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

Author

Listed:
  • Manuel A. Rivas

    (Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School)

  • Daniel Graham

    (Broad Institute of MIT and Harvard)

  • Patrick Sulem

    (deCODE Genetics, Amgen Inc.)

  • Christine Stevens

    (Broad Institute of MIT and Harvard)

  • A. Nicole Desch

    (Broad Institute of MIT and Harvard)

  • Philippe Goyette

    (Research Center, Montreal Heart Institute)

  • Daniel Gudbjartsson

    (deCODE Genetics, Amgen Inc.
    School of Engineering and Natural Sciences, University of Iceland)

  • Ingileif Jonsdottir

    (deCODE Genetics, Amgen Inc.
    Landspitali, the National University Hospital of Iceland
    Faculty of Medicine, University of Iceland)

  • Unnur Thorsteinsdottir

    (deCODE Genetics, Amgen Inc.
    Faculty of Medicine, University of Iceland)

  • Frauke Degenhardt

    (Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel)

  • Sören Mucha

    (Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel)

  • Mitja I. Kurki

    (Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School)

  • Dalin Li

    (F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center
    Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center)

  • Mauro D’Amato

    (Karolinska Institutet
    BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science)

  • Vito Annese

    (Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital
    Strutture Organizzative Dipartimentali (SOD) Gastroenterologia 2, Azienda Ospedaliero Universitaria (AOU) Careggi)

  • Severine Vermeire

    (Translational Research in GastroIntestinal Disorders (TARGID), Katholieke Universiteit (KU) Leuven
    University Hospital Gasthuisberg)

  • Rinse K. Weersma

    (University of Groningen and University Medical Center Groningen)

  • Jonas Halfvarson

    (Faculty of Medicine and Health, Örebro University)

  • Paulina Paavola-Sakki

    (University of Helsinki
    Helsinki University Hospital
    Clinic of Gastroenterology, Helsinki University Hospital)

  • Maarit Lappalainen

    (University of Helsinki
    Helsinki University Hospital
    Research Programs Unit, Immunobiology, University of Helsinki)

  • Monkol Lek

    (Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School)

  • Beryl Cummings

    (Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School)

  • Taru Tukiainen

    (Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School)

  • Talin Haritunians

    (F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center
    Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center)

  • Leena Halme

    (University of Helsinki)

  • Lotta L. E. Koskinen

    (Research Programs Unit, Immunobiology, University of Helsinki
    Biomedicum Helsinki, University of Helsinki)

  • Ashwin N. Ananthakrishnan

    (Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School
    Harvard Medical School)

  • Yang Luo

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Graham A. Heap

    (IBD Pharmacogenetics, Royal Devon and Exeter NHS Trust)

  • Marijn C. Visschedijk

    (University of Groningen and University Medical Center Groningen)

  • Daniel G. MacArthur

    (Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School)

  • Benjamin M. Neale

    (Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School)

  • Tariq Ahmad

    (Peninsula College of Medicine and Dentistry)

  • Carl A. Anderson

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Steven R. Brant

    (Meyerhoff Inflammatory Bowel Disease Center, School of Medicine, Johns Hopkins University
    Bloomberg School of Public Health, Johns Hopkins University)

  • Richard H. Duerr

    (Hepatology and Nutrition, University of Pittsburgh School of Medicine
    University of Pittsburgh Graduate School of Public Health)

  • Mark S. Silverberg

    (Inflammatory Bowel Disease Centre, Mount Sinai Hospital)

  • Judy H Cho

    (Yale School of Medicine)

  • Aarno Palotie

    (Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School
    Institute for Molecular Medicine Finland, University of Helsinki
    Massachusetts General Hospital, Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit)

  • Päivi Saavalainen

    (Research Programs Unit, Immunobiology, University of Helsinki)

  • Kimmo Kontula

    (University of Helsinki
    Helsinki University Hospital)

  • Martti Färkkilä

    (University of Helsinki
    Helsinki University Hospital
    Clinic of Gastroenterology, Helsinki University Hospital)

  • Dermot P. B. McGovern

    (F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center
    Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center)

  • Andre Franke

    (Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel)

  • Kari Stefansson

    (deCODE Genetics, Amgen Inc.
    Faculty of Medicine, University of Iceland)

  • John D. Rioux

    (Research Center, Montreal Heart Institute
    Faculté de Médecine, Université de Montréal)

  • Ramnik J. Xavier

    (Broad Institute of MIT and Harvard
    Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School)

  • Mark J. Daly

    (Broad Institute of MIT and Harvard
    Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School)

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.

Suggested Citation

  • Manuel A. Rivas & Daniel Graham & Patrick Sulem & Christine Stevens & A. Nicole Desch & Philippe Goyette & Daniel Gudbjartsson & Ingileif Jonsdottir & Unnur Thorsteinsdottir & Frauke Degenhardt & Söre, 2016. "A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis," Nature Communications, Nature, vol. 7(1), pages 1-8, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12342
    DOI: 10.1038/ncomms12342
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