Genetic drivers of heterogeneity in type 2 diabetes pathophysiology
Authors: Suzuki Ken , Hatzikotoulas Konstantinos , Southam Lorraine , Taylor Henry J. , Yin Xianyong , Lorenz Kim M. , Mandla Ravi , Huerta-Chagoya Alicia , Melloni Giorgio E. M. , Kanoni Stavroula , Rayner Nigel W. , Bocher Ozvan , Arruda Ana Luiza , Sonehara Kyuto , Namba Shinichi , Lee Simon S. K. , Preuss Michael H. , Petty Lauren E. , Schroeder Philip , Vanderwerff Brett , Kals Mart , Bragg Fiona , Lin Kuang , Guo Xiuqing , Zhang Weihua , Yao Jie , Kim Young Jin , Graff Mariaelisa , Takeuchi Fumihiko , Nano Jana , Lamri Amel , Nakatochi Masahiro , Moon Sanghoon , Scott Robert A. , Cook James P. , Lee Jung-Jin , Pan Ian , Taliun Daniel , Parra Esteban J. , Chai Jin-Fang , Bielak Lawrence F. , Tabara Yasuharu , Hai Yang , Thorleifsson Gudmar , Grarup Niels , Sofer Tamar , Wuttke Matthias , Sarnowski Chloé , Gieger Christian , Nousome Darryl , Trompet Stella , Kwak Soo-Heon , Long Jirong , Sun Meng , Tong Lin , Chen Wei-Min , Nongmaithem Suraj S. , Noordam Raymond , Lim Victor J. Y. , Tam Claudia H. T. , Joo Yoonjung Yoonie , Chen Chien-Hsiun , Raffield Laura M. , Prins Bram Peter , Nicolas Aude , Yanek Lisa R. , Chen Guanjie , Brody Jennifer A. , Kabagambe Edmond , An Ping , Xiang Anny H. , Choi Hyeok Sun , Cade Brian E. , Tan Jingyi , Broadaway K. Alaine , Williamson Alice , Kamali Zoha , Cui Jinrui , Thangam Manonanthini , Adair Linda S. , Adeyemo Adebowale , Aguilar-Salinas Carlos A. , Ahluwalia Tarunveer S. , Anand Sonia S. , Bertoni Alain , Bork-Jensen Jette , Brandslund Ivan , Buchanan Thomas A. , Burant Charles F. , Butterworth Adam S. , Canouil Mickaël , Chan Juliana C. N. , Chang Li-Ching , Chee Miao-Li , Chen Ji , Chen Shyh-Huei , Chen Yuan-Tsong , Chen Zhengming , Chuang Lee-Ming , Cushman Mary , Danesh John , Das Swapan K. , de Silva H. Janaka , Dedoussis George , Dimitrov Latchezar , Doumatey Ayo P. , Du Shufa , Duan Qing , Eckardt Kai-Uwe , Emery Leslie S. , Evans Daniel S. , Evans Michele K. , Fischer Krista , Floyd James S. , Ford Ian , Franco Oscar H. , Frayling Timothy M. , Freedman Barry I. , Genter Pauline , Gerstein Hertzel C. , Giedraitis Vilmantas , González-Villalpando Clicerio , González-Villalpando Maria Elena , Gordon-Larsen Penny , Gross Myron , Guare Lindsay A. , Hackinger Sophie , Hakaste Liisa , Han Sohee , Hattersley Andrew T. , Herder Christian , Horikoshi Momoko , Howard Annie-Green , Hsueh Willa , Huang Mengna , Huang Wei , Hung Yi-Jen , Hwang Mi Yeong , Hwu Chii-Min , Ichihara Sahoko , Ikram Mohammad Arfan , Ingelsson Martin , Islam Md. Tariqul , Isono Masato , Jang Hye-Mi , Jasmine Farzana , Jiang Guozhi , Jonas Jost B. , Jørgensen Torben , Kamanu Frederick K. , Kandeel Fouad R. , Kasturiratne Anuradhani , Katsuya Tomohiro , Kaur Varinderpal , Kawaguchi Takahisa , Keaton Jacob M. , Kho Abel N. , Khor Chiea-Chuen , Kibriya Muhammad G. , Kim Duk-Hwan , Kronenberg Florian , Kuusisto Johanna , Läll Kristi , Lange Leslie A. , Lee Kyung Min , Lee Myung-Shik , Lee Nanette R. , Leong Aaron , Li Liming , Li Yun , Li-Gao Ruifang , Ligthart Symen , Lindgren Cecilia M. , Linneberg Allan , Liu Ching-Ti , Liu Jianjun , Locke Adam E. , Louie Tin , Luan Jian’an , Luk Andrea O. , Luo Xi , Lv Jun , Lynch Julie A. , Lyssenko Valeriya , Maeda Shiro , Mamakou Vasiliki , Mansuri Sohail Rafik , Matsuda Koichi , Meitinger Thomas , Melander Olle , Metspalu Andres , Mo Huan , Morris Andrew D. , Moura Filipe A. , Nadler Jerry L. , Nalls Michael A. , Nayak Uma , Ntalla Ioanna , Okada Yukinori , Orozco Lorena , Patel Sanjay R. , Patil Snehal , Pei Pei , Pereira Mark A. , Peters Annette , Pirie Fraser J. , Polikowsky Hannah G. , Porneala Bianca , Prasad Gauri , Rasmussen-Torvik Laura J. , Reiner Alexander P. , Roden Michael , Rohde Rebecca , Roll Katheryn , Sabanayagam Charumathi , Sandow Kevin , Sankareswaran Alagu , Sattar Naveed , Schönherr Sebastian , Shahriar Mohammad , Shen Botong , Shi Jinxiu , Shin Dong Mun , Shojima Nobuhiro , Smith Jennifer A. , So Wing Yee , Stančáková Alena , Steinthorsdottir Valgerdur , Stilp Adrienne M. , Strauch Konstantin , Taylor Kent D. , Thorand Barbara , Thorsteinsdottir Unnur , Tomlinson Brian , Tran Tam C. , Tsai Fuu-Jen , Tuomilehto Jaakko , Tusie-Luna Teresa , Udler Miriam S. , Valladares-Salgado Adan , van Dam Rob M. , van Klinken Jan B. , Varma Rohit , Wacher-Rodarte Niels , Wheeler Eleanor , Wickremasinghe Ananda R. , van Dijk Ko Willems , Witte Daniel R. , Yajnik Chittaranjan S. , Yamamoto Ken , Yamamoto Kenichi , Yoon Kyungheon , Yu Canqing , Yuan Jian-Min , Yusuf Salim , Zawistowski Matthew , Zhang Liang , Zheng Wei ,   VA Million Veteran Program,   AMED GRIFIN Diabetes Initiative Japan,   Biobank Japan Project,   Penn Medicine BioBank,   Regeneron Genetics Center,   Genes & Health Research Team, Kanona Stavroula , van Heel David A. ,   eMERGE Consortium,   International Consortium of Blood Pressure (ICBP),   Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), Raffel Leslie J. , Igase Michiya , Ipp Eli , Redline Susan , Cho Yoon Shin , Lind Lars , Province Michael A. , Fornage Myriam , Hanis Craig L. , Ingelsson Erik , Zonderman Alan B. , Psaty Bruce M. , Wang Ya-Xing , Rotimi Charles N. , Becker Diane M. , Matsuda Fumihiko , Liu Yongmei , Yokota Mitsuhiro , Kardia Sharon L. R. , Peyser Patricia A. , Pankow James S. , Engert James C. , Bonnefond Amélie , Froguel Philippe , Wilson James G. , Sheu Wayne H. H. , Wu Jer-Yuarn , Hayes M. Geoffrey , Ma Ronald C. W. , Wong Tien-Yin , Mook-Kanamori Dennis O. , Tuomi Tiinamaija , Chandak Giriraj R. , Collins Francis S. , Bharadwaj Dwaipayan , Paré Guillaume , Sale Michèle M. , Ahsan Habibul , Motala Ayesha A. , Shu Xiao-Ou , Park Kyong-Soo , Jukema J. Wouter , Cruz Miguel , Chen Yii-Der Ida , Rich Stephen S. , McKean-Cowdin Roberta , Grallert Harald , Cheng Ching-Yu , Ghanbari Mohsen , Tai E-Shyong , Dupuis Josee , Kato Norihiro , Laakso Markku , Köttgen Anna , Koh Woon-Puay , Bowden Donald W. , Palmer Colin N. A. , Kooner Jaspal S. , Kooperberg Charles , Liu Simin , North Kari E. , Saleheen Danish , Hansen Torben , Pedersen Oluf , Wareham Nicholas J. , Lee Juyoung , Kim Bong-Jo , Millwood Iona Y. , Walters Robin G. , Stefansson Kari , Ahlqvist Emma , Goodarzi Mark O. , Mohlke Karen L. , Langenberg Claudia , Haiman Christopher A. , Loos Ruth J. F. , Florez Jose C. , Rader Daniel J. , Ritchie Marylyn D. , Zöllner Sebastian , Mägi Reedik , Marston Nicholas A. , Ruff Christian T. , van Heel David A. , Finer Sarah , Denny Joshua C. , Yamauchi Toshimasa , Kadowaki Takashi , Chambers John C. , Ng Maggie C. Y. , Sim Xueling , Below Jennifer E. , Tsao Philip S. , Chang Kyong-Mi , McCarthy Mark I. , Meigs James B. , Mahajan Anubha , Spracklen Cassandra N. , Mercader Josep M. , Boehnke Michael , Rotter Jerome I. , Vujkovic Marijana , Voight Benjamin F. , Morris Andrew P. , Zeggini Eleftheria 
Published: February 2024

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. 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 scores5 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.