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Nature. 2017 Jul 13;547(7662):173-178. doi: 10.1038/nature22969. Epub 2017 Jun 28.

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

Author information

1
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
2
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02141, USA.
3
Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège, 4000 Liège, Belgium.
4
Faculty of Veterinary Medicine, University of Liège, 4000 Liège, Belgium.
5
Wellcome Trust Centre for Human Genetics, University of Oxford, Headington OX3 7BN, UK.
6
Christ Church, University of Oxford, St Aldates OX1 1DP, UK.
7
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
8
Research Center, Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada.
9
Focused research unit for Molecular Diagnostic and Clinical Research (MOK), IRS-Center Sonderjylland, Hospital of Southern Jutland, 6200 Åbenrå, Denmark.
10
Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark.
11
Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
12
Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
13
Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, 17176 Stockholm, Sweden.
14
Department of Gastrointestinal and Liver Diseases, BioDonostia Health Research Institute, 20014 San Sebastián, Spain.
15
IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain.
16
Illumina, San Diego, California 92122, USA.
17
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany.
18
Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE-70182 Örebro, Sweden.
19
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
20
Data Science Institute and Lancaster Medical School, Lancaster University, Lancaster LA1 4YG, UK.
21
Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco, Western Australia 6008, Australia.
22
Harry Perkins Institute for Medical Research, School of Medicine and Pharmacology, University of Western Australia, Murdoch, Western Australia 6150, Australia.
23
Gastrointestinal Unit, Western General Hospital University of Edinburgh, Edinburgh, UK.
24
Division of Gastroenterology, Centre Hospitalier Universitaire (CHU) de Liège, 4000 Liège, Belgium.
25
Institute of Livestock and Aquacultural Sciences, Norwegian University of Life Sciences, 1430 Ås, Norway.
26
Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa 230-0045, Japan.
27
Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
28
Open Targets, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.
29
Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9700RB Groningen, The Netherlands.
30
Division of Gastroenterology, University Hospital Gasthuisberg, 3000 Leuven, Belgium.
31
Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
32
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
33
Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA.
34
Department of Medical and Molecular Genetics, King's College London, London SE1 9RT, UK.
35
Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg 2193, South Africa.
36
Faculté de Médecine, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
37
Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.

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.

PMID:
28658209
PMCID:
PMC5511510
DOI:
10.1038/nature22969
[Indexed for MEDLINE]
Free PMC Article
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