Development and Validation of a Clinical Polygenic Risk Report in U.S.-Based Health Systems for 8 Cardiovascular Conditions.
Anika, M., Amanda, J., Sara, H., Emma, P., Lisa, M., J, O.K., Anna, N., Limin, H., Buu, T., Krishna, A., C, F.A., Shaan, K., T, E.P., F, L.A.C., Niall, L., Whitney, H., S, L.M., W, K.E., Pradeep, N., & P, P.A. (2026). Development and Validation of a Clinical Polygenic Risk Report in U.S.-Based Health Systems for 8 Cardiovascular Conditions.. J Am Coll Cardiol. https://doi.org/10.1016/j.jacc.2026.03.035
Anika M, Amanda J, Sara H, Emma P, Lisa M, J OK, et al. Development and Validation of a Clinical Polygenic Risk Report in U.S.-Based Health Systems for 8 Cardiovascular Conditions.. J Am Coll Cardiol. 2026; doi: 10.1016/j.jacc.2026.03.035
Anika M, Amanda J, Sara H, et al. Development and Validation of a Clinical Polygenic Risk Report in U.S.-Based Health Systems for 8 Cardiovascular Conditions.[J]. J Am Coll Cardiol. 2026. DOI: 10.1016/j.jacc.2026.03.035.
@article{anika2026,
author = {Misra Anika and Jowell Amanda and Haidermota Sara and Perez Emma and Mahanta Lisa and O'Brien Kimberly J and Nagy Anna and Hao Limin and Truong Buu and Aragam Krishna and Fahed Akl C and Khurshid Shaan and Ellinor Patrick T and Lewis Anna C F and Lennon Niall and Hornsby Whitney and Lebo Matthew S and Karlson Elizabeth W and Natarajan Pradeep and Patel Aniruddh P},
title = {Development and Validation of a Clinical Polygenic Risk Report in U.S.-Based Health Systems for 8 Cardiovascular Conditions.},
journal = {J Am Coll Cardiol},
year = {2026},
doi = {10.1016/j.jacc.2026.03.035},
note = {PMID: 42053472},
}
TY - JOUR AU - Misra Anika AU - Jowell Amanda AU - Haidermota Sara AU - Perez Emma AU - Mahanta Lisa AU - O'Brien Kimberly J AU - Nagy Anna AU - Hao Limin AU - Truong Buu AU - Aragam Krishna AU - Fahed Akl C AU - Khurshid Shaan AU - Ellinor Patrick T AU - Lewis Anna C F AU - Lennon Niall AU - Hornsby Whitney AU - Lebo Matthew S AU - Karlson Elizabeth W AU - Natarajan Pradeep AU - Patel Aniruddh P TI - Development and Validation of a Clinical Polygenic Risk Report in U.S.-Based Health Systems for 8 Cardiovascular Conditions. T2 - J Am Coll Cardiol PY - 2026 DO - 10.1016/j.jacc.2026.03.035 AN - PMID:42053472 ER -
Polygenic risk scores (PRS) stratify inherited cardiovascular risk, but their path to clinical implementation remains unclear. We aimed to develop and validate integrated PRS for 8 cardiovascular conditions and outline a framework for their clinical reporting. We analyzed genotype and clinical data from 245,394 All of Us Research Program participants. Publicly available PRS for 8 traits-coronary artery disease, atrial fibrillation, type 2 diabetes, venous thromboembolism (VTE), thoracic aortic aneurysm (TAA), extreme hypertension, severe hypercholesterolemia, and elevated lipoprotein(a)-were combined using PRSmix, an elastic-net approach. Integrated PRS were externally validated in 53,306 Mass General Brigham Biobank participants using logistic regression, adjusting for age, sex, and ancestry. Of 53,306 genotyped Mass General Brigham Biobank participants (55.6% women, mean age 53 ± 17 years), integrated PRS demonstrated robust discrimination and appropriate calibration across 8 cardiovascular traits. Comparing high genetic risk (top 10% of PRS distribution, or top 20% for rarer TAA and VTE) vs average risk (26th-75th percentiles, or 21st-80th percentiles for TAA and VTE) yielded ORs: coronary artery disease (3.7 [95% CI: 3.4-4.1]), type 2 diabetes (3.1 [95% CI: 2.8-3.3]), atrial fibrillation (3.0 [95% CI: 2.7-3.3]), VTE (1.9 [95% CI: 1.6-2.0]), TAA (1.7 [95% CI: 1.5-1.9]), hypertension (2.1 [95% CI: 1.8-2.3]), hypercholesterolemia (4.1 [95% CI: 3.7-4.5]), and lipoprotein(a) (41.0 [95% CI: 27.0-62.2]). Incorporating integrated PRS into clinical models improved risk classification, while prospective analyses confirmed significant associations with incident cardiovascular outcomes. Integrated PRS offer an implementable framework for genetic risk reporting, and are now available as a clinically orderable test. Broader prospective validation studies are needed to further establish clinical utility.