Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility
Nature Genetics, vol. 54, pp. 1275–1283
Abstract
Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.
Authors 100
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Affiliation as printed
Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Broad Institute · Massachusetts General Hospital · Stanley Center for Psychiatric Research
Affiliation as printed
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Affiliation as printed
Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
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Broad Institute · Massachusetts General Hospital · Stanley Center for Psychiatric Research
Affiliation as printed
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Affiliation as printed
Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Affiliation as printed
Crohn's and Colitis Center, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
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Royal Devon and Exeter Hospital
Affiliation as printed
Royal Devon and Exeter Hospital, Exeter, UK
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Inserm · Université Paris Cité · Assistance Publique – Hôpitaux de Paris · Hôpital Saint-Louis · Ecotaxie, Microenvironnement et développement lymphocytaire
Affiliation as printed
Hopital Saint-Louis, APHP, Universite de Paris, INSERM U1160, Paris, France
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Massachusetts General Hospital
Affiliation as printed
Division of Gastroenterology, Crohn's and Colitis Center, Massachusetts General Hospital, Boston, MA, USA
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Albert Einstein College of Medicine · University of Haifa
Affiliation as printed
Department for Human Biology, University of Haifa, Haifa, Israel
Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
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Affiliation as printed
Regeneron Genetics Center, Tarrytown, NY, USA
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Affiliation as printed
Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Albert Einstein College of Medicine · Yeshiva University
Affiliation as printed
Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
The Institute for Aging Research, The Nathan Shock Center of Excellence in the Basic Biology of Aging and the Paul F. Glenn Center for the Biology of Human Aging Research at Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA
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Sorbonne Université · Hôpital Saint-Antoine
Affiliation as printed
Gastroenterology Department, Sorbonne Universite, Saint Antoine Hospital, Paris, France
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Affiliation as printed
John P. Hussman Institute for Human Genomics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
The Dr. John T. Macdonald Foundation Department of Human Genetics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
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Affiliation as printed
University of Manitoba, Winnipeg, Manitoba, Canada
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McGill University Health Centre · McGill University
Affiliation as printed
McGill University and McGill University Health Centre, Montreal, Quebec, Canada
McGill University and McGill University Health Centre, Montreal, Quebec, Canada
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University Hospital Schleswig-Holstein
Affiliation as printed
Department of Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany
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Brigham and Women's Hospital · Massachusetts General Hospital
Affiliation as printed
Channing Division of Network Medicine, Department of Medicine, Brigham and Womens Hospital, Boston, MA, USA
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
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Massachusetts General Hospital
Affiliation as printed
Massachusetts General Hospital, Boston, MA, USA
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Affiliation as printed
Department of Human Genetics, KU Leuven, Leuven, Belgium
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Assistance Publique – Hôpitaux de Paris
Affiliation as printed
Professeur Chef de Service chez APHP and Universite Paris-6, Paris, France
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Emory University · Children's Healthcare of Atlanta
Affiliation as printed
Department of Human Genetics, Emory University, Atlanta, GA, USA
Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA
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Affiliation as printed
Human Genetics Informatics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Affiliation as printed
University of Miami, Miami, FL, USA
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Johns Hopkins University · Johns Hopkins Medicine
Affiliation as printed
Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Children's Hospital of Philadelphia · University of Pennsylvania
Affiliation as printed
Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
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Children's Hospital of Philadelphia · Institute of Genetic and Biomedical Research · University of Pennsylvania · Sapienza University of Rome
Affiliation as printed
Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
IRGB - CNR, Cagliari, Italy
Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
University of Rome Sapienza, Rome, Italy
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Broad Institute · Massachusetts Institute of Technology
Affiliation as printed
Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Christian-Albrechts-Universität zu Kiel
Affiliation as printed
Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
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Affiliation as printed
Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Affiliation as printed
Helsinki University Central Hospital, Helsinki, Finland
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Affiliation as printed
Mayo Clinic, Rochester, Rochester, MN, USA
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Affiliation as printed
Regeneron Genetics Center, Tarrytown, NY, USA
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Affiliation as printed
Erasme Hospital, ULB, Brussels, Belgium
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Broad Institute · Massachusetts Institute of Technology
Affiliation as printed
Genomics Platform, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Broad Institute · Massachusetts General Hospital · Stanley Center for Psychiatric Research
Affiliation as printed
Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA
Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Affiliation as printed
University of Liège, ULG, Liège, Belgium
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Icahn School of Medicine at Mount Sinai
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Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Icahn School of Medicine at Mount Sinai
Affiliation as printed
Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Hebrew University of Jerusalem · Hadassah Medical Center
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Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
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University Hospital Schleswig-Holstein
Affiliation as printed
University Medical Center Schleswig-Holstein, Kiel, Germany
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Affiliation as printed
Research Center Montreal Heart Institute, Montreal, Quebec, Canada
Research Center Montreal Heart Institute, Montreal, Quebec, Canada
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Broad Institute · Massachusetts General Hospital · Center for Computational and Integrative Biology, Massachusetts General Hospital
Affiliation as printed
Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
Infectious Disease and Microbiome Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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University of Helsinki · Institute for Molecular Medicine Finland · HiLIFE – Elämäntieteiden Instituutti
Affiliation as printed
Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
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Cedars-Sinai Medical Center · F. Widjaja Inflammatory Bowel Disease Institute
Affiliation as printed
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
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Royal Devon and Exeter Hospital
Affiliation as printed
Royal Devon and Exeter Hospital, Exeter, UK
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Affiliation as printed
Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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Christian-Albrechts-Universität zu Kiel
Affiliation as printed
Christian-Albrechts-University of Kiel, Kiel, Germany
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Affiliation as printed
Regeneron Genetics Center, Tarrytown, NY, USA
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Guy's Hospital · St Thomas' Hospital · King's College London
Affiliation as printed
Department of Gastroenterology, Guys and Saint Thomas Hospital, London, UK
School of Immunology and Microbial Sciences, Kings College London, London, UK
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Affiliation as printed
Human Genetics Informatics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Affiliation as printed
Director of Genetic Resources and Services, Center for Rare Jewish Genetic Disorders, Bonei Olam, Brooklyn, NY, USA
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Children's Hospital of Philadelphia · University of Pennsylvania
Affiliation as printed
Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
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Massachusetts General Hospital
Affiliation as printed
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
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University of Chicago · University of Chicago Medical Center
Affiliation as printed
Department of Gastroenterology, University of Chicago Medicine, Chicago, IL, USA
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University of Helsinki · Helsinki University Hospital
Affiliation as printed
Department of Medicine, Helsinki University Hospital, and Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
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University of Helsinki · Institute for Molecular Medicine Finland · HiLIFE – Elämäntieteiden Instituutti
Affiliation as printed
Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
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Emory University · Children's Healthcare of Atlanta
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Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA
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Lithuanian University of Health Sciences
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Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
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Newcastle upon Tyne Hospitals NHS Foundation Trust · Newcastle University
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Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
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University Hospital Schleswig-Holstein
Affiliation as printed
University Medical Center Schleswig-Holstein, Kiel, Germany
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Affiliation as printed
Research Center Montreal Heart Institute, Montreal, Quebec, Canada
Research Center Montreal Heart Institute, Montreal, Quebec, Canada
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Affiliation as printed
University College London, London, UK
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Crohn's and Colitis Foundation · University of Pennsylvania
Affiliation as printed
Crohn's and Colitis Foundation, New York, NY, USA
Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
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Affiliation as printed
Erasme Hospital, ULB, Brussels, Belgium
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Christian-Albrechts-Universität zu Kiel
Affiliation as printed
Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
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Affiliation as printed
University of Liège, ULG, Liège, Belgium
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Newcastle upon Tyne Hospitals NHS Foundation Trust · Newcastle University
Affiliation as printed
Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
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Christian-Albrechts-Universität zu Kiel
Affiliation as printed
Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
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Affiliation as printed
John P. Hussman Institute for Human Genomics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
The Dr. John T. Macdonald Foundation Department of Human Genetics, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
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Cedars-Sinai Medical Center · F. Widjaja Inflammatory Bowel Disease Institute
Affiliation as printed
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
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Affiliation as printed
University of Liège, ULG, Liège, Belgium
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Affiliation as printed
McMaster University, Hamilton, Ontario, Canada
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Massachusetts General Hospital
Affiliation as printed
Massachusetts General Hospital, Boston, MA, USA
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Washington University in St. Louis
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Washington University School of Medicine, St. Louis, MO, USA
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Crohn's and Colitis Foundation
Affiliation as printed
Crohn’s and Colitis Foundation, New York, NY, USA
Crohn's and Colitis Foundation, New York, NY, USA
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Emory University · Institut National de Santé Publique · Children's Healthcare of Atlanta
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Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA
Institut National de Sante Publique (INSP), Abidjan, Côte d'Ivoire
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands
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Albert Einstein College of Medicine
Affiliation as printed
Albert Einstein College of Medicine, Bronx, NY, USA
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Broad Institute · University of Helsinki · Massachusetts General Hospital · Institute for Molecular Medicine Finland · HiLIFE – Elämäntieteiden Instituutti · Stanley Center for Psychiatric Research
Affiliation as printed
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland
Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Affiliation as printed
Research Center Montreal Heart Institute, Montreal, Quebec, Canada
Research Center Montreal Heart Institute, Montreal, Quebec, Canada
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University of Chicago · University of Chicago Medical Center
Affiliation as printed
Department of Gastroenterology, University of Chicago Medicine, Chicago, IL, USA
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Icahn School of Medicine at Mount Sinai
Affiliation as printed
Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Maastricht University Medical Centre
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Department of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, The Netherlands
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Amsterdam University Medical Centers
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Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, The Netherlands
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Affiliation as printed
University College London, London, UK
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Affiliation as printed
Department of Medical and Molecular Genetics, Kings College London, London, UK
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Affiliation as printed
School of Medicine, Johns Hopkins University, Baltimore, MD, USA
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Affiliation as printed
University of Liège, ULG, Liège, Belgium
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Affiliation as printed
Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Affiliation as printed
Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
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Icahn School of Medicine at Mount Sinai
Affiliation as printed
Icahn School of Medicine at Mount Sinai, New York, NY, USA
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University of North Carolina at Chapel Hill
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Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, NC, USA
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Affiliation as printed
University College London, London, UK
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Christian-Albrechts-Universität zu Kiel
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Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
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Affiliation as printed
Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
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Affiliation as printed
University College London, London, UK
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Sorbonne Université · Hôpital Saint-Antoine
Affiliation as printed
Gastroenterology Department, Sorbonne Universite, Saint Antoine Hospital, Paris, France
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Cambridge University Hospitals NHS Foundation Trust · NIHR BioResource
Affiliation as printed
IBD BioResource, NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK