Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
Jennifer Wessel(Richard M. Fairbanks Foundation), Audrey Y. Chu(Brigham and Women's Hospital), Sara M. Willems(University of Cambridge), Shuai Wang(Boston University), Hanieh Yaghootkar(University of Exeter), Jennifer A. Brody(University of Washington), Marco Dauriz(University of Verona), Marie‐France Hivert(Université de Sherbrooke), Sridharan Raghavan(Harvard University), Leonard Lipovich(Wayne State University), Bertha Hidalgo(University of Alabama at Birmingham), Keolu Fox(University of Washington), Jennifer E. Huffman(National Heart Lung and Blood Institute), Ping An(Washington University in St. Louis), Yingchang Lu(Icahn School of Medicine at Mount Sinai), Laura J. Rasmussen‐Torvik(Northwestern University), Niels Grarup(University of Copenhagen), Margaret G. Ehm(GlaxoSmithKline (United States)), Li Li(University of Cambridge), Abigail S. Baldridge(Northwestern University), Alena Stančáková(University of Eastern Finland), Ravinder Abrol(Cedars-Sinai Medical Center), Céline Besse(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Anne Boland(Commissariat à l'Énergie Atomique et aux Énergies Alternatives), Jette Bork‐Jensen(University of Copenhagen), Myriam Fornage(Brown Foundation), Daniel F. Freitag(University of Cambridge), Melissa E. Garcia(Institute on Aging), Xiuqing Guo(The Lundquist Institute), Kazuo Hara(Icahn School of Medicine at Mount Sinai), Aaron Isaacs(Erasmus MC), Jóhanna Jakobsdóttir(Icelandic Heart Association), Leslie A. Lange(University of North Carolina at Chapel Hill), Jill Layton(Richard M. Fairbanks Foundation), Man Li(Brigham and Women's Hospital), Wei Zhao(University of Cambridge), Karina Meidtner(German Institute of Human Nutrition), Alanna C. Morrison(The University of Texas Health Science Center at Houston), Mike A. Nalls(National Institute on Aging), Marjolein J. Peters(Erasmus MC), Maria Sabater‐Lleal(Karolinska Institutet), Claudia Schurmann(Icahn School of Medicine at Mount Sinai), Angela Silveira(Karolinska Institutet), Albert V. Smith(Icelandic Heart Association), Lorraine Southam(Wellcome Sanger Institute), Marcus H. Stoiber(Lawrence Berkeley National Laboratory), Rona J. Strawbridge(Karolinska Institutet), Kent D. Taylor(The Lundquist Institute), Tibor V. Varga(Lund University), Kristine H. Allin(University of Copenhagen), Najaf Amin(Erasmus MC), Jennifer L. Aponte(GlaxoSmithKline (United States)), Tin Aung(National University of Singapore), Caterina Barbieri(Vita-Salute San Raffaele University), Nathan A. Bihlmeyer(Johns Hopkins University), Michael Boehnke(University of Michigan), Cristina Bombieri(University of Verona), Donald W. Bowden(Wake Forest University), Sean M. Burns(Massachusetts General Hospital), Yuning Chen(Boston University), Yii-DerI Chen(Boston University), Ching‐Yu Cheng(National University of Singapore), Adolfo Correa(University of Mississippi Medical Center), Jacek Czajkowski(Washington University in St. Louis), Abbas Dehghan(Erasmus MC), Georg Ehret(Johns Hopkins University), Guðný Eiríksdóttir(Icelandic Heart Association), Stefan Andersson Escher(Lund University), Aliki‐Eleni Farmaki(Harokopio University of Athens), Mattias Frånberg(Stockholm University), Giovanni Gambaro(Agostino Gemelli University Polyclinic), Franco Giulianini(Brigham and Women's Hospital), William A. Goddard(California Institute of Technology), Anuj Goel(Centre for Human Genetics), Omri Gottesman(Child Health and Development Institute), Megan L. Grove(The University of Texas Health Science Center at Houston), Stefan Gustafsson(Uppsala University), Yang Hai(The Lundquist Institute), Göran Hallmans(Umeå University), Jiyoung Heo(Sangmyung University), Per Hoffmann(University of Bonn), M. Kamran Ikram(Singapore National Eye Center), Richard A. Jensen(University of Washington), Marit E. Jørgensen(Steno Diabetes Centers), Torben Jørgensen(Glostrup Hospital), Maria Karaleftheri(ECA Medical (United States)), Chiea Chuen Khor(National University of Singapore), Andrea Kirkpatrick(California Institute of Technology), Aldi T. Kraja(Washington University in St. Louis), Johanna Kuusisto(University of Eastern Finland), Ethan M. Lange(University of North Carolina at Chapel Hill), I. T. Lee(National Yang Ming Chiao Tung University), Wen‐Jane Lee(Taichung Veterans General Hospital), Aaron Leong(Harvard University), Jiemin Liao(National University of Singapore), Chunyu Liu(National Heart Lung and Blood Institute), Ching‐Ti Liu(Wake Forest University), Cecilia M. Lindgren(Centre for Human Genetics), Allan Linneberg(Glostrup Hospital), Giovanni Malerba(University of Verona), Vasiliki Mamakou(National and Kapodistrian University of Athens), Eirini Marouli(Harokopio University of Athens), Nisa M. Maruthur(Johns Hopkins University), Angela Matchan(Wellcome Sanger Institute), Roberta McKean‐Cowdin(University of Southern California), Olga McLeod(Karolinska Institutet), Ginger Metcalf(Baylor College of Medicine), Karen L. Mohlke(University of North Carolina at Chapel Hill), Donna M. Muzny(Baylor College of Medicine), Ιωάννα Ντάλλα(Harokopio University of Athens), Nicholette D Palmer(Wake Forest University), Dorota Pasko(University of Exeter), Andreas Peter(Deutsches Diabetes-Zentrum e.V.), Nigel W. Rayner(Centre for Human Genetics), Frida Renström(Lund University), Kenneth Rice(University of Washington), Cinzia Sala(Vita-Salute San Raffaele University), Bengt Sennblad(Science for Life Laboratory), Ioannis Serafetinidis(General Hospital of Athens G. Genimatas), Jennifer A. Smith(University of Michigan), Nicole Soranzo(Wellcome Sanger Institute), Elizabeth K. Speliotes(University of Michigan), Eli A. Stahl(Icahn School of Medicine at Mount Sinai), Kathleen Stirrups(Queen Mary University of London), N. Tentolouris(Laiko General Hospital of Athens), Anastasia Thanopoulou(National and Kapodistrian University of Athens), Mina Torres(University of Southern California), Michela Traglia(Vita-Salute San Raffaele University), Emmanouil Tsafantakis, Sundas Javad(University of Cambridge), Lisa R. Yanek(Johns Hopkins University), Eleni Zengini(University of Sheffield), Diane M. Becker(Johns Hopkins University), Joshua C Bis(University of Washington), James Brown(Lawrence Berkeley National Laboratory), L. Adrienne Cupples(Boston University), Torben Hansen(University of Copenhagen), Erik Ingelsson(Uppsala University), Andrew J. Karter(Kaiser Permanente), Carlos Lorenzo(The University of Texas at San Antonio Health Science Center), Rasika A. Mathias(Johns Hopkins University), Jill M. Norris(Colorado School of Public Health), Gina M. Peloso(Broad Institute), Wayne H.-H. Sheu(National Yang Ming Chiao Tung University), Daniela Toniolo(Vita-Salute San Raffaele University), Dhananjay Vaidya(Johns Hopkins University), Rohit Varma(University of Southern California), Lynne E. Wagenknecht(Wake Forest University), Heiner Boeing(German Institute of Human Nutrition), Erwin P. Böttinger(Child Health and Development Institute), George Dedoussis(Harokopio University of Athens), Panos Deloukas(Queen Mary University of London), Ele Ferrannini(Istituto di Fisiologia Clinica), Oscar H. Franco(Erasmus MC), Paul W. Franks(Lund University), Richard A. Gibbs(Baylor College of Medicine), Vilmundur Guðnason(University of Iceland), Anders Hamsten(Karolinska Institutet), Tamara B. Harris(Institute on Aging), Andrew T. Hattersley(University of Exeter), Caroline Hayward(Institute of Genetics and Cancer), Albert Hofman(Erasmus MC), Jan-Håkan Jansson(Skellefteå Hospital), Claudia Langenberg(University of Cambridge), Lenore J. Launer(Institute on Aging), Daniel Levy(National Institutes of Health), Ben A. Oostra(Erasmus MC), Christopher J. O’Donnell(Massachusetts General Hospital), Stephen O’Rahilly(University of Cambridge), Sandosh Padmanabhan(University of Glasgow), James S. Pankow(University of Minnesota), Ozren Polašek(University of Split), Michael A. Province(Washington University in St. Louis), Stephen S. Rich(Office of Public Health Genomics), Paul M. Ridker(Brigham and Women's Hospital), Igor Rudan(MRC Centre for Reproductive Health), Matthias B. Schulze(Deutsches Diabetes-Zentrum e.V.), Blair H. Smith(University of Dundee), André G. Uitterlinden(Erasmus MC), Mark Walker(Newcastle University), Hugh Watkins(Centre for Human Genetics), Tien Yin Wong(National University of Singapore), Eleftheria Zeggini(Wellcome Sanger Institute), Stephen J. Sharp(University of Cambridge), Nita G. Forouhi(University of Cambridge), Nicola D. Kerrison(University of Cambridge), Debora Lucarelli(University of Cambridge), Matt Sims(University of Cambridge), Inês Barroso(University of Cambridge), Mark I. McCarthy(Centre for Human Genetics), Larraitz Arriola(Basque Government), Beverley Balkau(Université Paris-Sud), Aurelio Barricarte(Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública), Carlos A. González(Institut Català d'Ornitologia), Sara Grioni(National Centre for Disease Prevention and Control), Rudolf Kaaks(German Cancer Research Center), Timothy J. Key(University of Oxford), Carmen Navarro(Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública), Peter M. Nilsson(Lund University), Kim Overvad(Aarhus University), Domenico Palli(Piedmont Reference Center for Epidemiology and Cancer Prevention), Salvatore Panico(Federico II University Hospital), J. Ramón Quirós(Gobierno del Principado de Asturias), Olov Rolandsson(Umeå University), Carlotta Sacerdote(Italian institute for Genomic Medicine), María‐José Sánchez(Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública), Nadia Slimani(Centre international de recherche sur le cancer), Anne Tjønneland(Danish Cancer Society), Rosario Tumino(University of Ragusa), Daphne L. van der A(National Institute for Public Health and the Environment), Yvonne T. van der Schouw(University Medical Center Utrecht), Elio Ríboli(Imperial College London), Markku Laakso(University of Eastern Finland), Ingrid B. Borecki(Washington University in St. Louis), Daniel I. Chasman(Brigham and Women's Hospital), Oluf Pedersen(University of Copenhagen), Bruce M. Psaty(Group Health Cooperative), E Shyong Tai(National University of Singapore), Cornelia M. van Duijn(Erasmus MC), Nicholas J. Wareham(University of Cambridge), Dawn Waterworth(GlaxoSmithKline (United States)), Eric Boerwinkle(Baylor College of Medicine), W.H. Linda Kao(Johns Hopkins University), José C. Florez(Broad Institute), Ruth J. F. Loos(Child Health and Development Institute), James G. Wilson(University of Mississippi Medical Center), Timothy M. Frayling(University of Exeter), David S. Siscovick(New York Academy of Medicine), Josée Dupuis(Boston University), Jerome I. Rotter(The Lundquist Institute), James B. Meigs(Harvard University), Robert A. Scott(University of Cambridge), Mark O. Goodarzi(Cedars-Sinai Medical Center)
Cited by 201Open Access
Abstract
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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