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

摘要

Crohn’s disease (CD) and ulcerative colitis (UC), 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 (GWAS) and subsequent meta-analyses of CD and UC^, as separate phenotypes implicated previously unsuspected mechanisms, such as autophagy, in pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand knowledge of relevant pathways by undertaking a meta-analysis of CD and UC genome-wide association scans, with validation of significant findings in 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 and balancing 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 striking 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.