title: A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis.
abstract: Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Manuel A
authors: MA
authors: Rivas
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors: Daniel
authors: D
authors: Graham
authors: deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland.
authors: Patrick
authors: 0000-0001-7123-6123
authors: P
authors: Sulem
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors: Christine
authors: C
authors: Stevens
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors: A Nicole
authors: AN
authors: Desch
authors: Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T1C8.
authors: Philippe
authors: P
authors: Goyette
authors: deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland.
authors: Daniel
authors: 0000-0002-5222-9857
authors: D
authors: Gudbjartsson
authors: deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland.|Department of Immunology, Landspitali, the National University Hospital of Iceland, 101 Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
authors: Ingileif
authors: I
authors: Jonsdottir
authors: deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
authors: Unnur
authors: U
authors: Thorsteinsdottir
authors: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany.
authors: Frauke
authors: F
authors: Degenhardt
authors: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany.
authors: Sören
authors: S
authors: Mucha
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Mitja I
authors: MI
authors: Kurki
authors: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.|Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA.
authors: Dalin
authors: D
authors: Li
authors: Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Stockholm, Sweden.|BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, 48903 Bilbao, Spain.
authors: Mauro
authors: M
authors: D'Amato
authors: Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, 71013 San Giovanni Rotondo, Italy.|Strutture Organizzative Dipartimentali (SOD) Gastroenterologia 2, Azienda Ospedaliero Universitaria (AOU) Careggi, 50134 Florence, Italy.
authors: Vito
authors: V
authors: Annese
authors: Department of Clinical and Experimental Medicine, Translational Research in GastroIntestinal Disorders (TARGID), Katholieke Universiteit (KU) Leuven, Leuven 3000, Belgium.|Division of Gastroenterology, University Hospital Gasthuisberg, BE-3000 Leuven, Belgium.
authors: Severine
authors: S
authors: Vermeire
authors: Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.
authors: Rinse K
authors: RK
authors: Weersma
authors: Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE 701 82 Örebro, Sweden.
authors: Jonas
authors: J
authors: Halfvarson
authors: Department of Medicine, University of Helsinki, 00100 Helsinki, Finland.|Helsinki University Hospital, 00100 Helsinki, Finland.|Clinic of Gastroenterology, Helsinki University Hospital, 00100 Helsinki, Finland.
authors: Paulina
authors: P
authors: Paavola-Sakki
authors: Department of Medicine, University of Helsinki, 00100 Helsinki, Finland.|Helsinki University Hospital, 00100 Helsinki, Finland.|Research Programs Unit, Immunobiology, and Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland.
authors: Maarit
authors: M
authors: Lappalainen
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Monkol
authors: M
authors: Lek
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Beryl
authors: B
authors: Cummings
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Taru
authors: T
authors: Tukiainen
authors: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.|Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA.
authors: Talin
authors: T
authors: Haritunians
authors: Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland.
authors: Leena
authors: L
authors: Halme
authors: Research Programs Unit, Immunobiology, and Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland.|Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00100 Helsinki, Finland.
authors: Lotta L E
authors: LL
authors: Koskinen
authors: Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.|Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Ashwin N
authors: AN
authors: Ananthakrishnan
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors: Yang
authors: Y
authors: Luo
authors: IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
authors: Graham A
authors: 0000-0003-4131-6792
authors: GA
authors: Heap
authors: Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.
authors: Marijn C
authors: MC
authors: Visschedijk
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Daniel G
authors: DG
authors: MacArthur
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Benjamin M
authors: 0000-0003-1513-6077
authors: BM
authors: Neale
authors: Peninsula College of Medicine and Dentistry, Exeter PL6 8BU, UK.
authors: Tariq
authors: T
authors: Ahmad
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors: Carl A
authors: CA
authors: Anderson
authors: Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21205, USA.|Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, 21205, USA.
authors: Steven R
authors: SR
authors: Brant
authors: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.|Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA.
authors: Richard H
authors: 0000-0001-6586-3905
authors: RH
authors: Duerr
authors: Department of Medicine, Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
authors: Mark S
authors: MS
authors: Silverberg
authors: Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors: Judy H
authors: JH
authors: Cho
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.|Institute for Molecular Medicine Finland, University of Helsinki, 00100 Helsinki, Finland.|Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Boston, Massachusetts 02114, USA.
authors: Aarno
authors: A
authors: Palotie
authors: Research Programs Unit, Immunobiology, University of Helsinki, 00100 Helsinki, Finland.
authors: Päivi
authors: P
authors: Saavalainen
authors: Department of Medicine, University of Helsinki, 00100 Helsinki, Finland.|Helsinki University Hospital, 00100 Helsinki, Finland.
authors: Kimmo
authors: K
authors: Kontula
authors: Department of Medicine, University of Helsinki, 00100 Helsinki, Finland.|Helsinki University Hospital, 00100 Helsinki, Finland.|Clinic of Gastroenterology, Helsinki University Hospital, 00100 Helsinki, Finland.
authors: Martti
authors: M
authors: Färkkilä
authors: F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.|Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA.
authors: Dermot P B
authors: DP
authors: McGovern
authors: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany.
authors: Andre
authors: A
authors: Franke
authors: deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
authors: Kari
authors: K
authors: Stefansson
authors: Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T1C8.|Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada H3T 1J4.
authors: John D
authors: JD
authors: Rioux
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Ramnik J
authors: RJ
authors: Xavier
authors: Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors: Mark J
authors: 0000-0002-0949-8752
authors: MJ
authors: Daly
authors: IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
authors: J
authors: J
authors: Barrett
authors: IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
authors: K
authors: K
authors: de Lane
authors: Department of Gastroenterology, Torbay Hospital, Devon, UK.
authors: C
authors: C
authors: Edwards
authors: Department of Medicine, St. Mark's Hospital, Middlesex, UK.
authors: A
authors: A
authors: Hart
authors: Nottingham Digestive Disease Centre, Queens Medical Centre, Nottingham, UK.
authors: C
authors: C
authors: Hawkey
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK.|Christ Church, University of Oxford, Oxford, UK.
authors: L
authors: L
authors: Jostins
authors: Gastrointestinal Unit, Wester General Hospital, University of Edinburgh, Edinburgh, UK.
authors: N
authors: N
authors: Kennedy
authors: Newcastle University, Newcastle upon Tyne, UK.
authors: C
authors: C
authors: Lamb
authors: Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.
authors: J
authors: J
authors: Lee
authors: Gastrointestinal Unit, Wester General Hospital, University of Edinburgh, Edinburgh, UK.
authors: C
authors: C
authors: Lees
authors: Newcastle University, Newcastle upon Tyne, UK.
authors: J
authors: J
authors: Mansfield
authors: Department of Medical and Molecular Genetics, Guy's Hospital, London, UK.|Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.
authors: C
authors: C
authors: Mathew
authors: Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK.
authors: C
authors: C
authors: Mowatt
authors: Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK.|The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
authors: B
authors: B
authors: Newman
authors: Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
authors: E
authors: E
authors: Nimmo
authors: Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.
authors: M
authors: M
authors: Parkes
authors: IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
authors: M
authors: M
authors: Pollard
authors: Department of Medical and Molecular Genetics, Guy's Hospital, London, UK.|Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.
authors: N
authors: N
authors: Prescott
authors: IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
authors: J
authors: J
authors: Randall
authors: IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK.
authors: D
authors: D
authors: Rice
authors: Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
authors: J
authors: J
authors: Satsangi
authors: Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.|Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors: A
authors: A
authors: Simmons
authors: Gastroenterology &General Medicine, Norfolk and Norwich University Hospital, Norwich, UK.
authors: M
authors: M
authors: Tremelling
authors: Translational Gastroenterology Unit and the Department of Pediatrics, University of Oxford, Oxford, UK.
authors: H
authors: H
authors: Uhlig
authors: Pediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK.|Child Life and Health, University of Edinburgh, Edinburgh, UK.
authors: D
authors: D
authors: Wilson
authors: Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors: C
authors: C
authors: Abraham
authors: Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA.|Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors: J P
authors: JP
authors: Achkar
authors: Division of Gastroenterology, Royal Victoria Hospital, Montréal, Québec, Canada.
authors: A
authors: A
authors: Bitton
authors: Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T1C8.
authors: G
authors: G
authors: Boucher
authors: Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors: K
authors: K
authors: Croitoru
authors: Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland.
authors: P
authors: P
authors: Fleshner
authors: Division of Gastroenterology, Royal Victoria Hospital, Montréal, Québec, Canada.
authors: J
authors: J
authors: Glas
authors: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors: S
authors: S
authors: Kugathasan
authors: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada.
authors: J V
authors: JV
authors: Limbergen
authors: Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors: R
authors: R
authors: Milgrom
authors: Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors: D
authors: D
authors: Proctor
authors: Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA.
authors: M
authors: M
authors: Regueiro
authors: Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA.
authors: P L
authors: PL
authors: Schumm
authors: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors: Y
authors: Y
authors: Sharma
authors: Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors: J M
authors: JM
authors: Stempak
authors: Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland.
authors: S R
authors: SR
authors: Targan
authors: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors: M H
authors: MH
authors: Wang
mesh_terms: D000483:Alleles; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000517:prevention & control*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D009154:Mutation / Q000235:genetics*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; C587047:RNF186 protein, human; D044767:Ubiquitin-Protein Ligases