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

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 Deffontaine, Julia Dmitrieva, Elisa Docampo, Mahmoud Elansary, Kyle Kai-How Farh, Andre Franke, Ann-Stephan Gori, Philippe Goyette, Jonas Halfvarson, Talin Haritunians, Jo Knight, Ian C. Lawrance, Charlie W. Lees, Edouard Louis, Rob Mariman, Theo Meuwissen, Myriam Mni, Yukihide Momozawa, Miles Parkes, Sarah L. Spain, Emilie Théâtre, Gosia Trynka, Jack Satsangi, Suzanne van Sommeren, Severine Vermeire, Ramnik J. Xavier, Rinse K. Weersma, Richard H. Duerr, Christopher G. Mathew, John D. Rioux, Dermot P. B. McGovern, Judy H. Cho, Michel Georges (), Mark J. Daly () and Jeffrey C. Barrett ()
Additional contact information
Hailiang Huang: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School
Ming Fang: Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
Luke Jostins: Wellcome Trust Centre for Human Genetics, 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
Isabelle Cleynen: Department of Human Genetics
Adrian Cortes: Wellcome Trust Centre for Human Genetics, University of Oxford
François Crins: Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
Mauro D’Amato: Clinical Epidemiology Unit, Karolinska Institutet
Valérie Deffontaine: Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
Julia Dmitrieva: Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
Elisa Docampo: Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
Mahmoud Elansary: Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
Kyle Kai-How Farh: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School
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
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
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
Rob Mariman: Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, 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
Yukihide Momozawa: Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège
Miles Parkes: Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital
Sarah L. Spain: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Emilie Théâtre: Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, 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
Ramnik J. Xavier: Broad Institute of MIT and Harvard
Rinse K. Weersma: University of Groningen and University Medical Center Groningen
Richard H. Duerr: Hepatology and Nutrition, University of Pittsburgh School of Medicine
Christopher G. Mathew: King’s College London
John D. Rioux: Research Center, Montreal Heart Institute
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
Mark J. Daly: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School
Jeffrey C. Barrett: Wellcome Trust Sanger Institute, Wellcome Genome Campus

Nature, 2017, vol. 547, issue 7662, 173-178

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature22969

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