Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

作者：A. Mahajan, C. Spracklen, Weihua Zhang, M. Ng, L. Petty, Hidetoshi Kitajima, G. Yu, S. Rüeger, L. Speidel, Y. J. Kim, M. Horikoshi, J. Mercader, D. Taliun, Sanghoon Moon, S. Kwak, N. Robertson, N. W. Rayner, M. Loh, Bong-Jo Kim, Joshua Chiou, I. Miguel-Escalada, Pietro della Briotta Parolo, Kuang Lin, F. Bragg, Michael H. Preuss, F. Takeuchi, J. Nano, Xiuqing Guo, A. Lamri, M. Nakatochi, R. Scott, Jung-Jin Lee, A. Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, E. Parra, Jie Yao, L. Bielak, Y. Tabara, Y. Hai, V. Steinthorsdottir, J. Cook, M. Kals, N. Grarup, Ellen M. Schmidt, I. Pan, T. Sofer, M. Wuttke, C. Sarnowski, C. Gieger, Darryl Nousome, S. Trompet, J. Long, Meng Sun, L. Tong, Wei-Min Chen, Meraj Ahmad, R. Noordam, V. J. Lim, Claudia H. T. Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, L. Raffield, C. Lecoeur, N. Maruthur, B. Prins, A. Nicolas, L. Yanek, Guanjie Chen, R. Jensen, S. Tajuddin, E. Kabagambe, P. An, A. Xiang, Hyeok Sun Choi, B. Cade, Jingyi Tan, F. Abaitua, L. Adair, A. Adeyemo, C. Aguilar-Salinas, M. Akiyama, Sonia S Anand, A. Bertoni, Z. Bian, J. Bork-Jensen, I. Brandslund, J. Brody, C. Brummett, T. Buchanan, M. Canouil, J. Chan, Li-Ching Chang, M. Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, L. Chuang, M. Cushman, S. Das, H. J. de Silva, G. Dedoussis, Latchezar Dimitrov, A. Doumatey, S. Du, Qing Duan, K. Eckardt, L. Emery, Daniel S. Evans, M. Evans, K. Fischer, J. Floyd, I. Ford, M. Fornage, O. Franco, T. Frayling, B. Freedman, C. Fuchsberger, P. Genter, H. Gerstein, V. Giedraitis, C. González‐Villalpando, M. González-Villalpando, M. Goodarzi, P. Gordon-Larsen, David U. Gorkin, M. Gross, Yu Guo, S. Hackinger, Sohee Han, A. Hattersley, C. Herder, A. Howard, W. Hsueh, Mengna Huang, Wei Huang, Y. Hung, M. Y. Hwang, C. Hwu, S. Ichihara, M. Ikram, M. Ingelsson, Md. Tariqul Islam, M. Isono, Hye-Mi Jang, F. Jasmine, Guozhi Jiang, J. Jonas, M. Jørgensen, T. Jørgensen, Y. Kamatani, F. Kandeel, A. Kasturiratne, T. Katsuya, V. Kaur, T. Kawaguchi, Jacob M. Keaton, A. Kho, C. Khor, M. Kibriya, Duk-Hwan Kim, K. Kohara, J. Kriebel, F. Kronenberg, J. Kuusisto, Kristi Läll, L. Lange, Myung-Shik Lee, N. Lee, A. Leong, Liming Li, Yun Li, R. Li-Gao, Symen Ligthart, C. Lindgren, A. Linneberg, Ching‐Ti Liu, Jianjun Liu, A. Locke, T. Louie, J. Luan, A. Luk, Xi Luo, J. Lv, V. Lyssenko, Vasiliki Mamakou, K. R. Mani, T. Meitinger, A. Metspalu, A. Morris, G. Nadkarni, Jerry L. Nadler, M. Nalls, U. Nayak, I. Ntalla, Y. Okada, L. Orozco, Sanjay R. Patel, Mark A Pereira, A. Peters, F. Pirie, Bianca C. Porneala, Gauri Prasad, Sebastian Preissl, L. Rasmussen-Torvik, A. Reiner, M. Roden, Rebecca R. Rohde, K. Roll, C. Sabanayagam, M. Sander, K. Sandow, N. Sattar, S. Schönherr, C. Schurmann, M. Shahriar, Jinxiu Shi, Dong Mun Shin, D. Shriner, Jennifer A. Smith, W. So, A. Stančáková, A. Stilp, K. Strauch, Ken Suzuki, A. Takahashi, K. Taylor, B. Thorand, G. Thorleifsson, U. Thorsteinsdóttir, B. Tomlinson, Jason M. Torres, F. Tsai, J. Tuomilehto, Teresa Tusié-Luna, M. Udler, A. Valladares-Salgado, R. V. van Dam, J. V. van Klinken, R. Varma, Marijana Vujković, N. Wacher-Rodarte, Ellie Wheeler, E. Whitsel, A. R. Wickremasinghe, K. W. van Dijk, D. Witte, C. Yajnik, Ken Yamamoto, T. Yamauchi, L. Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, S. Yusuf, Liang Zhang, Wei Zheng, Finngen, L. Raffel, M. Igase, E. Ipp, S. Redline, Y. Cho, L. Lind, M. Province, C. Hanis, P. Peyser, E. Ingelsson, A. Zonderman, B. Psaty, Yaxing Wang, C. Rotimi, D. Becker, F. Matsuda, Yongmei Liu, E. Zeggini, M. Yokota, S. Rich, C. Kooperberg, J. Pankow, J. Engert, Y. Chen, P. Froguel, James G. Wilson, W. Sheu, S. Kardia, Jer-Yuarn Wu, M. Hayes, R. Ma, T. Wong, L. Groop, D. Mook-Kanamori, G. Chandak, F. Collins, D. Bharadwaj, G. Paré, M. Sale, H. Ahsan, A. Motala, X. Shu, K. Park, J. Jukema, M. Cruz, R. Mckean-Cowdin, H. Grallert, Ching-Yu Cheng, E. Bottinger, A. Dehghan, E. Tai, J. Dupuis, N. Kato, M. Laakso, A. Köttgen, W. Koh, C. Palmer, Simin Liu, G. Abecasis, J. Kooner, R. Loos, K. North, C. Haiman, J. Florez, D. Saleheen, T. Hansen, O. Pedersen, R. Mägi, C. Langenberg, N. Wareham, S. Maeda, T. Kadowaki, Juyoung Lee, I. Millwood, R. Walters, K. Stefánsson, S. Myers, J. Ferrer, K. Gaulton, J. Meigs, K. Mohlke, A. Gloyn, D. Bowden, J. Below, J. Chambers, X. Sim, M. Boehnke, J. Rotter, M. McCarthy, A. Morris · 发表于：Nature Genetics · 年份：2022 · DOI：10.1038/s41588-022-01058-3 · 被引用次数：589

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10−9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.