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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

2017; American Diabetes Association; Volume: 66; Issue: 11 Linguagem: Inglês

10.2337/db16-1253

1939-327X

Robert A. Scott, Laura J. Scott, Reedik Mägi, Letizia Marullo, Kyle J. Gaulton, Marika Kaakinen, Natalia Pervjakova, Tune H. Pers, Andrew D. Johnson, John D. Eicher, Anne Jackson, Teresa Ferreira, Yeji Lee, Clement Ma, Valgerður Steinthórsdóttir, Guðmar Þorleifsson, Lu Qi, Natalie R. van Zuydam, Anubha Mahajan, Han Chen, Peter Almgren, Benjamin F. Voight, Harald Grallert, Martina Müller‐Nurasyid, Janina S. Ried, Nigel W. Rayner, Neil Robertson, Lennart C. Karssen, Jin‐Moo Lee, Sara M. Willems, Christian Fuchsberger, Phoenix Kwan, Tanya M. Teslovich, Pritam Chanda, Man Li, Yingchang Lu, Christian Dina, Dorothée Thuillier, Loïc Yengo, Longda Jiang, Thomas Sparsø, Hans A. Kestler, Himanshu Chheda, Lewin Eisele, Stefan Gustafsson, Mattias Frånberg, Rona J. Strawbridge, Rafn Benediktsson, Ástráður B. Hreiðarsson, Augustine Kong, Gunnar Sigurðsson, Nicola D. Kerrison, Jian’an Luan, Liming Liang, Thomas Meitinger, Michael Roden, Barbara Thorand, Tõnu Esko, Evelin Mihailov, Caroline S. Fox, Yongmei Liu, Denis Rybin, Bo Isomaa, Valeriya Lyssenko, Jaakko Tuomilehto, David Couper, James S. Pankow, Niels Grarup, Christian Theil Have, Marit E. Jørgensen, Torben Jørgensen, Allan Linneberg, Marilyn C. Cornelis, Rob M. van Dam, Sarah Hunt, Peter Kraft, Qi Sun, Sarah Edkins, Katharine R. Owen, John R. B. Perry, Andrew R. Wood, Eleftheria Zeggini, Juan Tajes-Fernandes, Gonçalo R. Abecasis, Lori L. Bonnycastle, Peter S. Chines, Heather M. Stringham, Heikki A. Koistinen, Leena Kinnunen, Bengt Sennblad, Hae‐Won Uh, Markus M. Nöthen, Sonali Pechlivanis, Damiano Baldassarre, Karl Gertow, Steve E. Humphries, Elena Tremoli, Norman Klopp, Julia Meyer, Gerald Steinbach, Roman Wennauer, Johan G. Eriksson, Satu Männistö, Leena Peltonen, Emmi Tikkanen, G. Charpentier, Elodie Eury, Stéphane Lobbens, Bruna Gigante, Karin Leander, Olga McLeod, Erwin P. Böttinger, Omri Gottesman, Douglas M. Ruderfer, Matthias Blüher, Péter Kovács, Anke Tönjes, Nisa M. Maruthur, Chiara Scapoli, Raimund Erbel, Karl‐Heinz Jöckel, Susanne Moebus, Ulf dé Fairé, Anders Hamsten, Michael Stümvoll, Panos Deloukas, Peter Donnelly, Timothy M. Frayling, Andrew T. Hattersley, Samuli Ripatti, Veikko Salomaa, Nancy L. Pedersen, Bernhard O. Boehm, Richard N. Bergman, Francis S. Collins, Karen L. Mohlke, Jaakko Tuomilehto, Torben Hansen, Oluf Pedersen, Inês Barroso, Lars Lannfelt, Erik Ingelsson, Lars Lind, Cecilia M. Lindgren, Stéphane Cauchi, Philippe Froguel, Ruth J. F. Loos, Beverley Balkau, Heiner Boeing, Paul W. Franks, Aurelio Barricarte Gurrea, Domenico Palli, Yvonne T. van der Schouw, David Altshuler, Leif Groop, Claudia Langenberg, Nicholas J. Wareham, Eric J.G. Sijbrands, Cornelia M. van Duijn, José C. Florez, James B. Meigs, Eric Boerwinkle, Christian Gieger, Konstantin Strauch, Andres Metspalu, Andrew D. Morris, Colin N. A. Palmer, Frank B. Hu, Unnur Þorsteinsdóttir, Kāri Stefánsson, Josée Dupuis, Andrew P. Morris, Michael Boehnke, Mark I. McCarthy, Inga Prokopenko,

Epigenetics and DNA Methylation

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 < 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.