Validation Study from Mass General Brigham Reveals New Tool Can Predict Patients’ Genetic Risk of Eight Cardiovascular Conditions

The Polygenic Risk Score, which is available to clinicians across the U.S., has potential to improve early detection and prevention of multiple cardiovascular diseases.

Researchers at Mass General Brigham Heart and Vascular Institute and collaborators have developed and validated a new genetic risk test that can estimate a person’s inherited risk for eight common cardiovascular conditions, offering a more comprehensive approach to prevention. In their validation study, they showed that individuals with high genetic risk scores had significantly greater odds of developing disease compared to those with average risk. Results are published in the Journal of the American College of Cardiology.

They note that the test, which is currently available through the Mass General Brigham Laboratory for Molecular Medicine and the Broad Clinical Labs, offers a more comprehensive approach to prevention.

“Interpreting DNA risk is new for the public as well as clinicians,” said co-senior author Pradeep Natarajan, MD, director of Preventive Cardiology at Mass General Brigham Heart and Vascular Institute. Natarajan is also an associate member at the Broad Institute of MIT and Harvard. “It was very important to us to provide a clear genetic risk report that would be accessible and patient friendly.”

Cardiovascular disease remains the leading cause of death worldwide. Identifying individuals at high risk, who can benefit from interventions such as medication or lifestyle changes, is critical for prevention. Traditional risk assessment relies on factors such as age, sex, blood pressure, and cholesterol. However, these measures may miss individuals who carry significant inherited risk.

To address this gap, Mass General Brigham researchers created an integrated polygenic risk score (PRS)—a single test that combines information from many genetic variants. The test evaluates a person’s genetic risk for eight conditions: coronary artery disease, atrial fibrillation, type 2 diabetes, venous thromboembolism, thoracic aortic aneurysm, extreme hypertension, severe hypercholesterolemia, and elevated lipoprotein(a).

The researchers used previously published genetic risk models from the Polygenic Score Catalog, a public database of validated DNA-based risk tools, and combined them into a single, more robust result for each condition. The tool was trained using genetic and health data from 245,000 participants in the National Institutes of Health’s All of Us Research Program and validated in 53,000 patients from the Mass General Brigham Biobank. Individuals with genetic risk scores in the top 10% were 3.7 times more likely to develop coronary artery disease, compared to those who were at average risk for coronary artery disease. Those in the highest genetic risk group for type 2 diabetes were 3.1 times more likely to develop the condition than those with average risk.

In addition to providing a patient’s genetic risk level for eight conditions (high, average, or low), the PRS report also explains each condition. The results are represented in easy-to-interpret graphs that show how the patient’s genetic risk compares to the general population. To make it easier for clinicians to consider a patient’s genetic risk in their healthcare decisions, the report integrates into electronic health records and patient portals.

The researchers note that while the test shows strong potential, additional studies are needed to determine how best to use genetic risk information in clinical decision-making and to ensure it performs well across diverse populations. A significant proportion of risk scores in the PGS Catalog, from which the PRS is based, are derived from populations of primarily European ancestry.

“Most patients who are at increased genetic risk for serious heart conditions have no idea because their traditional risk factors appear relatively normal. Our goal is to provide clinicians and patients with actionable, understandable information about their genetic risk for common cardiovascular diseases,” said co-senior Aniruddh Patel, MD, a cardiologist and researcher with Mass General Brigham Heart and Vascular Institute who helped develop the tool. “The tool already provides meaningful insight into cardiovascular risk, and we plan to continuously refine it as new genetic evidence emerges.”

Authorship: In addition to Natarajan and Patel, Mass General Brigham authors include 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, Whitney Hornsby, Matthew S. Lebo, and Elizabeth W. Karlson. Additional authors include Niall Lennon.

Disclosures: Perez reports consulting services for Allelica and Arboretum LifeSciences. Natarajan reports research grants from Allelica, Amgen, Apple, Boston Scientific, Cleerly, Genentech / Roche, Ionis, Novartis, and Silence Therapeutics, personal fees from Allelica, Apple, AstraZeneca, Bain Capital, Blackstone Life Sciences, Bristol Myers Squibb, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Esperion Therapeutics, Foresite Capital, Foresite Labs, Genentech / Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, Novo Nordisk, TenSixteen Bio, and Tourmaline Bio, equity in Bolt, Candela, Mercury, MyOme, Parameter Health, Preciseli, and TenSixteen Bio, royalties from Recora for intensive cardiac rehabilitation, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. Patel reports speaker’s fee from GenomicMD and investigator-sponsored research agreement with MyOme.

Funding: Research reported in this publication was supported by the US National Institutes of Health (NIH) for the Polygenic Risk Methods in Diverse Populations (PRIMED) Consortium, with grant funding for study site FFAIRR-PRS (U01HG011719) and the coordinating center (U01HG011697). This work was also supported by grants K23HL169839, K08HL168238 and R01HL127564 from the National Heart, Lung, and Blood Institute and grant 23CDA1050571 from the American Heart Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Paper cited: Misra A et al. “Development and Validation of a Clinical Polygenic Risk Report in US-Based Health Systems for Eight Cardiovascular Conditions” JACC DOI: 10.1016/j.jacc.2026.03.035