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

L Jostins, S Ripke, R Weersma, R Duerr, D McGovern, K Hui, James Lee, Phillip Schumm, Y Sharma, C Anderson, J Essers, M Mitrovic, K Ning, I Cleynen, E Theatre, S Spain, S Raychaudhuri, P Goyette, Z Wei, C AbrahamJ Achkar, T Ahmad, L Amininejad, A Ananthakrishnan, V Andersen, J Andrews, L Baidoo, T Balschun, Peter Bampton, A Bitton, G Boucher, S Brand, C Buning, A Cohain, S Chichon, M D'Amato, D De Jong, K Devaney, M Dubinsky, Cathryn Edwards, D Ellinghaus, Lynette Ferguson, D Franchimont, K Fransen, Richard Gearry, M Georges, C Gieger, J Glas, Talin Haritunians, Ailsa Hart, C Hawkey, M Hedl, X Hu, T Karlsen, L Kupcinskas, S Kugathasan, A Latiano, D Laukens, Ian Lawrance, C Lees, E Louis, G Mahy, J Mansfield, A Morgan, C Mowat, William Newman, O Palmieri, C Ponsioen, U Potocnik, N Prescott, M Regueiro, Jerome Rotter, R Russell, J Sanderson, M Sans, J Satsangi, S Schreiber, L Simms, J Sventoraityte, S Targen, Kent Taylor, M tremelling, H Verspaget, M De Vos, C Wijmenga, D Wilson, J Winkelmann, R Xavier, S Zeissig, B Zhang, C Zhang, H Zhao, M Silverberg, A Annese, H Hakonarson, S Brant, Graham Radford-Smith, CG Mathew, J Rioux, E Schadt, M Daly, A Franke, M Parkes, S Vermeire, J Barrett, J Cho

    Research output: Contribution to journalArticlepeer-review

    2712 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)119-124
    Number of pages6
    JournalNature
    Volume491
    Issue number7422
    DOIs
    Publication statusPublished - 1 Nov 2012

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