Development and Validation of a Clinical Polygenic Risk Report in U.S.-Based Health Systems for 8 Cardiovascular Conditions

Anika Misra; Amanda Jowell; Sara Haidermota; Emma Perez; Lisa Mahanta; Kimberly J O'Brien; Anna Nagy; Limin Hao; Buu Truong; Krishna Aragam; Akl C Fahed; Shaan Khurshid; Patrick T Ellinor; Anna C F Lewis; Niall Lennon; Whitney Hornsby; Matthew S Lebo; Elizabeth W Karlson; Pradeep Natarajan; Aniruddh P Patel

doi:10.1016/j.jacc.2026.03.035

Development and Validation of a Clinical Polygenic Risk Report in U.S.-Based Health Systems for 8 Cardiovascular Conditions

J Am Coll Cardiol. 2026 Apr 29:S0735-1097(26)05809-2. doi: 10.1016/j.jacc.2026.03.035. Online ahead of print.

Authors

Anika Misra¹, Amanda Jowell², Sara Haidermota¹, Emma Perez³, Lisa Mahanta⁴, Kimberly J O'Brien⁴, Anna Nagy⁴, Limin Hao⁴, Buu Truong⁵, Krishna Aragam⁵, Akl C Fahed⁶, Shaan Khurshid⁷, Patrick T Ellinor⁷, Anna C F Lewis⁸, Niall Lennon⁹, Whitney Hornsby¹, Matthew S Lebo¹⁰, Elizabeth W Karlson¹¹, Pradeep Natarajan¹², Aniruddh P Patel¹³

Affiliations

¹ Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
² Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; Mass General Brigham Department of Medicine, Boston, Massachusetts, USA.
³ Mass General Brigham Department of Medicine, Boston, Massachusetts, USA; Mass General Brigham Personalized Medicine, Boston, Massachusetts, USA.
⁴ Mass General Brigham Personalized Medicine, Boston, Massachusetts, USA.
⁵ Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
⁶ Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Mass General Brigham Heart and Vascular Institute, Boston, Massachusetts, USA.
⁷ Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Mass General Brigham Heart and Vascular Institute, Boston, Massachusetts, USA; Telemachus and Irene Demoulas Family Foundation Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁸ Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Department of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.
⁹ Genomic Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹⁰ Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Mass General Brigham Personalized Medicine, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
¹¹ Mass General Brigham Department of Medicine, Boston, Massachusetts, USA; Mass General Brigham Personalized Medicine, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
¹² Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Mass General Brigham Heart and Vascular Institute, Boston, Massachusetts, USA. Electronic address: pnatarajan@mgh.harvard.edu.
¹³ Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Mass General Brigham Heart and Vascular Institute, Boston, Massachusetts, USA. Electronic address: apatel32@mgh.harvard.edu.

PMID: 42053472
DOI: 10.1016/j.jacc.2026.03.035

Abstract

Background: Polygenic risk scores (PRS) stratify inherited cardiovascular risk, but their path to clinical implementation remains unclear.

Objectives: We aimed to develop and validate integrated PRS for 8 cardiovascular conditions and outline a framework for their clinical reporting.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: biobank; genomics; prevention; risk stratification; screening.

Abstract

Grants and funding