The Trans-Ancestral Genomic Architecture of Glycaemic Traits
Authors: Chen Ji , Spracklen Cassandra N. , Marenne Gaëlle , Varshney Arushi , Corbin Laura J , Luan Jian’an , Willems Sara , Wu Ying , Zhang Xiaoshuai , Horikoshi Momoko , Boutin Thibaud S , Mägi Reedik , Waage Johannes , Pitsilides Achilleas , Li-Gao Ruifang , Hang Kei , Yao Jie , Anasanti Mila D , Chu Audrey Y , Claringbould Annique , Heikkinen Jani , Hong Jaeyoung , Hottenga Jouke-Jan , Huo Shaofeng , Kaakinen Marika A. , Louie Tin , März Winfried , Moreno-Macias Hortensia , Ndungu Anne , Nelson Sarah C. , Nolte Ilja M. , North Kari , Raulerson Chelsea K. , Ray Debashree , Rohde Rebecca , Rybin Denis , Schurmann Claudia , Sim Xueling , Southam Loz , Stewart Isobel , Wang Carol A. , Wang Yujie , Wu Peitao , Zhang Weihua , Ahluwalia Tarunveer S. , Appel Emil VR , Bielak Lawrence F. , Brody Jennifer A. , Burtt Noel P , Cabrera Claudia P , Cade Brian E , Chai Jin Fang , Chai Xiaoran , Chang Li-Ching , Chen Chien-Hsiun , Chen Brian H , Chitrala Kumaraswamy N , Chiu Yen-Feng , de Haan Hugoline G. , Delgado Graciela E , Demirkan Ayse , Duan Qing , Engmann Jorgen , Fatumo Segun A , Gayán Javier , Giulianini Franco , Gong Jung Ho , Gustafsson Stefan , Hai Yang , Hartwig Fernando P , He Jing , Heianza Yoriko , Huang Tao , Huerta-Chagoya Alicia , Hwang Mi Yeong , Jensen Richard A. , Kawaguchi Takahisa , Kentistou Katherine A , Kim Young Jin , Kleber Marcus E , Kooner Ishminder K , Lai Shuiqing , Lange Leslie A , Langefeld Carl D , Lauzon Marie , Li Man , Ligthart Symen , Liu Jun , Loh Marie , Long Jirong , Lyssenko Valeriya , Mangino Massimo , Marzi Carola , Montasser May E , Nag Abhishek , Nakatochi Masahiro , Noce Damia , Noordam Raymond , Pistis Giorgio , Preuss Michael , Raffield Laura , Rasmussen-Torvik Laura J. , Rich Stephen S , Robertson Neil R , Rueedi Rico , Ryan Kathleen , Sanna Serena , Saxena Richa , Schraut Katharina E , Sennblad Bengt , Setoh Kazuya , Smith Albert V , Southam Lorraine , Sparsø Thomas , Strawbridge Rona J , Takeuchi Fumihiko , Tan Jingyi , Trompet Stella , van den Akker Erik , Van der Most Peter J , Verweij Niek , Vogel Mandy , Wang Heming , Wang Chaolong , Wang Nan , Warren Helen R , Wen Wanqing , Wilsgaard Tom , Wong Andrew , Wood Andrew R , Xie Tian , Zafarmand Mohammad Hadi , Zhao Jing-Hua , Zhao Wei , Amin Najaf , Arzumanyan Zorayr , Astrup Arne , Bakker Stephan JL , Baldassarre Damiano , Beekman Marian , Bergman Richard N , Bertoni Alain , Blüher Matthias , Bonnycastle Lori L. , Bornstein Stefan R , Bowden Donald W , Cai Qiuyin , Campbell Archie , Campbell Harry , Chang Yi Cheng , de Geus Eco J.C. , Dehghan Abbas , Du Shufa , Eiriksdottir Gudny , Farmaki Aliki Eleni , Frånberg Mattias , Fuchsberger Christian , Gao Yutang , Gjesing Anette P , Goel Anuj , Han Sohee , Hartman Catharina A , Herder Christian , Hicks Andrew A. , Hsieh Chang-Hsun , Hsueh Willa A. , Ichihara Sahoko , Igase Michiya , Ikram M. Arfan , Johnson W. Craig , Jørgensen Marit E , Joshi Peter K , Kalyani Rita R , Kandeel Fouad R. , Katsuya Tomohiro , Khor Chiea Chuen , Kiess Wieland , Kolcic Ivana , Kuulasmaa Teemu , Kuusisto Johanna , Läll Kristi , Lam Kelvin , Lawlor Deborah A , Lee Nanette R. , Lemaitre Rozenn N. , Li Honglan , Study Lifelines Cohort , Lin Shih-Yi , Lindström Jaana , Linneberg Allan , Liu Jianjun , Lorenzo Carlos , Matsubara Tatsuaki , Matsuda Fumihiko , Mingrone Geltrude , Mooijaart Simon , Moon Sanghoon , Nabika Toru , Nadkarni Girish N. , Nadler Jerry L. , Nelis Mari , Neville Matthew J , Norris Jill M , Ohyagi Yasumasa , Peters Annette , Peyser Patricia A. , Polasek Ozren , Qi Qibin , Raven Dennis , Reilly Dermot F , Reiner Alex , Rivideneira Fernando , Roll Kathryn , Rudan Igor , Sabanayagam Charumathi , Sandow Kevin , Sattar Naveed , Schürmann Annette , Shi Jinxiu , Stringham Heather M , Taylor Kent D. , Teslovich Tanya M. , Thuesen Betina , Timmers Paul RHJ , Tremoli Elena , Tsai Michael Y , Uitterlinden Andre , van Dam Rob M , van Heemst Diana , van Hylckama Vlieg Astrid , Van Vliet-Ostaptchouk Jana V , Vangipurapu Jagadish , Vestergaard Henrik , Wang Tao , van Dijk Ko Willems , Xiang Yongbing , Zemunik Tatijana , Abecasis Goncalo R , Adair Linda S. , Aguilar-Salinas Carlos Alberto , Alarcón-Riquelme Marta E , An Ping , Aviles-Santa Larissa , Becker Diane M , Beilin Lawrence J , Bergmann Sven , Bisgaard Hans , Black Corri , Boehnke Michael , Boerwinkle Eric , Böhm Bernhard O , Bønnelykke Klaus , Boomsma D I. , Bottinger Erwin P. , Buchanan Thomas A , Canouil Mickaël , Caulfield Mark J , Chambers John C. , Chasman Daniel I. , Chen Yii-Der Ida , Cheng Ching-Yu , Collins Francis S. , Correa Adolfo , Cucca Francesco , de Silva H. Janaka , Dedoussis George , Elmståhl Sölve , Evans Michele K. , Ferranni Ele , Ferruci Luigi , Florez Jose C , Franks Paul , Frayling Timothy M , Froguel Philippe , Gigante Bruna , Goodarzi Mark O. , Gordon-Larsen Penny , Grallert Harald , Grarup Niels , Grimsgaard Sameline , Groop Leif , Gudnason Vilmundur , Guo Xiuqing , Hamsten Anders , Hansen Torben , Hayward Caroline , Heckbert Susan R. , Horta Bernardo L , Huang Wei , Ingelsson Erik , James Pankow S , Jonas Jost B , Jukema J. Wouter , Kaleebu Pontiano , Kaplan Robert , Kardia Sharon L.R. , Kato Norihiro , Keinanen-Kiukaanniemi Sirkka M. , Kim Bong-Jo , Kivimaki Mika , Koistinen Heikki A. , Kooner Jaspal S. , Körner Antje , Kovacs Peter , Kuh Diana , Kumari Meena , Kutalik Zoltan , Laakso Markku , Lakka Timo A. , Launer Lenore J , Leander Karin , Li Huaixing , Lin Xu , Lind Lars , Lindgren Cecilia , Liu Simin , Loos Ruth J.F. , Magnusson Patrik , Mahajan Anubha , Metspalu Andres , Mook-Kanamori Dennis O , Mori Trevor A , Munroe Patricia B , Njølstad Inger , O’Connell Jeffrey R , Oldehinkel Albertine J , Ong Ken K , Padmanabhan Sandosh , Palmer Colin N.A. , Palmer Nicholette D , Pedersen Oluf , Pennell Craig E , Porteous David J , Pramstaller Peter P. , Province Michael A. , Psaty Bruce M. , Qi Lu , Raffel Leslie J. , Rauramaa Rainer , Redline Susan , Ridker Paul M , Rosendaal Frits R. , Saaristo Timo E. , Sandhu Manjinder , Saramies Jouko , Schneiderman Neil , Schwarz Peter , Scott Laura J. , Selvin Elizabeth , Sever Peter , Shu Xiao-ou , Slagboom P Eline , Small Kerrin S , Smith Blair H , Snieder Harold , Sofer Tamar , Sørensen Thorkild I.A. , Spector Tim D , Stanton Alice , Steves Claire J , Stumvoll Michael , Sun Liang , Tabara Yasuharu , Tai E Shyong , Timpson Nicholas J , Tönjes Anke , Tuomilehto Jaakko , Tusie Teresa , Uusitupa Matti , van der Harst Pim , van Duijn Cornelia , Vitart Veronique , Vollenweider Peter , Vrijkotte Tanja GM , Wagenknecht Lynne E , Walker Mark , Wang Ya X , Wareham Nick J , Watanabe Richard M , Watkins Hugh , Wei Wen B , Wickremasinghe Ananda R , Willemsen Gonneke , Wilson James F , Wong Tien-Yin , Wu Jer-Yuarn , Xiang Anny H , Yanek Lisa R , Yengo Loïc , Yokota Mitsuhiro , Zeggini Eleftheria , Zheng Wei , Zonderman Alan B , Rotter Jerome I , Gloyn Anna L , McCarthy Mark I. , Dupuis Josée , Meigs James B , Scott Robert , Prokopenko Inga , Leong Aaron , Liu Ching-Ti , Parker Stephen CJ , Mohlke Karen L. , Langenberg Claudia , Wheeler Eleanor , Morris Andrew P. , Barroso Inês 
Published: July 2020

Glycaemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycaemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated haemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel;P<5×10-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.