The genetic architecture of type 2 diabetes

Christian Fuchsberger, Jason Flannick, Tanya M. Teslovich, Anubha Mahajan, Vineeta Agarwala, Kyle J. Gaulton, Clement Ma, Pierre Fontanillas, Loukas Moutsianas, Davis J. McCarthy, Manuel A. Rivas, John R.B. Perry, Xueling Sim, Thomas W. Blackwell, Neil R. Robertson, N. William Rayner, Pablo Cingolani, Adam Locke, Juan Fernandez Tajes, Heather M. HighlandJosee Dupuis, Peter S. Chines, Cecilia M. Lindgren, Christopher Hartl, Anne U. Jackson, Han Chen, Jeroen R. Huyghe, Martijn Van De Bunt, Richard D. Pearson, Ashish Kumar, Martina Müller-Nurasyid, Niels Grarup, Heather M. Stringham, Eric R. Gamazon, Jaehoon Lee, Yuhui Chen, Robert A. Scott, Jennifer E. Below, Peng Chen, Jinyan Huang, Min Jin Go, Michael L. Stitzel, Dorota Pasko, Stephen C.J. Parker, Tibor V. Varga, Todd Green, Nicola L. Beer, Aaron G. Day-Williams, Teresa Ferreira, Tasha Fingerlin, Momoko Horikoshi, Cheng Hu, Iksoo Huh, Mohammad Kamran Ikram, Bong Jo Kim, Yongkang Kim, Young Jin Kim, Min Seok Kwon, Juyoung Lee, Selyeong Lee, Keng Han Lin, Taylor J. Maxwell, Yoshihiko Nagai, Xu Wang, Ryan P. Welch, Joon Yoon, Weihua Zhang, Nir Barzilai, Benjamin F. Voight, Bok Ghee Han, Christopher P. Jenkinson, Teemu Kuulasmaa, Johanna Kuusisto, Alisa Manning, Maggie C.Y. Ng, Nicholette D. Palmer, Beverley Balkau, Alena Stančáková, Hanna E. Abboud, Heiner Boeing, Vilmantas Giedraitis, Dorairaj Prabhakaran, Omri Gottesman, James Scott, Jason Carey, Phoenix Kwan, George Grant, Joshua D. Smith, Benjamin M. Neale, Shaun Purcell, Adam S. Butterworth, Joanna M.M. Howson, Heung Man Lee, Yingchang Lu, Soo Heon Kwak, Wei Zhao, John Danesh, Vincent K.L. Lam, Kyong Soo Park, Danish Saleheen, Wing Yee So, Claudia H.T. Tam, Uzma Afzal, David Aguilar, Rector Arya, Tin Aung, Edmund Chan, Carmen Navarro, Ching Yu Cheng, Domenico Palli, Adolfo Correa, Joanne E. Curran, Denis Rybin, Vidya S. Farook, Sharon P. Fowler, Barry I. Freedman, Michael Griswold, Daniel Esten Hale, Pamela J. Hicks, Chiea Chuen Khor, Satish Kumar, Benjamin Lehne, Dorothée Thuillier, Wei Yen Lim, Jianjun Liu, Yvonne T. Van Der Schouw, Marie Loh, Solomon K. Musani, Sobha Puppala, William R. Scott, Loic Yengo, Sian Tsung Tan, Herman A. Taylor, Farook Thameem, Gregory Wilson, Tien Yin Wong, Pal Rasmus Njolstad, Jonathan C. Levy, Massimo Mangino, Lori L. Bonnycastle, Thomas Schwarzmayr, Joao Fadista, Gabriela L. Surdulescu, Christian Herder, Christopher J. Groves, Thomas Wieland, Jette Bork-Jensen, Ivan Brandslund, Cramer Christensen, Heikki A. Koistinen, Alex S.F. Doney, Leena Kinnunen, Tonu Esko, Andrew J. Farmer, Liisa Hakaste, Dylan Hodgkiss, Jasmina Kravic, Valeriya Lyssenko, Mette Hollensted, Marit E. Jorgensen, Torben Jorgensen, Claes Ladenvall, Johanne Marie Justesen, Annemari Käräjämäki, Jennifer Kriebel, Wolfgang Rathmann, Lars Lannfelt, Torsten Lauritzen, Narisu Narisu, Allan Linneberg, Olle Melander, Lili Milani, Matt Neville, Marju Orho-Melander, Lu Qi, Qibin Qi, Michael Roden, Olov Rolandsson, Amy Swift, Anders H. Rosengren, Kathleen Stirrups, Andrew R. Wood, Evelin Mihailov, Christine Blancher, Mauricio O. Carneiro, Jared Maguire, Ryan Poplin, Khalid Shakir, Timothy Fennell, Mark DePristo, Martin Hrabé De Angelis, Panos Deloukas, Anette P. Gjesing, Goo Jun, Peter Nilsson, Jacquelyn Murphy, Robert Onofrio, Barbara Thorand, Torben Hansen, Christa Meisinger, Frank B. Hu, Bo Isomaa, Fredrik Karpe, Liming Liang, Annette Peters, Cornelia Huth, Stephen P. O'Rahilly, Colin N.A. Palmer, Oluf Pedersen, Rainer Rauramaa, Jaakko Tuomilehto, Veikko Salomaa, Richard M. Watanabe, Ann Christine Syvänen, Richard N. Bergman, Dwaipayan Bharadwaj, Erwin P. Bottinger, Yoon Shin Cho, Giriraj R. Chandak, Juliana C.N. Chan, Kee Seng Chia, Mark J. Daly, Shah B. Ebrahim, Claudia Langenberg, Paul Elliott, Kathleen A. Jablonski, Donna M. Lehman, Weiping Jia, Ronald C.W. Ma, Toni I. Pollin, Manjinder Sandhu, Nikhil Tandon, Philippe Froguel, Ines Barroso, Yik Ying Teo, Eleftheria Zeggini, Ruth J.F. Loos, Kerrin S. Small, Janina S. Ried, Ralph A. DeFronzo, Harald Grallert, Benjamin Glaser, Andres Metspalu, Nicholas J. Wareham, Mark Walker, Eric Banks, Christian Gieger, Erik Ingelsson, Hae Kyung Im, Thomas Illig, Paul W. Franks, Gemma Buck, Joseph Trakalo, David Buck, Inga Prokopenko, Reedik Mägi, Lars Lind, Yossi Farjoun, Katharine R. Owen, Anna L. Gloyn, Konstantin Strauch, Tiinamaija Tuomi, Jaspal Singh Kooner, Jong Young Lee, Taesung Park, Peter Donnelly, Andrew D. Morris, Andrew T. Hattersley, Donald W. Bowden, Francis S. Collins, Gil Atzmon, John C. Chambers, Timothy D. Spector, Markku Laakso, Tim M. Strom, Graeme I. Bell, John Blangero, Ravindranath Duggirala, E. Shyong Tai, Gilean McVean, Craig L. Hanis, James G. Wilson, Mark Seielstad, Timothy M. Frayling, James B. Meigs, Nancy J. Cox, Rob Sladek, Eric S. Lander, Stacey Gabriel, Noël P. Burtt, Karen L. Mohlke, Thomas Meitinger, Leif Groop, Goncalo Abecasis, Jose C. Florez, Laura J. Scott, Andrew P. Morris, Hyun Min Kang, Michael Boehnke, David Altshuler, Mark I. McCarthy

Research output: Contribution to journalArticlepeer-review

503 Scopus citations

Abstract

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

Original languageEnglish
Pages (from-to)41-47
Number of pages7
JournalNature
Volume536
Issue number7614
DOIs
StatePublished - Jul 11 2016

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