Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

Authors:
Luke Jostins, Stephan Ripke, Rinse K Weersma, Richard H Duerr, Dermot P McGovern, Ken Y Hui, James C Lee, L Philip Schumm, Yashoda Sharma, Carl A Anderson, Jonah Essers, Mitja Mitrovic, Kaida Ning, Isabelle Cleynen, Emilie Theatre, Sarah L Spain, Soumya Raychaudhuri, Philippe Goyette, Zhi Wei, Clara Abraham, Jean-Paul Achkar, Tariq Ahmad, Leila Amininejad, Ashwin N Ananthakrishnan, Vibeke Andersen, Jane M Andrews, Leonard Baidoo, Tobias Balschun, Peter A Bampton, Alain Bitton, Gabrielle Boucher, Stephan Brand, Carsten Büning, Ariella Cohain, Sven Cichon, Mauro D'Amato, Dirk De Jong, Kathy L Devaney, Marla Dubinsky, Cathryn Edwards, David Ellinghaus, Lynnette R Ferguson, Denis Franchimont, Karin Fransen, Richard Gearry, Michel Georges, Christian Gieger, Jürgen Glas, Talin Haritunians, Ailsa Hart, Chris Hawkey, Matija Hedl, Xinli Hu, Tom H Karlsen, Limas Kupcinskas, Subra Kugathasan, Anna Latiano, Debby Laukens, Ian C Lawrance, Charlie W Lees, Edouard Louis, Gillian Mahy, John Mansfield, Angharad R Morgan, Craig Mowat, William Newman, Orazio Palmieri, Cyriel Y Ponsioen, Uros Potocnik, Natalie J Prescott, Miguel Regueiro, Jerome I Rotter, Richard K Russell, Jeremy D Sanderson, Miquel Sans, Jack Satsangi, Stefan Schreiber, Lisa A Simms, Jurgita Sventoraityte, Stephan R Targan, Kent D Taylor, Mark Tremelling, Hein W Verspaget, Martine De Vos, Cisca Wijmenga, David C Wilson, Juliane Winkelmann, Ramnik J Xavier, Sebastian Zeissig, Bin Zhang, Clarence K Zhang, Hongyu Zhao, - -, Mark S Silverberg, Vito Annese, Hakon Hakonarson, Steven R Brant, Graham Radford-Smith, Christopher G Mathew, John D Rioux, Eric E Schadt, Mark J Daly, Andre Franke, Miles Parkes, Severine Vermeire, Jeffrey C Barrett, Judy H Cho
Year of publication:
2012
Volume:
491
Issue:
7422
Issn:
0028-0836
Journal title abbreviated:
NATURE
Journal title long:
Nature : a weekly illustrated journal of science
Impact factor:
41.577
Abstract:
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. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. 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.