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

By Anubha Mahajan, Cassandra N. Spracklen, Weihua Zhang, Maggie C.Y. Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rueger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M. Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M. Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor JY Lim, Claudia HT Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M. Raffield, Cecile Lecoeur, Nisa M Maruthur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond Kabagambe, Ping An, Anny H. Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A. Brody, Chad M. Brummett, Thomas A Buchanan, Mickael Canouil, Juliana CN Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H. Janaka de Silva, George V. Dedoussis, Latchezar Dimitrov, Ayo P. Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M. Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio Gonzalez-Villalpando, Maria Elena Gonzalez-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md. Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jorgensen, Torben Jorgensen, Yoichiro Kamatani, Fouad R. Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M. Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G. Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Lall, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian'an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N. Nadkarni, Jerry L. Nadler, Michael A. Nalls, Uma Nayak, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R. Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schonherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A. Smith, Wing Yee So, Alena Stancakova, Adrienne M. Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam Udler, Adan Valladares-Salgado, Rob M van Dam, Jan B van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Ellie Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Konstantin Willems van Dijk, Daniel R Witte, Yong-Bing Xiang, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loic Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A. Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N. Rotimi, Diane M. Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne HH Sheu, Sharon LR Kardia, Jer-Yuarn Wu, M. Geoffrey Hayes, Ronald CW Ma, Tien-Yin Wong, Leif Groop, Dennis O. Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Pare, Michele M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J. Wouter Jukema, Miguel Cruz, Roberta McKean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P. Bottinger, Abbas Dehghan, E-Shyong Tai, Josee Dupuis, Norihiro Kato, Markku Laakso, Anna Kottgen, Woon-Puay Koh, Colin N.A. Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth JF Loos, Kari E. North, Christopher A. Haiman, Jose C. Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Magi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y. Millwood, Robin G Walters, Kari Stefansson, Simon R. Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L. Mohlke, Anna L. Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I. Rotter, Mark I. McCarthy, Andrew P Morris

Posted 23 Sep 2020
medRxiv DOI: 10.1101/2020.09.22.20198937

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p<5x10-8), including 237 attaining a more stringent trans-ancestry threshold (p<5x10-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved 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 foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

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