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The Trans-Ancestral Genomic Architecture of Glycaemic Traits

Authors
Ji Chen,Cassandra Spracklen
Gaëlle Marenne,Arushi Varshney,Laura Corbin,Jian’an Luan,Sara Willems,Ying Wu,Xiaoshuai Zhang,Momoko Horikoshi,Thibaud Boutin,Reedik Mägi,Johannes Waage,Achilleas Pitsilides,Ruifang Li‐Gao,Kei Hang,Jie Yao,Mila Anasanti,Audrey Chu,Annique Claringbould,Jani Heikkinen,Jaeyoung Hong,Jouke‐Jan Hottenga,Shaofeng Huo,Marika Kaakinen,Tin Louie,Winfried März,Hortensia Moreno-Macías,Anne Ndungu,Sarah Nelson,Ilja Nolte,Kari North,Chelsea Raulerson,Debashree Ray,Rebecca Rohde,Denis Rybin,Claudia Schurmann,Xueling Sim,Loz Southam,Isobel Stewart,Carol Wang,Yujie Wang,Peitao Wu,Weihua Zhang,Tarunveer Ahluwalia,Emil Appel,Lawrence Bielak,Jennifer Brody,Noël Burtt,Claudia Cabrera,Brian Cade,Jin Chai,Xiaoran Chai,Li-Ching Chang,Chien-Hsiun Chen,Brian Chen,Kumaraswamy Chitrala,Yen‐Feng Chiu,Hugoline Haan,Graciela Delgado,Ayşe Demirkan,Qing Duan,Jorgen Engmann,Segun Fatumo,Javier Gayán,Franco Giulianini,Jung Gong,Stefan Gustafsson,Yang Hai,Fernando Hartwig,Jing He,Yoriko Heianza,Tao Huang,Alicia Huerta-Chagoya,Mi Hwang,Richard Jensen,Takahisa Kawaguchi,Katherine Kentistou,Young Kim,Marcus Kleber,Ishminder Kooner,Shuiqing Lai,Leslie Lange,Carl Langefeld,Marie Lauzon,Man Li,Symen Ligthart,Jun Li,Marie Loh,Jirong Long,Valeriya Lyssenko,Massimo Mangino,Carola Marzi,May Montasser,Abhishek Nag,Masahiro Nakatochi,Damia Noce,Raymond Noordam,Giorgio Pistis,Michael Preuss,Laura Raffield,Laura Rasmussen‐Torvik,Stephen Rich,Neil Robertson,Rico Rueedi,Kathleen Ryan,Serena Sanna,Richa Saxena,Katharina Schraut,Bengt Sennblad,Kazuya Setoh,Albert Smith,Lorraine Southam,Thomas Sparsø,Rona Strawbridge,Fumihiko Takeuchi,Jingyi Tan,Stella Trompet,Erik Akker,Peter Most,Niek Verweij,Mandy Vogel,Heming Wang,Chaolong Wang,Nan Wang,Helen Warren,Wanqing Wen,Tom Wilsgaard,Andrew Wong,Andrew Wood,Tian Xie,Mohammad Zafarmand,Jinghua Zhao,Wei Zhao,Najaf Amin,Zorayr Arzumanyan,Arne Astrup,Stephan Bakker,Damiano Baldassarre,Marian Beekman,Richard Bergman,Alain Bertoni,Matthias Blüher,Lori Bonnycastle,Stefan Bornstein,Donald Bowden,Qiuyin Cai,Archie Campbell,Harry Campbell,Yi‐Cheng Chang,E.J.C. Geus,Abbas Dehghan,Shufa Du,Guðný Eiríksdóttir,Aliki Farmaki,Mattias Frånberg,Christian Fuchsberger,Yu‐Tang Gao,Anette Gjesing,Anuj Goel,Sohee Han,Catharina Hartman,Christian Herder,Andrew Hicks,Chang‐Hsun Hsieh,Willa Hsueh,Sahoko Ichihara,Michiya Igase,M. Ikram,W. Johnson,Marit Jørgensen,Peter Joshi,Rita Kalyani,Fouad Kandeel,Tomohiro Katsuya,Chiea Khor,Wieland Kieß,Ivana Kolčić,Teemu Kuulasmaa,Johanna Kuusisto,Kristi Läll,Kelvin Lam,Deborah Lawlor,Nanette Lee,Rozenn Lemaître,Honglan Li,Lifelines Study,Shih-Yi Lin,Jaana Lindström,Allan Linneberg,Jianjun Li,Carlos Lorenzo,Tatsuaki Matsubara,Fumihiko Matsuda,Geltrude Mingrone,Simon Mooijaart,Sanghoon Moon,Toru Nabika,Girish Nadkarni,Jerry Nadler,Mari Nelis,Matt Neville,Jill Norris,Yasumasa Ohyagi,Annette Peters,Patricia Peyser,Ozren Polašek,Qibin Qi,Dennis Raven,Dermot Reilly,Alex Reiner,Fernando Rivideneira,Kathryn Roll,Igor Rudan,Charumathi Sabanayagam,Kevin Sandow,Naveed Sattar,Annette Schürmann,Jianxin Shi,Heather Stringham,Kent Taylor,Tanya Teslovich,Betina Thuesen,Paul Timmers,Elena Tremoli,Michael Tsai,André Uitterlinden,Rob Dam,Diana Heemst,Astrid Vlieg,Jana Vliet-Ostaptchouk,Jagadish Vangipurapu,Henrik Vestergaard,Tao Wang,Ko Dijk,Yong‐Bing Xiang,Tatijana Zemunik,Gonçalo Abecasis,Linda Adair,Carlos Aguilar‐Salinas,Marta Alarcón‐Riquelme,Ping An,Larissa Avilés-Santa,Diane Becker,Lawrence Beilin,Sven Bergmann,Hans Bisgaard,Corri Black,Michael Boehnke,Eric Boerwinkle,Bernhard Böhm,Klaus Bønnelykke,Dorret Boomsma,Erwin Böttinger,Thomas Buchanan,Mickaël Canouil,Mark Caulfield,John Chambers,Daniel Chasman,Yii‐Der Chen,Ching-Yu Cheng,Francis Collins,Adolfo Correa,Francesco Cucca,H. Silva,George Dedoussis,Sölve Elmståhl,Michele Evans,Ele Ferranni,Luigi Ferruci,José Florez,Paul Franks,Timothy Frayling,Philippe Froguel,Bruna Gigante,Mark Goodarzi,Penny Gordon‐Larsen,Harald Grallert,Niels Grarup,Sameline Grimsgaard,Leif Groop,Vilmundur Guðnason,Xiuqing Guo,Anders Hamsten,Torben Hansen,Caroline Hayward,Susan Heckbert,Bernardo Horta,Wei Huang,Erik Ingelsson,Pankow James,Jost Jonas,J. Jukema,Pontiano Kaleebu,Robert Kaplan,Sharon Kardia,Norihiro Kato,Sirkka Keinänen‐Kiukaanniemi,Bong‐Jo Kim,Mika Kivimäki,Heikki Koistinen,Jaspal Kooner,Antje Körner,Péter Kovács,Diana Kuh,Meena Kumari,Zoltán Kutalik,Markku Laakso,Timo Lakka,Lenore Launer,Karin Leander,Huaixing Li,Xu Lin,Lars Lind,Cecilia Lindgren,Simin Liu,Ruth Loos,Patrik Magnusson,Anubha Mahajan,Andres Metspalu,Dennis Mook‐Kanamori,Trevor Mori,Patricia Munroe,Inger Njølstad,Jeffrey O’Connell,Albertine Oldehinkel,Ken Ong,Sandosh Padmanabhan,Colin Palmer,Nicholette Palmer,Oluf Pedersen,Craig Pennell,David Porteous,Peter Pramstaller,Michael Province,Bruce Psaty, Qi,Leslie Raffel,Rainer Rauramaa,Susan Redline,Paul Ridker,Frits Rosendaal,Timo Saaristo,Manjinder Sandhu,Jouko Saramies,Neil Schneiderman,Peter Schwarz,Laura Scott,Elizabeth Selvin,Peter Sever,Xiao‐Ou Shu,P. Slagboom,Kerrin Small,Blair Smith,Harold Snieder,Tamar Sofer,Thorkild Sørensen,Tim Spector,Alice Stanton,Claire Steves,Michael Stümvoll,Liang Sun,Yasuharu Tabara,E Tai,Nicholas Timpson,Anke Tönjes,Jaakko Tuomilehto,Teresa Tusié,Matti Uusitupa,Pim Harst,Cornelia Duijn,Véronique Vitart,Péter Vollenweider,Tanja Vrijkotte,Lynne Wagenknecht,Mark Walker,Ya Wang,Nick Wareham,Richard Watanabe,Hugh Watkins,Wen Wei,Ananda Wickremasinghe,Gonneke Willemsen,James Wilson,Tien‐Yin Wong,Jer‐Yuarn Wu,Anny Xiang,Lisa Yanek,Loïc Yengo,Mitsuhiro Yokota,Eleftheria Zeggini,Zheng Wang,Alan Zonderman,Jerome Rotter,Anna Gloyn,Mark McCarthy,Josée Dupuis,James Meigs,Robert Scott,Inga Prokopenko,Aaron Leong,Ching‐Ti Liu,Stephen Parker,Karen Mohlke,Claudia Langenberg,Eleanor Wheeler,Andrew Morris,Inês Barroso,Wei Zheng,Jouke Hottenga,Yukui Zhang,Rosanna Asselta,Jin-Fang Chai
+411 authors
,Jun Liu
Published
Jul 25, 2020
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Abstract

Abstract 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.

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