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

• Type of Material: Article
• Authors: Luke Jostins, Wellcome Trust Sanger Institute; Stephan Ripke, Harvard University; Rinse K Weersma, University of Groningen; Richard H Duerr, University of Pittsburgh; Dermot P McGovern, Cedars-Sinai F. Widjaja Inflammatory Bowel and Immunobiology Research Institute; Ken Y Hui, Yale University; James C Lee, University of Cambridge; L Philip Schumm, University of Chicago; Yashoda Sharma, Yale University; Carl A Anderson, Wellcome Trust Sanger Institute; Jonah Essers, Harvard University; Mitja Mitrovic, University of Groningen; Kaida Ning, Yale University; Isabelle Cleynen, Katholieke University Leuven; Emilie Theatre, University of Liege; Sarah L Spain, Kings College; Soumya Raychaudhuri, Brigham & Women's Hospital; Philippe Goyette, University of Montreal; Zhi Wei, New Jersey Institute of Technology; Clara Abraham, Yale University; Subramaniam Kugathasan, Emory University
• Language: English
• Date: 2012-11-01
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Macmillan Publishers Limited. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/nature11582
• Title of Journal or Parent Work: Nature
• ISSN: 0028-0836
• Volume: 491
• Issue: 7422
• Start Page: 119
• End Page: 124
• Grant/Funding Information: Complete funding list available in full text.
• Keywords: Science & Technology; METAANALYSIS; RISK LOCI; MUTATIONS; SUSCEPTIBILITY; HYPER-IGE SYNDROME; Multidisciplinary Sciences; Science & Technology - Other Topics; EXPRESSION; TUBERCULOSIS; NETWORK; NUMBER
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics

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.