Abstract
Several bacteria in the gut microbiota have been shown to be associated with inflammatory bowel disease (IBD), and dozens of IBD genetic variants have been identified in genome-wide association studies. However, the role of the microbiota in the etiology of IBD in terms of host genetic susceptibility remains unclear. Here, we studied the association between four major genetic variants associated with an increased risk of IBD and bacterial taxa in up to 633 IBD cases. We performed systematic screening for associations, identifying and replicating associations between NOD2 variants and two taxa: the Roseburia genus and the Faecalibacterium prausnitzii species. By exploring the overall association patterns between genes and bacteria, we found that IBD risk alleles were significantly enriched for associations concordant with bacteria-IBD associations. To understand the significance of this pattern in terms of the study design and known effects from the literature, we used counterfactual principles to assess the fitness of a few parsimonious gene-bacteria-IBD causal models. Our analyses showed evidence that the disease risk of these genetic variants were likely to be partially mediated by the microbiome. We confirmed these results in extensive simulation studies and sensitivity analyses using the association between NOD2 and F. prausnitzii as a case study.
Highlights
Most genetic analyses and twin studies published to date support a genetic component of inflammatory bowel disease (IBD) phenotypes [1]
These analyses confirmed the robustness of the identified associations and highlighted microbiota mediation as a potential mechanism underlying the association between IBD and those genetic variants while ruling out reverse causation and arguing against a bacteriaIBD association resulting from a shared genetic effect
Genome-wide association studies (GWASs) have identified more than 200 loci associated with IBD, most of which are shared between ulcerative colitis (UC) and Crohn’s disease (CD) [3,4,5]
Summary
Most genetic analyses and twin studies published to date support a genetic component of inflammatory bowel disease (IBD) phenotypes [1]. Genome-wide association studies (GWASs) have identified more than 200 loci associated with IBD, most of which are shared between UC and CD [3,4,5]. Identification of these loci has enhanced our understanding of the pathogenesis of IBD, provided perspective on key pathways, and highlighted an essential role for host defense against infection. Recent work noted a potential role of the intestinal microbiota in initiating, maintaining, and determining IBD-related phenotypes [6,7,8]. Generally the commensal microbiota is accepted to induce inappropriate activation of intestinal mucosal immunity, the precise role of the microbiota in the etiology of IBD in terms of host genetic susceptibility remains unclear
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