they are not synonymous.
  7. Another rapidly evolving area for use of PRS is for CV pharmacogenomics. The goals of pharmacogenomic PRS are prediction of gene variant impacts on drug efficacy, prediction of drug toxicity, identifying genetic subgroups of drug responders and prediction of adverse CV reactions for non-CV drugs.
  8. Healthcare systems wishing to implement PRS for CV risk prediction and mitigation are advised to first weigh the benefits and costs within three broad categories: efficacy of PRS in improving the accuracy of clinical risk tools above current levels, inclusion of guidance in addressing potential harms, particularly in areas where racial or ethnic disparities exist, and finally the logistics of acquiring high-quality genomic data for PRS calculation and education for their use.
  9. Practical considerations for commercial genetics organization and payors are discussed, including regulatory requirements for the development and certification of PRS tests, how to report an individual’s risk, and communication for medical follow up. Cost-benefit analysis of testing is also needed, as well ethical considerations for future use of the genetic information.
  10. Recent advances in understanding how genetic variants may contribute to risk of CVD has revealed that many have a polygenic basis and CV PRS are beginning to enter clinical practice. This scientific statement provides a concise summary of the current science, identifies knowledge gaps, and makes suggestions for improving performance and communication of polygenic risk scores


O’Sullivan JW, Raghavan S, Marquez-Luna C, Luzum JA, Damrauer SM, Ashley EA, O’Donnell CJ, Willer CJ, Natarajan P; on behalf of the American Heart Association Council on Genomic and Precision Medicine; Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease. Polygenic risk scores for cardiovascular disease: a scientific statement from the American Heart Association [published online ahead of print July 18, 2022]. Circulation. doi: 10.1161/CIR.0000000000001077