Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications
Authors: Suzuki Ken , Hatzikotoulas Konstantinos , Southam Lorraine , Taylor Henry J. , Yin Xianyong , Lorenz Kim M. , Mandla Ravi , Huerta-Chagoya Alicia , Rayner Nigel W. , Bocher Ozvan , Ana Luiza de S. V. Arruda , 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 , Alaine Broadaway K. , Williamson Alice , Kamali Zoha , Cui Jinrui , 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. , Janaka de Silva H. , 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 , 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 , 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 , Lithgart 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 , Metspalu Andres , Mo Huan , Morris Andrew D. , 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, Project Biobank Japan , BioBank Penn Medicine , Center Regeneron Genetics , Consortium eMERGE ,   International Consortium for 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 , Geoffrey Hayes M. , 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 , 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 , 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: March 2023

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. 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 previously unreported. We define eight non-overlapping clusters of T2D signals characterised 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, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.