title: 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.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: de Lange
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Loukas
authors.initials: L
authors.lastname: Moutsianas
authors.affiliation: Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: James C
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lamb
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.|Division of Genetics and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Precision Medicine Exeter, University of Exeter, Exeter, UK.|IBD Pharmacogenetics, Royal Devon and Exeter Foundation Trust, Exeter, UK.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Kennedy
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK.|Christ Church, University of Oxford, St Aldates, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Jostins
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Rice
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Javier
authors.initials: J
authors.lastname: Gutierrez-Achury
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Sun-Gou
authors.initials: SG
authors.lastname: Ji
authors.affiliation: Precision Medicine Exeter, University of Exeter, Exeter, UK.|IBD Pharmacogenetics, Royal Devon and Exeter Foundation Trust, Exeter, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Heap
authors.affiliation: Gastrointestinal Unit, Wester General Hospital University of Edinburgh, Edinburgh, UK.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Nimmo
authors.affiliation: Department of Gastroenterology, Torbay Hospital, Torbay, Devon, UK.
authors.forename: Cathryn
authors.initials: C
authors.lastname: Edwards
authors.affiliation: Department of Child Life and Health, University of Edinburgh, Edinburgh, UK.|Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children,Edinburgh, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Henderson
authors.affiliation: Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Mowat
authors.affiliation: Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, Department of Gastroenterology, London, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sanderson
authors.affiliation: Gastrointestinal Unit, Wester General Hospital University of Edinburgh, Edinburgh, UK.
authors.forename: Jack
authors.initials: J
authors.lastname: Satsangi
authors.affiliation: Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.|Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Simmons
authors.affiliation: Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK.|Child Life and Health, University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wilson
authors.affiliation: Gastroenterology & General Medicine, Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Tremelling
authors.affiliation: Department of Medicine, St Mark's Hospital, Harrow, Middlesex, UK.
authors.forename: Ailsa
authors.initials: A
authors.lastname: Hart
authors.affiliation: Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, UK.|Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of Witwatersrand, South Africa.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
authors.affiliation: Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK.|The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Miles
authors.initials: M
authors.lastname: Parkes
authors.affiliation: Gastrointestinal Unit, Wester General Hospital University of Edinburgh, Edinburgh, UK.
authors.forename: Charlie W
authors.initials: CW
authors.lastname: Lees
authors.affiliation: Translational Gastroenterology Unit and the Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
authors.forename: Holm
authors.initials: H
authors.lastname: Uhlig
authors.affiliation: Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Hawkey
authors.affiliation: Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, UK.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Prescott
authors.affiliation: Precision Medicine Exeter, University of Exeter, Exeter, UK.|IBD Pharmacogenetics, Royal Devon and Exeter Foundation Trust, Exeter, UK.
authors.forename: Tariq
authors.initials: T
authors.lastname: Ahmad
authors.affiliation: Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Mansfield
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Anderson
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Barrett
mesh_terms: D000483:Alleles; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D007249:Inflammation / Q000235:genetics; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D016023:Integrins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics
chemical_list: D016023:Integrins