title: The genetic background of inflammatory bowel disease: from correlation to causality.
abstract: Recent studies have greatly improved our insight into the genetic background of inflammatory bowel disease (IBD). New high-throughput technologies and large-scale international collaborations have contributed to the identification of 200 independent genetic risk loci for IBD. However, in most of these loci, it is unclear which gene conveys the risk for IBD. More importantly, it is unclear which variant within or near the gene is causal to the disease. Using targeted GWAS, imputation, resequencing of risk loci, and in silico fine-mapping of densely typed loci, several causal variants have been identified in IBD risk genes, and various pathological pathways have been uncovered. Current research in the field of IBD focuses on the effect of these causal variants on gene expression and protein function. However, more elements than only the genome must be taken into account to disentangle the multifactorial pathology of IBD. The genetic risk loci identified to date only explain a small part of genetic variance in disease risk. Currently, large multi-omics studies are incorporating factors ranging from the gut microbiome to the environment. In this review, we present the progress that has been made in IBD genetic research and stress the importance of studying causality to increase our understanding of the pathogenesis of IBD. We highlight important causal genetic variants in the candidate genes NOD2, ATG16L1, IRGM, IL23R, CARD9, RNF186, and PRDM1. We describe their downstream effects on protein function and their direct effects on the gut immune system. Furthermore, we discuss the future role of genetics in unravelling disease mechanisms in IBD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors: Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors: Werna Tc
authors: WT
authors: Uniken Venema
authors: Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors: Michiel D
authors: http://orcid.org/0000-0001-9285-9573
authors: MD
authors: Voskuil
authors: Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors: Gerard
authors: G
authors: Dijkstra
authors: Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors: Rinse K
authors: RK
authors: Weersma
authors: Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.|Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors: Eleonora Am
authors: EA
authors: Festen
mesh_terms: D000818:Animals; D003424:Crohn Disease / Q000235:genetics*; D000068617:Genetic Background; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*
keywords: Crohn's disease; causal variants; causality; environmental factors; genetics; inflammatory bowel disease; microbiome; pathways; ulcerative colitis