Guo Boya, Cai Yanwei, Kim Daeeun, Smit Roelof A J, Wang Zhe, Iyer Kruthika R, Hilliard Austin T, Haessler Jeffrey, Tao Ran, Broadaway K Alaine, Wang Yujie, Pozdeyev Nikita, Stæger Frederik F, Yang Chaojie, Vanderwerff Brett, Patki Amit D, Stalbow Lauren, Lin Meng, Rafaels Nicholas, Shortt Jonathan, Wiley Laura, Stanislawski Maggie, Pattee Jack, Davis Lea, Straub Peter S, Shuey Megan M, Cox Nancy J, Lee Nanette R, Jørgensen Marit E, Bjerregaard Peter, Larsen Christina, Hansen Torben, Moltke Ida, Meigs James B, Stram Daniel O, Yin Xianyong, Zhou Xiang, Chang Kyong-Mi, Clarke Shoa L, Guarischi-Sousa Rodrigo, Lankester Joanna, Tsao Philip S, Buyske Steven, Graff Mariaelisa, Raffield Laura M, Sun Quan, Wilkens Lynne R, Carlson Christopher S, Easton Charles B, Liu Simin, Manson JoAnn E, Marchand Loïc L, Haiman Christopher A, Mohlke Karen L, Gordon-Larsen Penny, Albrechtsen Anders, Boehnke Michael, Rich Stephen S, Manichaikul Ani, Rotter Jerome I, Yousri Noha A, Irvin Ryan M, Gignoux Chris, North Kari E, Loos Ruth J F, Assimes Themistocles L, Peters Ulrike, Kooperberg Charles, Raghavan Sridharan, Highland Heather M, Darst Burcu F
medRxiv. 2025 Feb 20:2025.02.15.25322341. doi: 10.1101/2025.02.15.25322341.
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.
多基因风险评分（PRS）对于识别2型糖尿病（T2D）风险较高的个体具有预后价值。然而，需要进一步的特征描述来了解T2D PRS在不同背景下的不同人群中的普遍性。我们在来自人群结构基因组学与流行病学（PAGE）研究的八个群体以及另外13个生物样本库和队列中的244,637例病例和637,891例对照中，对多血统T2D PRS进行了特征描述。PRS的表现取决于背景，在年龄较小、男性、有T2D家族史、无高血压且不肥胖或超重的人群中表现更好。此外，PRS与各种糖尿病相关的心脏代谢特征和T2D并发症相关，表明其在分层并发症风险和识别T2D与其他疾病之间共享遗传结构方面的效用。这些发现凸显了在评估PRS作为T2D风险预后工具时考虑背景的必要性，以及尽管T2D PRS在不同人群的T2D预测中表现不同，但它与糖尿病相关特征可能存在普遍关联。
