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

作者：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 Cruz Ferreira, Yeji Lee, Clement Ma, Valgerður Steinthórsdóttir, Guðmar Þorleifsson, Lu Qi, Natalie R. van Zuydam, Anubha Mahajan, Han Chen, Peter Almgren, Benjamin Franklin Voight, Harald Grallert, Martina Müller‐Nurasyid, Janina S. Ried, Nigel William Rayner, Neil R. Robertson, Lennart C. Karssen, Elisabeth M. van Leeuwen, 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 Th Sigurdsson, Nicola D. Kerrison, Jian’an Luan, Liming Liang, Thomas Meitinger, Michael Roden, Barbara Thorand, Tõnu Esko, Evelin Mihailov, Caroline S. Fox, Ching‐Ti Liu, Denis Rybin, Bo Isomaa, Valeriya Lyssenko, Tiinamaija Tuomi, David J. Couper, James S. Pankow, Niels Grarup, Christian T. Have, Marit E. Jørgensen, Torben Jørgensen, Allan R Linneberg, Marilyn C. Cornelis, Rob M. van Dam, Sarah E 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, Thomas W. Mühleisen, Markus Maria Nöthen, Sonali Pechlivanis, Damiano Baldassarre, Karl Gertow, Steve Eric Humphries, Elena Tremoli, Norman Klopp, Julia Meyer, Gerald Steinbach, Roman Wennauer, Johan Gunnar Eriksson, Satu Männistö, Leena Peltonen, Emmi Tikkanen, Guillaume Charpentier, Elodie Eury, Stéphane Lobbens, Bruna Gigante, Karin Leander, Olga McLeod, Erwin P. Böttinger, Omri Gottesman, Douglas M. Ruderfer, Matthias Blüher, Peter Louis Kovacs, Anke Tönjes, Nisa M. Maruthur, Chiara Scapoli, Raimund Erbel, Karl‐Heinz Jöckel, Susanne Moebus, Ulf dé Fairé, Anders Hamsten, Michael Stümvoll, Panagiotis Deloukas, Peter Donnelly, Timothy Mark Frayling, Andrew Tym Hattersley, Samuli Ripatti, Veikko V Salomaa, Nancy L. Pedersen, Bernhard Otto Boehm, Richard N. Bergman, Francis S. Collins, Karen L. Mohlke, Jaakko Tuomilehto, Torben F. Hansen, Oluf Borbye 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 Arna Thorsteinsdottir, Kāri Stefánsson, Josée Dupuis, Andrew Paul Morris, Michael Boehnke, Mark I. McCarthy, Inga Prokopenko · 发表于：Diabetes · 年份：2017 · DOI：10.2337/db16-1253 · 被引用次数：830 · 研究领域：Genetic Associations and Epidemiology、Genetic Mapping and Diversity in Plants and Animals、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 pathophysio...