Naderian, Mohammadreza; Smith, Johanna L.; Dikilitas, Ozan; Hamed, Marwan E.; Abul-Husn, Noura S.; Connolly, John J.; Cortopassi, Josh B.; Feng, Qiping; Hanks, Sarah C.; Irvin, Ryan; Jarvik, Gail P.; Kenny, Eimear E.; Khan, Atlas; Kottyan, Leah C.; Limdi, Nita A.; McNally, Elizabeth M.; Miller, Emily; Namjou-Khales, Bahram; Roy-Puckelwartz, Megan; Rowley, Robb; Tiwari, Hemant K.; Wei, Wei-Qi; Wiesner, Georgia; Manolio, Teri A.; Sharp, Richard R.; Kullo, Iftikhar J. (2026). . American Journal of Human Genetics, 113(8), 1618鈥�1629.
Genetic factors and family history can influence a person鈥檚 risk of coronary heart disease (CHD), but it is unclear how much they improve risk prediction across different racial and ethnic groups. This study examined two large and diverse U.S. cohorts: 19,348 participants from eMERGE and 239,645 from the All of Us Research Program. Researchers evaluated a polygenic risk score, which estimates genetic risk based on many common genetic variants, genetic variants linked to familial hypercholesterolemia (FH), an inherited condition causing very high cholesterol, and family history of CHD. The polygenic risk score and family history were independently associated with CHD, and their effects were additive and consistent among self-identified White, Black, and Latino participants. In eMERGE, adding these factors to a standard clinical risk calculator improved CHD prediction and reclassified 18.8% of participants at a commonly used 10-year risk threshold. This resulted in about four additional people with CHD being correctly identified per 1,000 people screened. Improvements were observed across all three racial and ethnic groups. These findings suggest that incorporating polygenic risk and family history into clinical risk assessments may improve the identification of people at increased risk of CHD across diverse populations.
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