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

A.P. Morris, B.F. Voight, T.M. Teslovich, T. Ferreira, A.V. Segrè, V. Steinthorsdottir, R.J. Strawbridge, H. Khan, H. Grallert, A. Mahajan, I. Prokopenko, H.M. Kang, C. Dina, T. Esko, R.M. Fraser, S. Kanoni, A. Kumar, V. Lagou, C. Langenberg, J. LuanC.M. Lindgren, M. Müller-Nurasyid, S. Pechlivanis, N.W. Rayner, L.J. Scott, S. Wiltshire, L. Yengo, L. Kinnunen, E.J. Rossin, S. Raychaudhuri, A.D. Johnson, A.S. Dimas, R.J.F. Loos, S. Vedantam, H. Chen, J.C. Florez, C. Fox, C.-T. Liu, D. Rybin, D.J. Couper, W.H.L. Kao, M. Li, M.C. Cornelis, P. Kraft, Q. Sun, R.M. Van Dam, H.M. Stringham, P.S. Chines, K. Fischer, P. Fontanillas, O.L. Holmen, S.E. Hunt, A.U. Jackson, A. Kong, Robert Lawrence, J. Meyer, J.R.B. Perry, C.G.P. Platou, S. Potter, E. Rehnberg, N. Robertson, S. Sivapalaratnam, A. Stančáková, K. Stirrups, G. Thorleifsson, E. Tikkanen, A.R. Wood, P. Almgren, M. Atalay, R. Benediktsson, L.L. Bonnycastle, N. Burtt, J. Carey, G. Charpentier, A.T. Crenshaw, A.S.F. Doney, M. Dorkhan, S. Edkins, V. Emilsson, E. Eury, T. Forsen, K. Gertow, B. Gigante, G.B. Grant, C.J. Groves, C. Guiducci, C. Herder, A.B. Hreidarsson, Jennie Hui, Alan James, A. Jonsson, W. Rathmann, N. Klopp, J. Kravic, K. Krjutškov, C. Langford, K. Leander, E. Lindholm, S. Lobbens, S. Männistö, G. Mirza, T.W. Mühleisen, B. Musk, M. Parkin, L. Rallidis, J. Saramies, B. Sennblad, S. Shah, G. Sigursson, A. Silveira, G. Steinbach, B. Thorand, J. Trakalo, F. Veglia, R. Wennauer, W. Winckler, D. Zabaneh, H. Campbell, C. Van Duijn, A.G. Uitterlinden, A. Hofman, E. Sijbrands, G.R. Abecasis, K.R. Owen, E. Zeggini, M.D. Trip, N.G. Forouhi, A.-C. Syvänen, J.G. Eriksson, L. Peltonen, M.M. Nöthen, B. Balkau, C.N.A. Palmer, V. Lyssenko, T. Tuomi, B. Isomaa, D.J. Hunter, L. Qi, A.R. Shuldiner, M. Roden, I. Barroso, T. Wilsgaard, John Beilby, K. Hovingh, J.F. Price, J.F. Wilson, R. Rauramaa, T.A. Lakka, L. Lind, G. Dedoussis, I. Njølstad, N.L. Pedersen, K.-T. Khaw, N.J. Wareham, S.M. Keinanen-Kiukaanniemi, T.E. Saaristo, E. Korpi-Hyövälti, J. Saltevo, M. Laakso, J. Kuusisto, A. Metspalu, F.S. Collins, K.L. Mohlke, R.N. Bergman, J. Tuomilehto, B.O. Boehm, C. Gieger, K. Hveem, S. Cauchi, P. Froguel, D. Baldassarre, E. Tremoli, S.E. Humphries, D. Saleheen, J. Danesh, E. Ingelsson, S. Ripatti, V. Salomaa, R. Erbel, K.-H. Jöckel, S. Moebus, A. Peters, T. Illig, U.D. Faire, A. Hamsten, A.D. Morris, P.J. Donnelly, T.M. Frayling, A.T. Hattersley, E. Boerwinkle, O. Melander, S. Kathiresan, P.M. Nilsson, P. Deloukas, U. Thorsteinsdottir, L.C. Groop, K. Stefansson, F. Hu, J.S. Pankow, J. Dupuis, J.B. Meigs, D. Altshuler, M. Boehnke, M.I. Mccarthy

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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)981-92
JournalNature Genetics
Volume44
Issue number9
Early online date12 Aug 2012
DOIs
Publication statusPublished - 1 Sep 2012

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Morris, A. P., Voight, B. F., Teslovich, T. M., Ferreira, T., Segrè, A. V., Steinthorsdottir, V., ... Mccarthy, M. I. (2012). Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nature Genetics, 44(9), 981-92. https://doi.org/10.1038/ng.2383