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, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been 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 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.

Figure 1. Likely causal missense variants.

For A) SLAMF8 and B) PLCG2, local association results are plotted with point size corresponding to LD to our lead variant and color to fine-mapping probability (purple > 50%, intermediate blue 10-50%, navy blue <10%). Gene body diagrams and protein domain annotations are taken from ENSEMBL, and partial predicted crystal structures for both proteins are obtained from the SWISS-MODEL repository.

Figure 2. Co-localization of disease association and stimulus response eQTLs in monocytes.

The local pattern of disease association (IBD: (A) ITGA4, (B) ITGB8, (C) ICAM1; (D) UC: ITGAL) in grey, and the association of that variant with response to LPS (lipopolysaccharide) stimulation in red. Evidence of co-localization (probability > 70%) is observed for all for signals.

Figure 3. IBD-associated loci containing genes in immune pathways related to classes of approved therapeutics.

All IBD loci are divided into the studies where they were first identified. Loci that contain a gene in one of four signalling pathways related to targets of three classes of approved IBD therapeutics (Online Methods) are highlighted, with those where the pathway gene has been confidently identified as the causal IBD gene labelled. Despite the general pattern that effect size decreases from left to right, therapeutically relevant associations continue to be found.