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

Australia and New Zealand IBDGC, Belgium Genetic Consortium, Initiative on Crohn and Colitis, NIDDK IBDGC, United Kingdom IBDGC, Wellcome Trust Case Control Consortium, The International IBD Genetics Consortium (IIBDGC), for The International IBD Genetics Consortium (IIBDGC)

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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 (US)
Pages (from-to)119-124
Number of pages6
JournalNature
Volume491
Issue number7422
DOIs
StatePublished - Nov 1 2012
Externally publishedYes

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ASJC Scopus subject areas

  • General

Cite this

Australia and New Zealand IBDGC, Belgium Genetic Consortium, Initiative on Crohn and Colitis, NIDDK IBDGC, United Kingdom IBDGC, Wellcome Trust Case Control Consortium, The International IBD Genetics Consortium (IIBDGC), & for The International IBD Genetics Consortium (IIBDGC) (2012). Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature, 491(7422), 119-124. https://doi.org/10.1038/nature11582