An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
Authors: Scott Robert A. , Scott Laura J. , Mägi Reedik , Marullo Letizia , Gaulton Kyle J. , Kaakinen Marika , Pervjakova Natalia , Pers Tune H. , Johnson Andrew D. , Eicher John D. , Jackson Anne U. , Ferreira Teresa , Lee Yeji , Ma Clement , Steinthorsdottir Valgerdur , Thorleifsson Gudmar , Qi Lu , Van Zuydam Natalie R. , Mahajan Anubha , Chen Han , Almgren Peter , Voight Ben F. , Grallert Harald , Müller-Nurasyid Martina , Ried Janina S. , Rayner Nigel W. , Robertson Neil , Karssen Lennart C. , van Leeuwen Elisabeth M. , Willems Sara M. , Fuchsberger Christian , Kwan Phoenix , Teslovich Tanya M. , Chanda Pritam , Li Man , Lu Yingchang , Dina Christian , Thuillier Dorothee , Yengo Loic , Jiang Longda , Sparso Thomas , Kestler Hans A. , Chheda Himanshu , Eisele Lewin , Gustafsson Stefan , Frånberg Mattias , Strawbridge Rona J. , Benediktsson Rafn , Hreidarsson Astradur B. , Kong Augustine , Sigurðsson Gunnar , Kerrison Nicola D. , Luan Jian'an , Liang Liming , Meitinger Thomas , Roden Michael , Thorand Barbara , Esko Tõnu , Mihailov Evelin , Fox Caroline , Liu Ching-Ti , Rybin Denis , Isomaa Bo , Lyssenko Valeriya , Tuomi Tiinamaija , Couper David J. , Pankow James S. , Grarup Niels , Have Christian T. , Jørgensen Marit E. , Jørgensen Torben , Linneberg Allan , Cornelis Marilyn C. , van Dam Rob M. , Hunter David J. , Kraft Peter , Sun Qi , Edkins Sarah , Owen Katharine R. , Perry John R.B. , Wood Andrew R. , Zeggini Eleftheria , Tajes-Fernandes Juan , Abecasis Goncalo R. , Bonnycastle Lori L. , Chines Peter S. , Stringham Heather M. , Koistinen Heikki A. , Kinnunen Leena , Sennblad Bengt , Mühleisen Thomas W. , Nöthen Markus M. , Pechlivanis Sonali , Baldassarre Damiano , Gertow Karl , Humphries Steve E. , Tremoli Elena , Klopp Norman , Meyer Julia , Steinbach Gerald , Wennauer Roman , Eriksson Johan G. , Mӓnnistö Satu , Peltonen Leena , Tikkanen Emmi , Charpentier Guillaume , Eury Elodie , Lobbens Stéphane , Gigante Bruna , Leander Karin , McLeod Olga , Bottinger Erwin P. , Gottesman Omri , Ruderfer Douglas , Blüher Matthias , Kovacs Peter , Tonjes Anke , Maruthur Nisa M. , Scapoli Chiara , Erbel Raimund , Jöckel Karl-Heinz , Moebus Susanne , de Faire Ulf , Hamsten Anders , Stumvoll Michael , Deloukas Panagiotis , Donnelly Peter J. , Frayling Timothy M. , Hattersley Andrew T. , Ripatti Samuli , Salomaa Veikko , Pedersen Nancy L. , Boehm Bernhard O. , Bergman Richard N. , Collins Francis S. , Mohlke Karen L. , Tuomilehto Jaakko , Hansen Torben , Pedersen Oluf , Barroso Inês , Lannfelt Lars , Ingelsson Erik , Lind Lars , Lindgren Cecilia M. , Cauchi Stephane , Froguel Philippe , Loos Ruth J.F. , Balkau Beverley , Boeing Heiner , Franks Paul W. , Barricarte Gurrea Aurelio , Palli Domenico , van der Schouw Yvonne T. , Altshuler David , Groop Leif C. , Langenberg Claudia , Wareham Nicholas J. , Sijbrands Eric , van Duijn Cornelia M. , Florez Jose C. , Meigs James B. , Boerwinkle Eric , Gieger Christian , Strauch Konstantin , Metspalu Andres , Morris Andrew D. , Palmer Colin N.A. , Hu Frank B. , Thorsteinsdottir Unnur , Stefansson Kari , Dupuis Josée , Morris Andrew P. , Boehnke Michael , McCarthy Mark I. , Prokopenko Inga 
Published: June 2017

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P &lt; 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.