From GWAS to systematic host-microbiome association studies in complex immune-mediated diseases – Biologisk Institut - Københavns Universitet

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From GWAS to systematic host-microbiome association studies in complex immune-mediated diseases

Speaker: Professor Andre Franke, Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel

Host: Professor Karsten Kristiansen, Cell Biology and Physiology, BIO-UCPH

Abstract
Genome-wide association (GWAS) have significantly contributed to our understanding of the etiology of chronic and complex immune-mediated diseases (CID). Inflammatory bowel diseases (IBD) with its main sub phenotypes Crohn’s disease and ulcerative colitis, are prototypic CIDs that affect about 2-3 persons out of a 1000 in Western countries. IBD shares part of its genetic and immunological background with diseases like psoriasis, ankylosing spondylitis, and primary sclerosis cholangitis). To this end, over 250 genetic susceptibility loci were identified in the past 10 years through GWAS and candidate-gene association studies. Complex immunogenetics efforts are currently being undertaken to solve CID. Still, the exact cause of most CID has not been identified and components of the gut microbiome are also likely disease-causing environmental factors for CID. In particular the complex interplay between our own immune system and the microbiome needs to be investigated in detail as both a dysbiosised microbiome as well as an inappropriate immune response contribute to CID.

Here, I will present our ongoing efforts in host-microbiome association analyses and allude to the methodological challenges of these kind of analyses. Previously, we performed a genome-wide association study (GWAS) of the gut microbiota using two cohorts from northern Germany totaling 1,812 individuals. Comprehensively controlling for diet and non-genetic parameters, we identified genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci, including the VDR gene (encoding vitamin D receptor). We observed significant shifts in the microbiota of Vdr-/- mice relative to control mice and correlations between the microbiota and serum measurements of selected bile and fatty acids in humans, including known ligands and downstream metabolites of VDR. Genome-wide significant (P < 5 × 10E-8) associations at multiple additional loci identify other important points of host-microbe intersection, notably several disease susceptibility genes and sterol metabolism pathway components. Non-genetic and genetic factors each account for approximately 10% of the variation in gut microbiota in this study, whereby individual effects were relatively small.