Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
Jostins, Luke 1,81; Ripke, Stephan 2,3,81; Weersma, Rinse K. 4; Duerr, Richard H. 5,6; McGovern, Dermot P. 7,8; Hui, Ken Y. 9; Lee, James C. 10; Philip Schumm, L. 11; Sharma, Yashoda 12; Anderson, Carl A. 1; Essers, Jonah 13; Mitrovic, Mitja 14,15; Ning, Kaida 12; Cleynen, Isabelle 16; Theatre, Emilie 17,18; Spain, Sarah L. 19; Raychaudhuri, Soumya 20,21,22; Goyette, Philippe 23; Wei, Zhi 24; Abraham, Clara 12; Achkar, Jean-Paul 25,26; Ahmad, Tariq 27; Amininejad, Leila 28; Ananthakrishnan, Ashwin N. 29; Andersen, Vibeke 30; Andrews, Jane M. 31; Baidoo, Leonard 5; Balschun, Tobias 32; Bampton, Peter A. 33; Bitton, Alain 34; Boucher, Gabrielle 23; Brand, Stephan 35; Buning, Carsten 36; Cohain, Ariella 37; Cichon, Sven 38; D'Amato, Mauro 39; De Jong, Dirk 4; Devaney, Kathy L. 29; Dubinsky, Marla 40; Edwards, Cathryn 41; Ellinghaus, David 32; Ferguson, Lynnette R. 42; Franchimont, Denis 28; Fransen, Karin 5,43; Gearry, Richard 44,45; Georges, Michel 17; Gieger, Christian 46; Glas, Jurgen 34; Haritunians, Talin 8; Hart, Ailsa 47; Hawkey, Chris 48; Hedl, Matija 12; Hu, Xinli 20; Karlsen, Tom H. 49; Kupcinskas, Limas 50; Kugathasan, Subra 51; Latiano, Anna 52; Laukens, Debby 53; Lawrance, Ian C. 54; Lees, Charlie W. 55; Louis, Edouard 18; Mahy, Gillian 56; Mansfield, John 57; Morgan, Angharad R. 42; Mowat, Craig 58; Newman, William 59; Palmieri, Orazio 52; Ponsioen, Cyriel Y. 60; Potocnik, Uros 14,61; Prescott, Natalie J. 19; Regueiro, Miguel 5; Rotter, Jerome I. 8; Russell, Richard K. 62; Sanderson, Jeremy D. 63; Sans, Miquel 64,65; Satsangi, Jack 55; Schreiber, Stefan 32,66; Simms, Lisa A. 67; Sventoraityte, Jurgita 50; Targan, Stephan R. 7; Taylor, Kent D. 7,8; Tremelling, Mark 68; Verspaget, Hein W. 69; De Vos, Martine 53; Wijmenga, Cisca 43; Wilson, David C. 62,70; Winkelmann, Juliane 71; Xavier, Ramnik J. 29,72; Zeissig, Sebastian 66; Zhang, Bin 37; Zhang, Clarence K. 73; Zhao, Hongyu 73; The International IBD Genetics Consortium (IIBDGC) 82; Silverberg, Mark S. 74; Annese, Vito 52,75; Hakonarson, Hakon 76,77; Brant, Steven R. 78; Radford-Smith, Graham 67,79; Mathew, Christopher G. 19; Rioux, John D. 23; Schadt, Eric E. 37; Daly, Mark J. 2,3; Franke, Andre 32; Parkes, Miles 10; Vermeire, Severine 16,80; Barrett, Jeffrey C. 1,81; Cho, Judy H 9,12,81,*
[Letter]
Nature.
491(7422):119-124, November 1, 2012.
(Format: HTML, PDF)
: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations 1. Genome-wide association studies and subsequent meta-analyses of these two diseases 2,3 as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy 4, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases 5. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
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