Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Abstract

Genetic association studies have identified 215 risk loci for inflammatory bowel disease 1-8, which have revealed fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals, and meta-analyzed with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new loci, three of which contain integrin genes that encode proteins in pathways identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4, ITGB8) and at previously implicated loci (ITGAL, ICAM1). In all four cases, the expression increasing allele also increases disease risk. We also identified likely causal missense variants in the primary immune deficiency gene PLCG2 and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new common variant associations continue to identify genes relevant to therapeutic target identification and prioritization. Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsInflammatory bowel disease (IBD) is a chronic, debilitating, disorder of the gastrointestinal tract that includes two common disease subtypes, Crohn's disease and ulcerative colitis. Disease pathogenesis is poorly understood but is likely driven by a dysregulated immune response to unknown environmental triggers in genetically susceptible individuals. Treatment regimes often use potent immunomodulators to achieve and maintain remission of symptoms. However, patients commonly experience side effects, lose response to treatment, or develop complications of IBD, with many ultimately requiring major abdominal surgery. Previous genome-wide association studies (GWAS) and targeted follow-up using the Immunochip have been very successful at identifying genetic risk loci for IBD, but increased biological understanding has not yet had a significant impact on therapy for these disorders.In order to further expand our understanding of the biology of these disorders we carried out a GWAS of 12,160 IBD cases and 13,145 population controls of European ancestry that had not been included in any genome-wide meta-analysis of IBD to date (Supplementary Table 1, Online Methods). We imputed genotypes using a reference panel comprising whole genome sequences from 4,686 IBD cases9 and 6,285 publically available population controls10,11. Following quality control (Online Methods) we tested 9.7 million sites for association. At the 232 IBD associated SNPs in the latest meta-analysis by the International IBD Genetics Consortium1, 228 had effects in the same direction in our data, 188 showed at least nominal evidence of replication (P<0.05) and none showed significant evidence of heterogeneity of effect by Cochrane's Q test. Among these replicated loci was a genomewide significant association on chromosome 10q25 that was only previously significantly associated with Crohn's disease in individuals of East Asian a...

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Making sense of the cause of Crohn’s – a new look at an old disease

“…Four SNPs had an OR exceeding 1.5 of which three were within NOD2 and the fourth was in IL23R . The mean difference in allele frequency between cases and controls was only 0.02 275 .…”

Inflammatory Bowel Disease Susceptibility Gene C1ORF106 Regulates Intestinal Epithelial Permeability

“…1A). Fine mapping of the loci reveals multiple missense, intronic, and intergenic single-nucleotide polymorphisms (SNPs) linked to increased disease susceptibility within the C1ORF106 locus (6,(9)(10)(11)(12). C1ORF106 is highly expressed in epithelial-rich tissues in both human and mouse, particularly in the gastrointestinal tract, as well as in other tissues with key roles in barrier function, such as skin (Fig.…”