Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
Authors: Mahajan Anubha , Spracklen Cassandra N , Zhang Weihua , Ng Maggie CY , Petty Lauren E , Kitajima Hidetoshi , Yu Grace Z , Rüeger Sina , Speidel Leo , Kim Young Jin , Horikoshi Momoko , Mercader Josep M , Taliun Daniel , Moon Sanghoon , Kwak Soo-Heon , Robertson Neil R , Rayner Nigel W , Loh Marie , Kim Bong-Jo , Chiou Joshua , Miguel-Escalada Irene , Briotta Parolo Pietro della , Lin Kuang , Bragg Fiona , Preuss Michael H , Takeuchi Fumihiko , Nano Jana , Guo Xiuqing , Lamri Amel , Nakatochi Masahiro , Scott Robert A , Lee Jung-Jin , Huerta-Chagoya Alicia , Graff Mariaelisa , Chai Jin-Fang , Parra Esteban J , Yao Jie , Bielak Lawrence F , Tabara Yasuharu , Hai Yang , Steinthorsdottir Valgerdur , Cook James P , Kals Mart , Grarup Niels , Schmidt Ellen M , Pan Ian , Sofer Tamar , Wuttke Matthias , Sarnowski Chloe , Gieger Christian , Nousome Darryl , Trompet Stella , Long Jirong , Sun Meng , Tong Lin , Chen Wei-Min , Ahmad Meraj , Noordam Raymond , Lim Victor JY , Tam Claudia HT , Joo Yoonjung Yoonie , Chen Chien-Hsiun , Raffield Laura M , Lecoeur Cécile , Maruthur Nisa M , Prins Bram Peter , Nicolas Aude , Yanek Lisa R , Chen Guanjie , Jensen Richard A , Tajuddin Salman , Kabagambe Edmond , An Ping , Xiang Anny H , Choi Hyeok Sun , Cade Brian E , Tan Jingyi , Abaitua Fernando , Adair Linda S , Adeyemo Adebowale , Aguilar-Salinas Carlos A , Akiyama Masato , Anand Sonia S , Bertoni Alain , Bian Zheng , Bork-Jensen Jette , Brandslund Ivan , Brody Jennifer A , Brummett Chad M , Buchanan Thomas A , Canouil Mickaël , Chan Juliana CN , Chang Li-Ching , Chee Miao-Li , Chen Ji , Chen Shyh-Huei , Chen Yuan-Tsong , Chen Zhengming , Chuang Lee-Ming , Cushman Mary , 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 , Fornage Myriam , Franco Oscar H , Frayling Timothy M , Freedman Barry I , Fuchsberger Christian , Genter Pauline , Gerstein Hertzel C , Giedraitis Vilmantas , González-Villalpando Clicerio , González-Villalpando Maria Elena , Goodarzi Mark O , Gordon-Larsen Penny , Gorkin David , Gross Myron , Guo Yu , Hackinger Sophie , Han Sohee , Hattersley Andrew T , Herder Christian , 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 Marit E , Jørgensen Torben , Kamatani Yoichiro , 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 , Kohara Katsuhiko , Kriebel Jennifer , Kronenberg Florian , Kuusisto Johanna , Läll Kristi , Lange Leslie A , 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 , Lyssenko Valeriya , Mamakou Vasiliki , Mani K Radha , Meitinger Thomas , Metspalu Andres , Morris Andrew D , Nadkarni Girish N. , Nadler Jerry L , Nalls Michael A , Nayak Uma , Ntalla Ioanna , Okada Yukinori , Orozco Lorena , Patel Sanjay R , Pereira Mark A , Peters Annette , Pirie Fraser J , Porneala Bianca , Prasad Gauri , Preissl Sebastian , Rasmussen-Torvik Laura J , Reiner Alexander P , Roden Michael , Rohde Rebecca , Roll Katheryn , Sabanayagam Charumathi , Sander Maike , Sandow Kevin , Sattar Naveed , Schönherr Sebastian , Schurmann Claudia , Shahriar Mohammad , Shi Jinxiu , Shin Dong Mun , Shriner Daniel , Smith Jennifer A , So Wing Yee , Stančáková Alena , Stilp Adrienne M , Strauch Konstantin , Suzuki Ken , Takahashi Atsushi , Taylor Kent D , Thorand Barbara , Thorleifsson Gudmar , Thorsteinsdottir Unnur , Tomlinson Brian , Torres Jason M , Tsai Fuu-Jen , Tuomilehto Jaakko , Tusie-Luna Teresa , Udler Miriam S , Valladares-Salgado Adan , van Dam Rob M , van Klinken Jan B , Varma Rohit , Vujkovic Marijana , Wacher-Rodarte Niels , Wheeler Ellie , Whitsel Eric A , Wickremasinghe Ananda R , van Dijk Konstantin Willems , Witte Daniel R , Yajnik Chittaranjan S , Yamamoto Ken , Yamauchi Toshimasa , Yengo Loïc , Yoon Kyungheon , Yu Canqing , Yuan Jian-Min , Yusuf Salim , Zhang Liang , Zheng Wei , FinnGen  , Raffel Leslie J , Igase Michiya , Ipp Eli , Redline Susan , Cho Yoon Shin , Lind Lars , Province Michael A , Hanis Craig L , Peyser Patricia A , Ingelsson Erik , Zonderman Alan B , Psaty Bruce M , Wang Ya-Xing , Rotimi Charles N , Becker Diane M , Matsuda Fumihiko , Liu Yongmei , Zeggini Eleftheria , Yokota Mitsuhiro , Rich Stephen S , Kooperberg Charles , Pankow James S , Engert James C , Chen Yii-Der Ida , Froguel Philippe , Wilson James G , Sheu Wayne HH , Kardia Sharon LR , Wu Jer-Yuarn , Hayes M Geoffrey , Ma Ronald CW , Wong Tien-Yin , Groop Leif , Mook-Kanamori Dennis O , 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 , McKean-Cowdin Roberta , Grallert Harald , Cheng Ching-Yu , Bottinger Erwin P , Dehghan Abbas , Tai E-Shyong , Dupuis Josee , Kato Norihiro , Laakso Markku , Köttgen Anna , Koh Woon-Puay , Palmer Colin NA , Liu Simin , Abecasis Goncalo , Kooner Jaspal S , Loos Ruth JF , North Kari E , Haiman Christopher A , Florez Jose C , Saleheen Danish , Hansen Torben , Pedersen Oluf , Mägi Reedik , Langenberg Claudia , Wareham Nicholas J , Maeda Shiro , Kadowaki Takashi , Lee Juyoung , Millwood Iona Y , Walters Robin G , Stefansson Kari , Myers Simon R , Ferrer Jorge , Gaulton Kyle J , Meigs James B , Mohlke Karen L , Gloyn Anna L , Bowden Donald W , Below Jennifer E , Chambers John C , Sim Xueling , Boehnke Michael , Rotter Jerome I , McCarthy Mark I , Morris Andrew P 
Published: September 2020

ABSTRACTWe 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<5×10-8), including 237 attaining a more stringent trans-ancestry threshold (p<5×10-9), 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.