TY - JOUR T1 - Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease JF - bioRxiv DO - 10.1101/058255 SP - 058255 AU - Katrina M. de Lange AU - Loukas Moutsianas AU - James C. Lee AU - Christopher A. Lamb AU - Yang Luo AU - Nicholas A. Kennedy AU - Luke Jostins AU - Daniel L. Rice AU - Javier Gutierrez-Achury AU - Sun-Gou Ji AU - Graham Heap AU - Elaine R. Nimmo AU - Cathryn Edwards AU - Paul Henderson AU - Craig Mowat AU - Jeremy Sanderson AU - Jack Satsangi AU - Alison Simmons AU - David C. Wilson AU - Mark Tremelling AU - Ailsa Hart AU - Christopher G. Mathew AU - William G. Newman AU - Miles Parkes AU - Charlie W. Lees AU - Holm Uhlig AU - Chris Hawkey AU - Natalie J. Prescott AU - Tariq Ahmad AU - John C. Mansfield AU - Carl A. Anderson AU - Jeffrey C. Barrett Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/06/10/058255.abstract N2 - Genetic association studies have identified 210 risk loci for inflammatory bowel disease1–7, 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. ER -