TY - JOUR
T1 - Polygenic risk score for type 2 diabetes shows context-dependent effects across populations
AU - The biobank at the Colorado Center for Personalized Medicine (CCPM)
AU - VA Million Veteran Program (MVP)
AU - Guo, Boya
AU - Cai, Yanwei
AU - Kim, Daeeun
AU - Smit, Roelof A.J.
AU - Wang, Zhe
AU - Iyer, Kruthika R.
AU - Hilliard, Austin T.
AU - Haessler, Jeffrey
AU - Tao, Ran
AU - Broadaway, K. Alaine
AU - Wang, Yujie
AU - Pozdeyev, Nikita
AU - Stæger, Frederik F.
AU - Yang, Chaojie
AU - Vanderwerff, Brett
AU - Patki, Amit D.
AU - Stalbow, Lauren
AU - Lin, Meng
AU - Rafaels, Nicholas
AU - Shortt, Jonathan
AU - Wiley, Laura
AU - Stanislawski, Maggie
AU - Pattee, Jack
AU - Davis, Lea
AU - Straub, Peter S.
AU - Shuey, Megan M.
AU - Cox, Nancy J.
AU - Lee, Nanette R.
AU - Jørgensen, Marit E.
AU - Bjerregaard, Peter
AU - Larsen, Christina
AU - Hansen, Torben
AU - Moltke, Ida
AU - Meigs, James B.
AU - Stram, Daniel O.
AU - Yin, Xianyong
AU - Zhou, Xiang
AU - Chang, Kyong Mi
AU - Clarke, Shoa L.
AU - Guarischi-Sousa, Rodrigo
AU - Lankester, Joanna
AU - Tsao, Philip S.
AU - Buyske, Steven
AU - Graff, Mariaelisa
AU - Raffield, Laura M.
AU - Sun, Quan
AU - Wilkens, Lynne R.
AU - Carlson, Christopher S.
AU - Easton, Charles B.
AU - Pyarajan, Saiju
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - Polygenic risk scores hold prognostic value for identifying individuals at higher risk of type 2 diabetes. However, further characterization is needed to understand the generalizability of type 2 diabetes polygenic risk scores in diverse populations across various contexts. We systematically characterize a multi-ancestry type 2 diabetes polygenic risk score among 244,637 cases and 637,891 controls across diverse populations from the Population Architecture Genomics and Epidemiology Study and 13 additional biobanks and cohorts. Polygenic risk score performance is context dependent, with better performance in those who are younger, male, without hypertension, and not obese or overweight. Additionally, the polygenic risk score is associated with various diabetes-related cardiometabolic traits and type 2 diabetes complications, suggesting its utility for stratifying risk of complications and identifying shared genetic architecture between type 2 diabetes and other diseases. These findings highlight the need to account for context when evaluating polygenic risk score as a tool for type 2 diabetes risk prognostication and the potentially generalizable associations of type 2 diabetes polygenic risk score with diabetes-related traits, despite differential performance in type 2 diabetes prediction across diverse populations. Our study provides a comprehensive resource to characterize a type 2 diabetes polygenic risk score.
AB - Polygenic risk scores hold prognostic value for identifying individuals at higher risk of type 2 diabetes. However, further characterization is needed to understand the generalizability of type 2 diabetes polygenic risk scores in diverse populations across various contexts. We systematically characterize a multi-ancestry type 2 diabetes polygenic risk score among 244,637 cases and 637,891 controls across diverse populations from the Population Architecture Genomics and Epidemiology Study and 13 additional biobanks and cohorts. Polygenic risk score performance is context dependent, with better performance in those who are younger, male, without hypertension, and not obese or overweight. Additionally, the polygenic risk score is associated with various diabetes-related cardiometabolic traits and type 2 diabetes complications, suggesting its utility for stratifying risk of complications and identifying shared genetic architecture between type 2 diabetes and other diseases. These findings highlight the need to account for context when evaluating polygenic risk score as a tool for type 2 diabetes risk prognostication and the potentially generalizable associations of type 2 diabetes polygenic risk score with diabetes-related traits, despite differential performance in type 2 diabetes prediction across diverse populations. Our study provides a comprehensive resource to characterize a type 2 diabetes polygenic risk score.
UR - https://www.scopus.com/pages/publications/105017565324
U2 - 10.1038/s41467-025-63546-4
DO - 10.1038/s41467-025-63546-4
M3 - Article
C2 - 41034193
AN - SCOPUS:105017565324
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 8632
ER -