Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation
Authors: Ng Natasha H. J. , Willems Sara M. , Fernandez Juan , Fine Rebecca S. , Wheeler Eleanor , Wessel Jennifer , Kitajima Hidetoshi , Marenne Gaelle , Rundle Jana K. , Sim Xueling , Yeghootkar Hanieh , Beer Nicola L. , Raimondo Anne , Tarasov Andrei I. , Thomsen Soren K. , van de Bunt Martijn , Wang Shuai , Chen Sai , Chen Yuning , Chen Yii-Der Ida , de Haan Hugoline G. , 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 , Hastoy Benoit , Jackson Anne U. , Jakobsdottir Johanna , Jarvelin Marjo-Riitta , Jensen Richard A. , Kanoni Stavroula , Keinanen-Kiukaanniemi Sirkka , Li Jin , Li Man , Lohman Kurt , Lu Yingchang , Luan Jian’an , Manning Alisa K. , Marten Jonathan , Marzi Carola , Meidtner Karina , Mook-Kanamori Dennis O. , Muka Taulant , Pistis Giorgio , Prins Bram , Rice Kenneth M. , Robertson Neil , Sanna Serena , Shi Yuan , Smith Albert Vernon , Smith Jennifer A. , Southam Lorraine , Stringham Heather M. , Tajuddin Salman M. , Tragante Vinicius , van der Laan Sander W. , Warren Helen R. , Yao Jie , Yiorkas Andrianos M. , Zhang Weihua , Zhao Wei , Ahlqvist Emma , Graff Mariaelisa , Highland Heather M. , Justice Anne E , Lo Ken Sin , 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 , Christensen Cramer , 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 , Jansson Jan-Håkan , Jhun Min A , 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. , Lee Jung-Jin , 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 , Clark Anne , 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 , Groop Leif , 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 , McCarthy Mark I , Meigs James B , Mahajan Anubha , Scott Robert A. , Gloyn Anna L , Barroso Inês 
Published: October 2019

SummaryMetabolic dysregulation in multiple tissues alters glucose homeostasis and influences risk for type 2 diabetes (T2D). To identify pathways and tissues influencing T2D-relevant glycemic traits (fasting glucose [FG], fasting insulin [FI], two-hour glucose [2hGlu] and glycated hemoglobin [HbA1c]), we investigated associations of exome-array variants in up to 144,060 individuals without diabetes of multiple ancestries. Single-variant analyses identified novel associations at 21 coding variants in 18 novel loci, whilst gene-based tests revealed signals at two genes, TF (HbA1c) and G6PC (FG, FI). Pathway and tissue enrichment analyses of trait-associated transcripts confirmed the importance of liver and kidney for FI and pancreatic islets for FG regulation, implicated adipose tissue in FI and the gut in 2hGlu, and suggested a role for the non-endocrine pancreas in glucose homeostasis. Functional studies demonstrated that a novel FG/FI association at the liver-enriched G6PC transcript was driven by multiple rare loss-of-function variants. The FG/HbA1c-associated, islet-specific G6PC2 transcript also contained multiple rare functional variants, including two alleles within the same codon with divergent effects on glucose levels. Our findings highlight the value of integrating genomic and functional data to maximize biological inference.Highlights23 novel coding variant associations (single-point and gene-based) for glycemic traits51 effector transcripts highlighted different pathway/tissue signatures for each traitThe exocrine pancreas and gut influence fasting and 2h glucose, respectivelyMultiple variants in liver-enriched G6PC and islet-specific G6PC2 influence glycemia