Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Authors: Ken Suzuki, Konstantinos Hatzikotoulas, Lorraine Southam, Henry J. Taylor, Xianyong Yin, Kimberly Lorenz, Ravi Mandla, Alicia Huerta‐Chagoya, Giorgio Melloni, Stavroula Kanoni, Nigel W. Rayner, Ozvan Bocher, Ana Luiza Arruda, Kyuto Sonehara, Shinichi Namba, Simon Lee, Michael Preuß, Lauren E. Petty, Philip Schroeder, Brett Vanderwerff, Mart Kals, Fiona Bragg, Kuang Lin, Xiuqing Guo, Weihua Zhang, Jie Yao, Young Jin Kim, Mariaelisa Graff, Fumihiko Takeuchi, Jana Nano, Amel Lamri, Masahiro Nakatochi, Sanghoon Moon, Robert A. Scott, James P. Cook, Jung‐Jin Lee, Ian Pan, Daniel Taliun, Esteban J. Parra, Jin Fang Chai, Lawrence F. Bielak, Yasuharu Tabara, Yang Hai, Guðmar Þorleifsson, Niels Grarup, Tamar Sofer, Matthias Wuttke, Chloé Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Soo‐Heon Kwak, Jirong Long, Meng Sun, Tong Lin, Wei‐Min Chen, Suraj S. Nongmaithem, Raymond Noordam, Victor Lim, Claudia H.T. Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M. Raffield, Bram P. Prins, Aude Nicolas, Lisa R. Yanek, Guanjie Chen, Jennifer A. Brody, Edmond K. Kabagambe, Ping An, Anny H. Xiang, Hyeok Sun Choi, Brian E. Cade, Jingyi Tan, K. Alaine Broadaway, Alice Williamson, Zoha Kamali, Jinrui Cui, Manonanthini Thangam, Linda S. Adair, Adebowale Adeyemo, Carlos A. Aguilar‐Salinas, Tarunveer S. Ahluwalia, Sonia S. Anand, Alain G. Bertoni, Jette Bork‐Jensen, Ivan Brandslund, Thomas A. Buchanan, Charles Burant, Adam S. Butterworth, Mickaël Canouil, Juliana C.N. Chan, Li-Ching Chang, Miao-Li Chee, Chen Ji, Shyh‐Huei Chen, Yuan‐Tsong Chen, Zhengming Chen, Lee‐Ming Chuang, Mary Cushman, John Danesh, Swapan K. Das, H. Janaka de Silva, George 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, Oscar H. Franco, Timothy M. Frayling, Barry I. Freedman, Pauline Genter, Hertzel C. Gerstein, Vilmantas Giedraitis, Clicerio González‐Villalpando, María Elena González-Villalpando, Penny Gordon‐Larsen, Myron D. Gross, Lindsay Guare, Sophie Hackinger, Liisa Hakaste, Sohee Han, Andrew T. Hattersley, Christian Herder, Momoko Horikoshi, Annie-Green Howard, Willa A. Hsueh, Mengna Huang, Wei Huang, Yi‐Jen Hung, Mi Yeong Hwang, Chii‐Min Hwu, Sahoko Ichihara, M. Arfan Ikram, Martin Ingelsson, Md. Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B. Jonas, Torben Jørgensen, Frederick Kamanu, Fouad Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M. Keaton, Abel Kho, Chiea Chuen Khor, Muhammad G. Kibriya, Duk-Hwan Kim, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A. Lange, Kyung Min Lee, 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. Y. Luk, Xi Luo, Jun Lv, Julie A. Lynch, Valeriya Lyssenko, Shiro Maeda, Vasiliki Mamakou, Sohail Rafik Mansuri, Koichi Matsuda, Thomas Meitinger, Olle Melander, Andres Metspalu, Huan Mo, Andrew D. Morris, Filipe A. Moura, Jerry L. Nadler, Michael A. Nalls, Uma Nayak, Ιωάννα Ντάλλα, Yukinori Okada, Lorena Orozco, Sanjay R. Patel, Snehal Patil, Pei Pei, Mark A. Pereira, Annette Peters, Fraser Pirie, Hannah G. Polikowsky, Bianca Porneala, Gauri Prasad, Laura J. Rasmussen‐Torvik, Alexander P. Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Kevin Sandow, Alagu Sankareswaran, Naveed Sattar, Sebastian Schönherr, Hasan Shahriar, Botong Shen, Jinxiu Shi, Dong Mun Shin, Nobuhiro Shojima, Jennifer A. Smith, Wing Yee So, Alena Stančáková, Valgerður Steinthórsdóttir, Adrienne M. Stilp, Konstantin Strauch, Kent D. Taylor, Barbara Thorand, Unnur Þorsteinsdóttir, Brian Tomlinson, Tam C. Tran, Fuu‐Jen Tsai, Jaakko Tuomilehto, Teresa Tusié‐Luna, Miriam S. Udler, Adán Valladares‐Salgado, Rob M. van Dam, Jan B. van Klinken, Rohit Varma, Niels Wacher-Rodarte, Eleanor Wheeler, Ananda R. Wickremasinghe, Ko Willems van Dijk, Daniel R. Witte, Chittaranjan S. Yajnik, Ken Yamamoto, Kenichi Yamamoto, Kyungheon Yoon, Canqing Yu, Jian‐Min Yuan, Salim Yusuf, Matthew Zawistowski, Liang Zhang, Wei Zheng, VA Million Veteran Program, AMED GRIFIN Diabetes Initiative Japan, Biobank Japan Project, Penn Medicine BioBank, Stavroula Kanona, David A. van Heel, Leslie J. Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A. Province, Myriam Fornage, Craig L. Hanis, Erik Ingelsson, Alan B. Zonderman, Bruce M. Psaty, Ya Xing Wang, Charles N. Rotimi, Diane M. Becker, Fumihiko Matsuda, Ching‐Ti Liu, Mitsuhiro Yokota, Sharon L.R. Kardia, Patricia A. Peyser, James S. Pankow, James C. Engert, Amélie Bonnefond, Philippe Froguel, James G. Wilson, Wayne Huey‐Herng Sheu, Jer‐Yuarn Wu, M. Geoffrey Hayes, C. W. Ronald, Tien Yin Wong, Dennis O. Mook‐Kanamori, Tiinamaija Tuomi, Giriraj R. Chandak, Francis S. Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M. Sale, Habibul Ahsan, Ayesha A. Motala, Xiao‐Ou Shu, Kyong Soo Park, J. Wouter Jukema, Miguel Cruz, Yii‐Der Ida Chen, Stephen S. Rich, Roberta McKean‐Cowdin, Harald Grallert, Ching‐Yu Cheng, Mohsen Ghanbari, E Shyong Tai, Josée Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon‐Puay Koh, Donald W. Bowden, Colin N. A. Palmer, Jaspal S. Kooner, Charles Kooperberg, Simin Liu, Kari E. North, Danish Saleheen, Torben Hansen, Oluf Pedersen, Nicholas J. Wareham, Juyoung Lee, Bong-Jo Kim, Iona Y. Millwood, Robin Walters, Kāri Stefánsson, Emma Ahlqvist, Mark O. Goodarzi, Karen L. Mohlke, Claudia Langenberg, Christopher A. Haiman, Ruth J. F. Loos, José C. Florez, Daniel J. Rader, Marylyn D. Ritchie, Sebastian Zöllner, Reedik Mägi, Nicholas Marston, Christian T. Ruff, David A. van Heel, Sarah Finer, Joshua C. Denny, Toshimasa Yamauchi, Takashi Kadowaki, John C. Chambers, Maggie Ng, Xueling Sim, Jennifer E. Below, Philip S. Tsao, Kyong‐Mi Chang, Mark I. McCarthy, James B. Meigs, Anubha Mahajan, Cassandra N. Spracklen, Josep M. Mercader, Michael Boehnke, Jerome I. Rotter, Marijana Vujković, Benjamin F. Voight, Andrew P. Morris, Eleftheria Zeggini - Nature 2024 cited by 513

Abstract Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes 1,2 and molecular mechanisms that are often specific to cell type 3,4 . Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance ( P < 5 × 10 −8 ) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores 5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.