Journal Article

Genetic effects on the commensal microbiota in inflammatory bowel disease patients

Beaugerie, Laurent, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI) ; Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Imhann, Floris, Seksik, Philippe, Aschard, Hugues, University of Groningen [Groningen], Laville, Vincent, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS) ; Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Zaitlen, Noah, Xavier, Ramnik, Centre de Recherche Saint-Antoine (CRSA) ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Harvard T.H. Chan School of Public Health, Weersma, Rinse, Harvard Medical School [Boston] (HMS), University of Minnesota [Twin Cities] (UMN) ; University of Minnesota System (UMN), University of California (UC), Silverberg, Mark, Knights, Dan, The Wharton School ; University of Penn

2019

Overview

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.

• Publisher: Public Library of Science,CCSD,Public Library of Science (PLoS)
• Subject: Adult / Alleles / Applications / Bacteria / Bacterial genetics / Bioinformatics / Biology and Life Sciences / CARD Signaling Adaptor Proteins / CARD Signaling Adaptor Proteins - genetics / Clostridiales / Clostridiales - genetics / Clostridiales - isolation & purification / Clostridiales - pathogenicity / Computer Science / Disease susceptibility / Epidemiology / Etiology / Etiology (Medicine) / Faecalibacterium prausnitzii / Faecalibacterium prausnitzii - genetics / Faecalibacterium prausnitzii - isolation & purification / Faecalibacterium prausnitzii - pathogenicity / Female / Fitness / Gastroenterology / Gastrointestinal diseases / Gastrointestinal Microbiome / Gastrointestinal Microbiome - genetics / Gene expression / Genes / Genetic aspects / Genetic Association Studies / Genetic diversity / Genetic Predisposition to Disease / Genetic research / Genetic Variation / Genetics / Genome-wide association studies / Genomes / Genomics / Health care / Hepatology / Hospitals / Host Microbial Interactions / Host Microbial Interactions - genetics / Human genetics / Humans / Inflammatory bowel disease / Inflammatory Bowel Diseases / Inflammatory Bowel Diseases - etiology / Inflammatory Bowel Diseases - genetics / Inflammatory Bowel Diseases - microbiology / Intestinal microflora / Intestine / Life Sciences / Male / Mediation / Medical schools / Medicine and Health Sciences / Methodology / Microbiomes / Microbiota / Microbiota (Symbiotic organisms) / Middle Aged / Models, Genetic / NOD2 protein / Nod2 Signaling Adaptor Protein / Nod2 Signaling Adaptor Protein - genetics / Pathogenesis / Physiological aspects / Polymorphism, Single Nucleotide / Reproductive fitness / Santé publique et épidémiologie / Sensitivity analysis / Social Sciences / Statistics / Studies