New polygenic risk scores improve prediction of metabolic disease outcomes

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. In the future, this genomic approach could complement established clinical risk factors to inform patient care and preventative strategies."

Min Seo Kim, MD, MSc, co-first author 

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."