A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

Manuel A Rivas; Daniel Graham; Patrick Sulem; Christine Stevens; A Nicole Desch; Philippe Goyette; Daniel Gudbjartsson; Ingileif Jonsdottir; Unnur Thorsteinsdottir; Frauke Degenhardt; Sören Mucha; Mitja I Kurki; Dalin Li; Mauro D'Amato; Vito Annese; Severine Vermeire; Rinse K Weersma; Jonas Halfvarson; Paulina Paavola-Sakki; Maarit Lappalainen; Monkol Lek; Beryl Cummings; Taru Tukiainen; Talin Haritunians; Leena Halme; Lotta L E Koskinen; Ashwin N Ananthakrishnan; Yang Luo; Graham A Heap; Marijn C Visschedijk; Daniel G MacArthur; Benjamin M Neale; Tariq Ahmad; Carl A Anderson; Steven R Brant; Richard H Duerr; Mark S Silverberg; Judy H Cho; Aarno Palotie; Päivi Saavalainen; Kimmo Kontula; Martti Färkkilä; Dermot P B McGovern; Andre Franke; Kari Stefansson; John D Rioux; Ramnik J Xavier; Mark J Daly; J Barrett; K de Lane; C Edwards; A Hart; C Hawkey; L Jostins; N Kennedy; C Lamb; J Lee; C Lees; J Mansfield; C Mathew; C Mowatt; B Newman; E Nimmo; M Parkes; M Pollard; N Prescott; J Randall; D Rice; J Satsangi; A Simmons; M Tremelling; H Uhlig; D Wilson; C Abraham; J P Achkar; A Bitton; G Boucher; K Croitoru; P Fleshner; J Glas; S Kugathasan; J V Limbergen; R Milgrom; D Proctor; M Regueiro; P L Schumm; Y Sharma; J M Stempak; S R Targan; M H Wang; NIDDK IBD Genetics Consortium

doi:10.1038/ncomms12342

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A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

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A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

Manuel A Rivas, Daniel Graham, Patrick Sulem, Christine Stevens, A Nicole Desch, Philippe Goyette, Daniel Gudbjartsson, Ingileif Jonsdottir, Unnur Thorsteinsdottir, Frauke Degenhardt, …

Nature communications, Vol.7(1), pp.12342-12342

08/09/2016

DOI: https://doi.org/10.1038/ncomms12342

PMCID: PMC4980482

PMID: 27503255

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.

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Title: A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis
Creators: Manuel A Rivas - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
Daniel Graham - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Patrick Sulem - deCODE Genetics, Amgen Inc., 101 Reykjavik, Iceland
Christine Stevens - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
A Nicole Desch - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Philippe Goyette - Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T1C8
Daniel Gudbjartsson - School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland
Ingileif Jonsdottir - Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
Unnur Thorsteinsdottir - Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
Frauke Degenhardt - Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany
Sören Mucha - Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany
Mitja I Kurki - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
Dalin Li - Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA
Mauro D'Amato - BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, 48903 Bilbao, Spain
Vito Annese - Strutture Organizzative Dipartimentali (SOD) Gastroenterologia 2, Azienda Ospedaliero Universitaria (AOU) Careggi, 50134 Florence, Italy
Severine Vermeire - Division of Gastroenterology, University Hospital Gasthuisberg, BE-3000 Leuven, Belgium
Rinse K Weersma - Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
Jonas Halfvarson - Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE 701 82 Örebro, Sweden
Paulina Paavola-Sakki - Clinic of Gastroenterology, Helsinki University Hospital, 00100 Helsinki, Finland
Maarit Lappalainen - Research Programs Unit, Immunobiology, and Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland
Monkol Lek - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
Beryl Cummings - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
Taru Tukiainen - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
Talin Haritunians - Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA
Leena Halme - Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland
Lotta L E Koskinen - Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00100 Helsinki, Finland
Ashwin N Ananthakrishnan - Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02114, USA
Yang Luo - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
Graham A Heap - IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK
Marijn C Visschedijk - Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
Daniel G MacArthur - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
Benjamin M Neale - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
Tariq Ahmad - Peninsula College of Medicine and Dentistry, Exeter PL6 8BU, UK
Carl A Anderson - Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
Steven R Brant - Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, 21205, USA
Richard H Duerr - Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA
Mark S Silverberg - Department of Medicine, Inflammatory Bowel Disease Centre, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5
Judy H Cho - Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA
Aarno Palotie - Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Boston, Massachusetts 02114, USA
Päivi Saavalainen - Research Programs Unit, Immunobiology, University of Helsinki, 00100 Helsinki, Finland
Kimmo Kontula - Helsinki University Hospital, 00100 Helsinki, Finland
Martti Färkkilä - Clinic of Gastroenterology, Helsinki University Hospital, 00100 Helsinki, Finland
Dermot P B McGovern - Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA
Andre Franke - Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany
Kari Stefansson - Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
John D Rioux - Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada H3T 1J4
Ramnik J Xavier - Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
Mark J Daly - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
J Barrett - IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK
K de Lane - IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK
C Edwards - Department of Gastroenterology, Torbay Hospital, Devon, UK
A Hart - Department of Medicine, St. Mark's Hospital, Middlesex, UK
C Hawkey - Nottingham Digestive Disease Centre, Queens Medical Centre, Nottingham, UK
L Jostins - Christ Church, University of Oxford, Oxford, UK
N Kennedy - Gastrointestinal Unit, Wester General Hospital, University of Edinburgh, Edinburgh, UK
C Lamb - Newcastle University, Newcastle upon Tyne, UK
J Lee - Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK
C Lees - Gastrointestinal Unit, Wester General Hospital, University of Edinburgh, Edinburgh, UK
J Mansfield - Newcastle University, Newcastle upon Tyne, UK
C Mathew - Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK
C Mowatt - Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK
B Newman - The Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK
E Nimmo - Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK
M Parkes - Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK
M Pollard - IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK
N Prescott - Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK
J Randall - IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK
D Rice - IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust, Exeter EX2 5DW, UK
J Satsangi - Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK
A Simmons - Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
M Tremelling - Gastroenterology &General Medicine, Norfolk and Norwich University Hospital, Norwich, UK
H Uhlig - Translational Gastroenterology Unit and the Department of Pediatrics, University of Oxford, Oxford, UK
D Wilson - Child Life and Health, University of Edinburgh, Edinburgh, UK
C Abraham - Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
J P Achkar - Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
A Bitton - Division of Gastroenterology, Royal Victoria Hospital, Montréal, Québec, Canada
G Boucher - Research Center, Montreal Heart Institute, Montréal, Québec, Canada H1T1C8
K Croitoru - Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
P Fleshner - Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland
J Glas - Division of Gastroenterology, Royal Victoria Hospital, Montréal, Québec, Canada
S Kugathasan - Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
J V Limbergen - Division of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada
R Milgrom - Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA
D Proctor - Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
M Regueiro - Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA
P L Schumm - Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA
Y Sharma - Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
J M Stempak - Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA
S R Targan - Department of Transplantation and Liver Surgery, University of Helsinki, 00100 Helsinki, Finland
M H Wang - Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
NIDDK IBD Genetics Consortium
Publication Details: Nature communications, Vol.7(1), pp.12342-12342
Date published: 08/09/2016
Grant note: MR/J00314X/1 / Medical Research Council U01 HG005923 / NHGRI NIH HHS U01 DK062413 / NIDDK NIH HHS U54 DE023789 / NIDCR NIH HHS MC_UU_12010/7 / Medical Research Council ETM/137 / Chief Scientist Office P01 DK046763 / NIDDK NIH HHS U01 DK062429 / NIDDK NIH HHS R01 DK092235 / NIDDK NIH HHS U01 DK062422 / NIDDK NIH HHS U01 DK062431 / NIDDK NIH HHS G0800759 / Medical Research Council P30 DK089502 / NIDDK NIH HHS U01 DK062423 / NIDDK NIH HHS P30 DK043351 / NIDDK NIH HHS MC_PC_15018 / Medical Research Council UL1 TR001863 / NCATS NIH HHS R01 DK064869 / NIDDK NIH HHS NIHR-RP-R3-12-026 / Department of Health U01 DK062420 / NIDDK NIH HHS U01 AI067068 / NIAID NIH HHS U01 DK062432 / NIDDK NIH HHS G0600329 / Medical Research Council
Academic Unit: Medicine - Gastroenterology and Hepatology (RWJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031665670604646