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

Document Type

Article

Publication Date

11-1-2012

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. © 2012 Macmillan Publishers Limited. All rights reserved.

Identifier

84868336049 (Scopus)

Publication Title

Nature

External Full Text Location

https://doi.org/10.1038/nature11582

e-ISSN

14764687

ISSN

00280836

PubMed ID

23128233

First Page

119

Last Page

124

Issue

7422

Volume

491

Grant

068545

Fund Ref

Wellcome Trust

This document is currently not available here.

Share

COinS