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Fine-mapping inflammatory bowel disease loci to single-variant resolution

Author

Listed:
  • Hailiang Huang

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

  • Ming Fang

    (Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
    Faculty of Veterinary Medicine, University of Liège)

  • Luke Jostins

    (Wellcome Trust Centre for Human Genetics, University of Oxford
    Christ Church, University of Oxford)

  • Maša Umićević Mirkov

    (Wellcome Trust Sanger Institute, Wellcome Genome Campus)

  • Gabrielle Boucher

    (Research Center, Montreal Heart Institute)

  • Carl A. Anderson

    (Wellcome Trust Sanger Institute, Wellcome Genome Campus)

  • Vibeke Andersen

    (Focused research unit for Molecular Diagnostic and Clinical Research (MOK), IRS-Center Sonderjylland, Hospital of Southern Jutland
    Institute of Molecular Medicine, University of Southern Denmark)

  • Isabelle Cleynen

    (Department of Human Genetics)

  • Adrian Cortes

    (Wellcome Trust Centre for Human Genetics, University of Oxford
    Oxford Centre for Neuroinflammation, John Radcliffe Hospital, University of Oxford)

  • François Crins

    (Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
    Faculty of Veterinary Medicine, University of Liège)

  • Mauro D’Amato

    (Clinical Epidemiology Unit, Karolinska Institutet
    BioDonostia Health Research Institute
    IKERBASQUE, Basque Foundation for Science)

  • Valérie Deffontaine

    (Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
    Faculty of Veterinary Medicine, University of Liège)

  • Julia Dmitrieva

    (Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
    Faculty of Veterinary Medicine, University of Liège)

  • Elisa Docampo

    (Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
    Faculty of Veterinary Medicine, University of Liège)

  • Mahmoud Elansary

    (Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
    Faculty of Veterinary Medicine, University of Liège)

  • Kyle Kai-How Farh

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

  • Andre Franke

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

  • Ann-Stephan Gori

    (Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
    Faculty of Veterinary Medicine, University of Liège)

  • Philippe Goyette

    (Research Center, Montreal Heart Institute)

  • Jonas Halfvarson

    (Faculty of Medicine and Health, Örebro University)

  • Talin Haritunians

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

  • Jo Knight

    (Data Science Institute and Lancaster Medical School, Lancaster University)

  • Ian C. Lawrance

    (Centre for Inflammatory Bowel Diseases, Saint John of God Hospital
    Harry Perkins Institute for Medical Research, School of Medicine and Pharmacology, University of Western Australia)

  • Charlie W. Lees

    (Gastrointestinal Unit, Western General Hospital University of Edinburgh)

  • Edouard Louis

    (Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
    Centre Hospitalier Universitaire (CHU) de Liège)

  • Rob Mariman

    (Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
    Faculty of Veterinary Medicine, University of Liège)

  • Theo Meuwissen

    (Institute of Livestock and Aquacultural Sciences, Norwegian University of Life Sciences)

  • Myriam Mni

    (Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
    Faculty of Veterinary Medicine, University of Liège)

  • Yukihide Momozawa

    (Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
    Faculty of Veterinary Medicine, University of Liège
    Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN)

  • Miles Parkes

    (Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital)

  • Sarah L. Spain

    (Wellcome Trust Sanger Institute, Wellcome Genome Campus
    Open Targets, Wellcome Trust Genome Campus)

  • Emilie Théâtre

    (Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
    Faculty of Veterinary Medicine, University of Liège)

  • Gosia Trynka

    (Wellcome Trust Sanger Institute, Wellcome Genome Campus)

  • Jack Satsangi

    (Gastrointestinal Unit, Western General Hospital University of Edinburgh)

  • Suzanne van Sommeren

    (University of Groningen and University Medical Center Groningen)

  • Severine Vermeire

    (Department of Human Genetics
    University Hospital Gasthuisberg)

  • Ramnik J. Xavier

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

  • Rinse K. Weersma

    (University of Groningen and University Medical Center Groningen)

  • Richard H. Duerr

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

  • Christopher G. Mathew

    (King’s College London
    Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand)

  • John D. Rioux

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

  • Dermot P. B. McGovern

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

  • Judy H. Cho

    (Yale School of Medicine)

  • Michel Georges

    (Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
    Faculty of Veterinary Medicine, University of Liège)

  • Mark J. Daly

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

  • Jeffrey C. Barrett

    (Wellcome Trust Sanger Institute, Wellcome Genome Campus)

Abstract

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn’s disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

Suggested Citation

  • Hailiang Huang & Ming Fang & Luke Jostins & Maša Umićević Mirkov & Gabrielle Boucher & Carl A. Anderson & Vibeke Andersen & Isabelle Cleynen & Adrian Cortes & François Crins & Mauro D’Amato & Valérie , 2017. "Fine-mapping inflammatory bowel disease loci to single-variant resolution," Nature, Nature, vol. 547(7662), pages 173-178, July.
    • Handle: RePEc:nat:nature:v:547:y:2017:i:7662:d:10.1038_nature22969
    DOI: 10.1038/nature22969
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