Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization
Authors: Willems Sara M. , Ng Natasha H. J. , Fernandez Juan , Fine Rebecca S. , Wheeler Eleanor , Wessel Jennifer , Kitajima Hidetoshi , Marenne Gaelle , Sim Xueling , Yaghootkar Hanieh , Wang Shuai , Chen Sai , Chen Yuning , Chen Yii-Der Ida , Grarup Niels , Li-Gao Ruifang , Varga Tibor V. , Asimit Jennifer L. , Feng Shuang , Strawbridge Rona J. , Kleinbrink Erica L. , Ahluwalia Tarunveer S. , An Ping , Appel Emil V. , Arking Dan E. , Auvinen Juha , Bielak Lawrence F. , Bihlmeyer Nathan A. , Bork-Jensen Jette , Brody Jennifer A. , Campbell Archie , Chu Audrey Y. , Davies Gail , Demirkan Ayse , Floyd James S. , Giulianini Franco , Guo Xiuqing , Gustafsson Stefan , Jackson Anne U. , Jakobsdottir Johanna , Järvelin Marjo-Riitta , Jensen Richard A. , Kanoni Stavroula , Keinanen-Kiukaanniemi Sirkka , Li Man , Lu Yingchang , Luan Jian'an , Manning Alisa K. , Marten Jonathan , Meidtner Karina , Mook-Kanamori Dennis O. , Muka Taulant , Pistis Giorgio , Prins Bram , Rice Kenneth M. , Sanna Serena , Smith Albert Vernon , Smith Jennifer A. , Southam Lorraine , Stringham Heather M. , Tragante Vinicius , van der Laan Sander W. , Warren Helen R. , Yao Jie , Yiorkas Andrianos M. , Zhang Weihua , Zhao Wei , Graff Mariaelisa , Highland Heather M. , Justice Anne E. , Marouli Eirini , Medina-Gomez Carolina , Afaq Saima , Alhejily Wesam A. , Amin Najaf , Asselbergs Folkert W. , Bonnycastle Lori L. , Bots Michiel L. , Brandslund Ivan , Chen Ji , Danesh John , de Mutsert Renée , Dehghan Abbas , Ebeling Tapani , Elliott Paul ,   EPIC-Interact Consortium, Farmaki Aliki-Eleni , Faul Jessica D. , Franks Paul W. , Franks Steve , Fritsche Andreas , Gjesing Anette P. , Goodarzi Mark O. , Gudnason Vilmundur , Hallmans Göran , Harris Tamara B. , Herzig Karl-Heinz , Hivert Marie-France , Jørgensen Torben , Jørgensen Marit E. , Jousilahti Pekka , Kajantie Eero , Karaleftheri Maria , Kardia Sharon L.R. , Kinnunen Leena , Koistinen Heikki A. , Komulainen Pirjo , Kovacs Peter , Kuusisto Johanna , Laakso Markku , Lange Leslie A. , Launer Lenore J. , Leong Aaron , Lindström Jaana , Manning Fox Jocelyn E. , Männistö Satu , Maruthur Nisa M. , Moilanen Leena , Mulas Antonella , Nalls Mike A. , Neville Matthew , Pankow James S. , Pattie Alison , Petersen Eva R.B. , Puolijoki Hannu , Rasheed Asif , Redmond Paul , Renström Frida , Roden Michael , Saleheen Danish , Saltevo Juha , Savonen Kai , Sebert Sylvain , Skaaby Tea , Small Kerrin S. , Stančáková Alena , Stokholm Jakob , Strauch Konstantin , Tai E-Shyong , Taylor Kent D. , Thuesen Betina H. , Tönjes Anke , Tsafantakis Emmanouil , Tuomi Tiinamaija , Tuomilehto Jaakko ,   Understanding Society Scientific Group, Uusitupa Matti , Vääräsmäki Marja , Vaartjes Ilonca , Zoledziewska Magdalena , Abecasis Goncalo , Balkau Beverley , Bisgaard Hans , Blakemore Alexandra I. , Blüher Matthias , Boeing Heiner , Boerwinkle Eric , Bønnelykke Klaus , Bottinger Erwin P. , Caulfield Mark J. , Chambers John C. , Chasman Daniel I. , Cheng Ching-Yu , Collins Francis S. , Coresh Josef , Cucca Francesco , de Borst Gert J. , Deary Ian J. , Dedoussis George , Deloukas Panos , den Ruijter Hester M. , Dupuis Josée , Evans Michele K. , Ferrannini Ele , Franco Oscar H. , Grallert Harald , Hansen Torben , Hattersley Andrew T. , Hayward Caroline , Hirschhorn Joel N. , Ikram Arfan , Ingelsson Erik , Karpe Fredrik , Kaw Kay-Tee , Kiess Wieland , Kooner Jaspal S. , Körner Antje , Lakka Timo , Langenberg Claudia , Lind Lars , Lindgren Cecilia M. , Linneberg Allan , Lipovich Leonard , Liu Ching-Ti , Liu Jun , Liu Yongmei , Loos Ruth J.F. , MacDonald Patrick E. , Mohlke Karen L. , Morris Andrew D. , Munroe Patricia B. , Murray Alison , Padmanabhan Sandosh , Palmer Colin N. A . , Pasterkamp Gerard , Pedersen Oluf , Peyser Patricia A. , Polasek Ozren , Porteous David , Province Michael A. , Psaty Bruce M. , Rauramaa Rainer , Ridker Paul M. , Rolandsson Olov , Rorsman Patrik , Rosendaal Frits R. , Rudan Igor , Salomaa Veikko , Schulze Matthias B. , Sladek Robert , Smith Blair H. , Spector Timothy D. , Starr John M. , Stumvoll Michael , van Duijn Cornelia M. , Walker Mark , Wareham Nick J. , Weir David R. , Wilson James G. , Wong Tien Yin , Zeggini Eleftheria , Zonderman Alan B. , Rotter Jerome I. , Morris Andrew P. , Boehnke Michael , Florez Jose C. , McCarthy Mark I. , Meigs James B. , Mahajan Anubha , Scott Robert A. , Gloyn Anna L. , Barroso Inês 
Published: October 2023

Background Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.