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

Citations Over Time

Abstract

Genetic association studies have identified 210 risk loci for inflammatory bowel disease 1–7 , which have revealed fundamental aspects of the molecular biology of the disease, including the roles of autophagy and Th17 cell signaling and development. 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 26 new genome-wide significant loci, three of which contain integrin genes that encode molecules in pathways identified as important therapeutic targets in inflammatory bowel disease. The associated variants are also correlated with expression changes in response to immune stimulus at two of these genes ( ITGA4, ITGB8 ) and at two previously implicated integrin loci ( ITGAL, ICAM1 ). In all four cases, the stimulus-dependent expression increasing allele also increases disease risk. We applied summary statistic fine-mapping and identified likely causal missense variants in the primary immune deficiency gene PLCG2 and the negative regulator of inflammation, SLAMF8 . Our results demonstrate that new common variant associations continue to identify genes and pathways of relevance to therapeutic target identification and prioritization.

Related Papers

• → Gene and pathway-based second-wave analysis of genome-wide association studies(2009)240 cited
• → The combination of a genome-wide association study of lymphocyte count and analysis of gene expression data reveals novel asthma candidate genes(2012)52 cited
• → Genome-wide association studies in aging-related processes such as diabetes mellitus, atherosclerosis and cancer(2007)43 cited
• → A genome-wide association study links small-vessel ischemic stroke to autophagy(2017)19 cited
• → GWAS summary-based pathway analysis correcting for the genetic confounding impact of environmental exposures(2017)4 cited