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

2012; Nature Portfolio; Volume: 44; Issue: 9 Linguagem: Inglês

10.1038/ng.2383

1546-1718

Andrew P. Morris, Benjamin F. Voight, Tanya M. Teslovich, Teresa Ferreira, Ayellet V. Segrè, Valgerður Steinthórsdóttir, Rona J. Strawbridge, Hassan Khan, Harald Grallert, Anubha Mahajan, Inga Prokopenko, Hyun Min Kang, Christian Dina, Tõnu Esko, Ross M. Fraser, Stavroula Kanoni, Ashish Kumar, Vasiliki Lagou, Claudia Langenberg, Jian’an Luan, Cecilia M. Lindgren, Martina Müller‐Nurasyid, Sonali Pechlivanis, Nigel W. Rayner, Laura J. Scott, Steven Wiltshire, Loïc Yengo, Leena Kinnunen, Elizabeth J. Rossin, Soumya Raychaudhuri, Andrew D. Johnson, Antigone S. Dimas, Ruth J. F. Loos, Sailaja Vedantam, Han Chen, José C. Florez, Caroline S. Fox, Yongmei Liu, Denis Rybin, David Couper, Wen Hong Linda 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 Hunt, Anne Jackson, Augustine Kong, Robert Lawrence, Julia Meyer, John R. B. Perry, Carl Platou, Simon Potter, Emil Rehnberg, Neil Robertson, Suthesh Sivapalaratnam, Alena Stančáková, Kathleen Stirrups, Guðmar Þorleifsson, Emmi Tikkanen, Andrew R. Wood, Peter Almgren, Mustafa Atalay, Rafn Benediktsson, Lori L. Bonnycastle, Noël P. Burtt, Jason Carey, G. Charpentier, Andrew Crenshaw, Alex S. F. Doney, Mozhgan Dorkhan, Sarah Edkins, Valur Emilsson, Elodie Eury, Tom Forsén, Karl Gertow, Bruna Gigante, George Grant, Christopher J. Groves, Candace Guiducci, Christian Herder, Ástráður B. Hreiðarsson, Jennie Hui, Anthony James, Anna Jonsson, Wolfgang Rathmann, Norman Klopp, Jasmina Kravić, Kaarel Krjutškov, Cordelia Langford, Karin Leander, Eero Lindholm, Stéphane Lobbens, Satu Männistö, Ghazala Mirza, Hae‐Won Uh, Bill Musk, Melissa Parkin, Lοukianos S. Rallidis, Jouko Saramies, Bengt Sennblad, Sonia Shah, Gunnar Sigurðsson, Angela Silveira, Gerald Steinbach, Barbara Thorand, Joseph Trakalo, Fabrizio Veglia, Roman Wennauer, Wendy Winckler, Delilah Zabaneh, Harry Campbell, Cornelia M. van Duijn, André G. Uitterlinden, Albert Hofman, Eric J.G. Sijbrands, Gonçalo 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, Nicholette D. Palmer, Valeriya Lyssenko, Jaakko Tuomilehto, Bo Isomaa, David J. Hunter, Lu Qi, Alan R. Shuldiner, Michael Roden, Inês 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 Keinänen‐Kiukaanniemi, Timo 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, Stéphane 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 dé Fairé, Anders Hamsten, Andrew D. Morris, Peter Donnelly, Timothy M. Frayling, Andrew T. Hattersley, Eric Boerwinkle, Olle Melander, Sekar Kathiresan, Peter M. Nilsson, Panos Deloukas, Unnur Þorsteinsdóttir, Leif Groop, Kári Stéfansson, Frank B. Hu, James S. Pankow, Josée Dupuis, James B. Meigs, David Altshuler, Michael Boehnke, Mark I. McCarthy,

Metabolism, Diabetes, and Cancer

Mark McCarthy, Michael Boehnke, Andrew Morris and colleagues perform large-scale association analyses using the Metabochip to gain insights into the genetic architecture of type 2 diabetes. They report several new susceptibility loci, including two that show sex-differentiated effects on disease risk. 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.