(Press-News.org) Type 2 diabetes (T2D) and obesity are metabolic conditions with many causes, including overlapping and distinct genetic features. A polygenic risk score (PRS) can capture multiple genetic risk factors to provide an estimate for whether a person may develop a complex medical condition and how they might fare long-term. By integrating genetic findings from several of the world’s largest biobanks, investigators from Mass General Brigham built metabolic PRSs for predicting obesity and T2D, which outperformed existing disease-prediction models and predicted downstream morbidity and clinical interventions. Findings are published in Cell Metabolism.
“Our intention was to not only capture the risk of being diagnosed with obesity or diabetes, but also to better predict health consequences across the life course by integrating many aspects of metabolic function,” said co-first author Min Seo Kim, MD, MSc. “In the future, this genomic approach could complement established clinical risk factors to inform patient care and preventative strategies.”
The metabolic PRS designed by the researchers includes one version optimized for obesity and another for T2D. Both scores look beyond widely utilized variables, such as body mass index, and focus on genes associated with 20 different traits related to metabolic function, such as fat distribution and insulin and glucose control. The team used genome-wide association studies (GWAS) performed in some of the largest datasets worldwide, which collectively encompass over 8.5 million participants globally.
The researchers found that the risk scores identified individuals at high risk for clinical outcomes like cardiovascular disease and stroke. Individuals with a high PRS who were initially healthy were about twice as likely to later receive GLP‑1 agonist medications or bariatric surgery compared to those with mid-range PRS scores, during a follow-up period of median 5.5 years.
The use of multi-ancestry GWAS data, with a particular focus on non-European populations, enabled the construction of obesity and T2D risk scores that surpassed prior PRS models in African, East Asian, and South Asian individuals.
Going forward, the researchers hope to continue refining understandings of the genetic subtypes of T2D and obesity to improve patient classification and stratification for clinical trials and ultimately foster more tailored interventions.
“We want clinicians to be able to think about metabolic conditions in terms beyond body mass index, with a focus more broadly on underlying genetic susceptibility,” said co-senior author Akl Fahed, MD, MPH, of the Cardiovascular Research Center at Massachusetts General Hospital and an interventional cardiologist with the Mass General Brigham Heart and Vascular Institute. “Early identification of people who are likely to have a worse trajectory of poor metabolic health, before they even develop these conditions, can help us improve prevention and clinical interventions. That is how we can cure disease, and that is the bold mission that we are after.”
Authorship: In addition to Kim and Fahed, Mass General Brigham authors include Yang Sui (co-first), Lu-Chen Weng, So Mi Jemma Cho, Satoshi Koyama, Pradeep Natarajan, and Patrick T. Ellinor (co-senior). Additional authors include Qiuli Chen (co-first), Xiong Yang, Shaoqi Wang, Xinyu Zhu, Kang Yu, Xingyu Chen, Rufan Zhang, Wanqing Yin, Shuangqiao Liao, Zhaoqi Liu3, Fowzan S Alkuraya, and Minxian Wang (co-senior).
Disclosures: Ellinor has received sponsored research support from Bayer AG, IBM Health, Bristol Myers Squibb and Pfizer and Novo Nordisk. Ellinor has also served on advisory boards or consulted for Bayer AG, MyoKardia, and Novartis. Natarajan reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech / Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Esperion Therapeutics, Foresite Labs, Genentech / Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, TenSixteen Bio, and Tourmaline Bio, equity in Bolt, Candela, Mercury, MyOme, Parameter Health, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. Fahed reports being co-founder of Goodpath, serving as scientific advisor to MyOme and HeartFlow, and receiving a research grant from Foresite Labs. The remaining authors declare no competing interests.
Funding: Sui is supported by the TOPMed fellowship from the National Heart Lung and Blood Institute. Wang was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project-2023ZD0503201 and the Pioneering Action Grants of the Chinese Academy of Sciences, National Natural Science Foundation of China (grant number 82470352), Strategic Priority Research Program of the Chinese Academy of Sciences, Grant No. XDA0460400. Natarajan is supported by grants from the National Institutes of Health (R01HL127564, U01HG011719), Ellinor is supported by grants from the National Institutes of Health (1R01HL092577, 1R01HL157635, 5R01HL139731), from the American Heart Association Strategically Focused Research Networks (18SFRN34110082), and from the European Union (MAESTRIA 965286). Natarajan is supported by grant from National Human Genome Research Institute (U01HG011719). Fahed is supported by grants from the National Heart Lung and Blood Institute (K08HL161448 and R01HL164629).
Paper cited: Kim MS et al. “Metabolic Polygenic Risk Scores for Prediction of Obesity, Type 2 Diabetes, and Related Morbidities” Cell Metabolism DOI: 10.1016/j.cmet.2026.02.009
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About Mass General Brigham
Mass General Brigham is an integrated academic health care system, uniting great minds to solve the hardest problems in medicine for our communities and the world. Mass General Brigham connects a full continuum of care across a system of academic medical centers, community and specialty hospitals, a health insurance plan, physician networks, community health centers, home care, and long-term care services. Mass General Brigham is a nonprofit organization committed to patient care, research, teaching, and service to the community. In addition, Mass General Brigham is one of the nation’s leading biomedical research organizations with several Harvard Medical School teaching hospitals. For more information, please visit massgeneralbrigham.org.
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