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

Abstract

A meta-analysis of previous genome-wide association studies of Crohn’s disease and ulcerative colitis, the two most common forms of inflammatory bowel disease, with a combined total of more than 75,000 cases and controls, finds that most loci contribute to both phenotypes and other immune-mediated disorders. Genetic studies have implicated unsuspected mechanisms in the pathogenesis of Crohn's disease and ulcerative colitis, two of the most common forms of inflammatory bowel disease. This paper presents a meta-analysis of published genome-wide association studies, together with validation in more than 75,000 cases and controls. In addition to several new associations, the authors find that most loci contribute to both phenotypes, but also to other immune-mediated disorders. The data reveal an overlap between susceptibility loci for inflammatory bowel disease and mycobacterial infection, and between the pathways that govern host responses to mycobacteria and those predisposing to inflammatory bowel disease. 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 populations1. Genome-wide association studies and subsequent meta-analyses of these two diseases2,3 as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy4, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases5. 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.