Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

Andrew P. Morris, Benjamin F. Voight, Tanya M. Teslovich, Teresa Ferreira, Ayellet V. Segrè, Valgerdur Steinthorsdottir, Rona J. Strawbridge, Hassan Khan, Harald Grallert, Anubha Mahajan, Inga Prokopenko, Hyun Min Kang, Christian Dina, Tonu Esko, Ross M. Fraser, Stavroula Kanoni, Ashish Kumar, Vasiliki Lagou, Claudia Langenberg, Jian'An LuanCecilia M. Lindgren, Martina Müller-Nurasyid, Sonali Pechlivanis, N. William Rayner, Laura J. Scott, Steven Wiltshire, Loic Yengo, Leena Kinnunen, Elizabeth J. Rossin, Soumya Raychaudhuri, Andrew D. Johnson, Antigone S. Dimas, Ruth J F Loos, Sailaja Vedantam, Han Chen, Jose C. Florez, Caroline Fox, Ching Ti Liu, Denis Rybin, David J. Couper, Wen Hong L Kao, Man Li, Marilyn C. Cornelis, Peter Kraft, Qi Sun, Rob M. Van Dam, Heather M. Stringham, Peter S. Chines, Krista Fischer, Pierre Fontanillas, Oddgeir L. Holmen, Sarah E. Hunt, Anne U. Jackson, Augustine Kong, Robert Lawrence, Julia Meyer, John R B Perry, Carl G P Platou, Simon Potter, Emil Rehnberg, Neil Robertson, Suthesh Sivapalaratnam, Alena Stančáková, Kathleen Stirrups, Gudmar Thorleifsson, Emmi Tikkanen, Andrew R. Wood, Peter Almgren, Mustafa Atalay, Rafn Benediktsson, Lori L. Bonnycastle, Noël Burtt, Jason Carey, Guillaume Charpentier, Andrew T. Crenshaw, Alex S F Doney, Mozhgan Dorkhan, Sarah Edkins, Valur Emilsson, Elodie Eury, Tom Forsen, Karl Gertow, Bruna Gigante, George B. Grant, Christopher J. Groves, Candace Guiducci, Christian Herder, Astradur B. Hreidarsson, Jennie Hui, Alan James, Anna Jonsson, Wolfgang Rathmann, Norman Klopp, Jasmina Kravic, Kaarel Krjutškov, Cordelia Langford, Karin Leander, Eero Lindholm, Stéphane Lobbens, Satu MäNnistö, Ghazala Mirza, Thomas W. MüHleisen, Bill Musk, Melissa Parkin, Loukianos Rallidis, Jouko Saramies, Bengt Sennblad, Sonia Shah, Gunnar Sigursson, Angela Silveira, Gerald Steinbach, Barbara Thorand, Joseph Trakalo, Fabrizio Veglia, Roman Wennauer, Wendy Winckler, Delilah Zabaneh, Harry Campbell, Cornelia Van Duijn, Andre G. Uitterlinden, Albert Hofman, Eric Sijbrands, Goncalo R. Abecasis, Katharine R. Owen, Eleftheria Zeggini, Mieke D. Trip, Nita G. Forouhi, Ann Christine Syvänen, Johan G. Eriksson, Leena Peltonen, Markus M. Nöthen, Beverley Balkau, Colin N A Palmer, Valeriya Lyssenko, Tiinamaija Tuomi, Bo Isomaa, David J. Hunter, Lu Qi, Alan R. Shuldiner, Michael Roden, Ines Barroso, Tom Wilsgaard, John Beilby, Kees Hovingh, Jackie F. Price, James F. Wilson, Rainer Rauramaa, Timo A. Lakka, Lars Lind, George Dedoussis, Inger NjøLstad, Nancy L. Pedersen, Kay Tee Khaw, Nicholas J. Wareham, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Eeva Korpi-HyöVäLti, Juha Saltevo, Markku Laakso, Johanna Kuusisto, Andres Metspalu, Francis S. Collins, Karen L. Mohlke, Richard N. Bergman, Jaakko Tuomilehto, Bernhard O. Boehm, Christian Gieger, Kristian Hveem, Stephane Cauchi, Philippe Froguel, Damiano Baldassarre, Elena Tremoli, Steve E. Humphries, Danish Saleheen, John Danesh, Erik Ingelsson, Samuli Ripatti, Veikko Salomaa, Raimund Erbel, Karl Heinz JöCkel, Susanne Moebus, Annette Peters, Thomas Illig, Ulf De Faire, Anders Hamsten, Andrew D. Morris, Peter J. Donnelly, Timothy M. Frayling, Andrew T. Hattersley, Eric Boerwinkle, Olle Melander, Sekar Kathiresan, Peter M. Nilsson, Panos Deloukas, Unnur Thorsteinsdottir, Leif C. Groop, Kari Stefansson, Frank Hu, James S. Pankow, Josée Dupuis, James B. Meigs, David Altshuler, Michael Boehnke, Mark I. McCarthy

Research output: Contribution to journalArticle

Abstract

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.

Original languageEnglish
Pages (from-to)981-990
Number of pages10
JournalNature Genetics
Volume44
Issue number9
DOIs
Publication statusPublished - Sep 2012

ASJC Scopus subject areas

  • Genetics

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    Morris, A. P., Voight, B. F., Teslovich, T. M., Ferreira, T., Segrè, A. V., Steinthorsdottir, V., Strawbridge, R. J., Khan, H., Grallert, H., Mahajan, A., Prokopenko, I., Kang, H. M., Dina, C., Esko, T., Fraser, R. M., Kanoni, S., Kumar, A., Lagou, V., Langenberg, C., ... McCarthy, M. I. (2012). Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nature Genetics, 44(9), 981-990. https://doi.org/10.1038/ng.2383