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[Preprint]. 2025 Feb 20:2025.02.15.25322341.
doi: 10.1101/2025.02.15.25322341.

Type 2 diabetes polygenic risk score demonstrates context-dependent effects and associations with type 2 diabetes-related risk factors and complications across diverse populations

Boya Guo, Yanwei Cai, Daeeun Kim, Roelof A J Smit, Zhe Wang, Kruthika R Iyer, Austin T Hilliard, Jeffrey Haessler, Ran Tao, K Alaine Broadaway, Yujie Wang, Nikita Pozdeyev, Frederik F Stæger, Chaojie Yang, Brett Vanderwerff, Amit D Patki, Lauren Stalbow, Meng Lin, Nicholas Rafaels, Jonathan Shortt, Laura Wiley, Maggie Stanislawski, Jack Pattee, Lea Davis, Peter S Straub, Megan M Shuey, Nancy J Cox, Nanette R Lee, Marit E Jørgensen, Peter Bjerregaard, Christina Larsen, Torben Hansen, Ida Moltke, James B Meigs, Daniel O Stram, Xianyong Yin, Xiang Zhou, Kyong-Mi Chang, Shoa L Clarke, Rodrigo Guarischi-Sousa, Joanna Lankester, Philip S Tsao, Steven Buyske, Mariaelisa Graff, Laura M Raffield, Quan Sun, Lynne R Wilkens, Christopher S Carlson, Charles B Easton, Simin Liu, JoAnn E Manson, Loïc L Marchand, Christopher A Haiman, Karen L Mohlke, Penny Gordon-Larsen, Anders Albrechtsen, Michael Boehnke, Stephen S Rich, Ani Manichaikul, Jerome I Rotter, Noha A Yousri, Ryan M Irvin; biobank at the Colorado Center for Personalized Medicine; VA Million Veteran Program; Population Architecture using Genomics and Epidemiology (PAGE) study; Chris Gignoux, Kari E North, Ruth J F Loos, Themistocles L Assimes, Ulrike Peters, Charles Kooperberg, Sridharan Raghavan, Heather M Highland, Burcu F Darst

Type 2 diabetes polygenic risk score demonstrates context-dependent effects and associations with type 2 diabetes-related risk factors and complications across diverse populations

Boya Guo et al. medRxiv. .

Abstract

Polygenic risk scores (PRS) hold prognostic value for identifying individuals at higher risk of type 2 diabetes (T2D). However, further characterization is needed to understand the generalizability of T2D PRS in diverse populations across various contexts. We characterized a multi-ancestry T2D PRS among 244,637 cases and 637,891 controls across eight populations from the Population Architecture Genomics and Epidemiology (PAGE) Study and 13 additional biobanks and cohorts. PRS performance was context dependent, with better performance in those who were younger, male, with a family history of T2D, without hypertension, and not obese or overweight. Additionally, the PRS was associated with various diabetes-related cardiometabolic traits and T2D complications, suggesting its utility for stratifying risk of complications and identifying shared genetic architecture between T2D and other diseases. These findings highlight the need to account for context when evaluating PRS as a tool for T2D risk prognostication and potentially generalizable associations of T2D PRS with diabetes-related traits despite differential performance in T2D prediction across diverse populations.

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