title: Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7.
abstract: To further resolve the genetic architecture of the inflammatory bowel diseases ulcerative colitis and Crohn's disease, we sequenced the whole genomes of 4,280 patients at low coverage and compared them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing genome-wide association study cohorts and tested for association at ∼12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles the risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn's disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve understanding of the biology of complex diseases.
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: 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 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: Loukas
authors.initials: L
authors.lastname: Moutsianas
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Joshua
authors.initials: J
authors.lastname: Randall
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: 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.
authors.forename: Shane
authors.initials: S
authors.lastname: McCarthy
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: Department of Gastroenterology, Torbay Hospital, Torbay, Devon, UK.
authors.forename: Cathryn
authors.initials: C
authors.lastname: Edwards
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Eva Goncalves
authors.initials: EG
authors.lastname: Serra
authors.affiliation: Department of Medicine, St Mark's Hospital, Harrow, Middlesex, UK.
authors.forename: Ailsa
authors.initials: A
authors.lastname: Hart
authors.affiliation: Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Hawkey
authors.affiliation: Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Mansfield
authors.affiliation: Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Mowat
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: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: Nichols
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Pollard
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: Gastroenterology & General Medicine, Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Tremelling
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: 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: Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: James C
authors.initials: JC
authors.lastname: Lee
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: Gastrointestinal Unit, Wester General Hospital University of Edinburgh, Edinburgh, UK.
authors.forename: Charlie W
authors.initials: CW
authors.lastname: Lees
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: Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Miles
authors.initials: M
authors.lastname: Parkes
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Anderson
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D000262:Adenylyl Cyclases; C473265:adenylyl cyclase 7