Fine-mapping inflammatory bowel disease loci to single-variant resolution
Number of Authors: 462017 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 547, no 7662, p. 173-+Article in journal (Refereed) Published
Abstract [en]
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.
Place, publisher, year, edition, pages
Nature Publishing Group, 2017. Vol. 547, no 7662, p. 173-+
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:oru:diva-58928DOI: 10.1038/nature22969ISI: 000405314500030PubMedID: 28658209Scopus ID: 2-s2.0-85024387670OAI: oai:DiVA.org:oru-58928DiVA, id: diva2:1134763
Funder
Swedish Research Council, 2010-2976 2013-3862 521 2011 2764
Note
Funding Agencies:
Helmsley grant 2015PG-IBD001
Crohn's AMP; Colitis Foundation of America
Wellcome Trust 098051 098759/Z/12/Z
Fonds de la Recherche Scientifique-FNRS WELBIO-CR-2012A-06
BELSPO-IUAP-P7/43-BeMGI
Federation Wallonie-Bruxelles (ARC IBD@Ulg)
Region Wallonne (CIBLES, FEDER)
ASHG/Charles J. Epstein Trainee Award
Olle Engkvist Foundation
VIDI grant from the Netherlands Organization for Scientific Research 016.136.308
Canada Research Chair
National Institute of Diabetes and Digestive and Kidney Diseases DK064869 DK062432
CIHR from the Canadian Institutes of Health Research GPG-102170
Genome Canada GPH-129341
Genome Quebec
Crohn's Colitis Canada
Sanford J. Grossman Charitable Trust
Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh U01DK062420 R01CA141743
Marie-Curie Fellowship
Fonds de la Recherche Scientifique-FNRS (F.R.S.-FNRS)
Fonds Leon Fredericq fellowships
Örebro University Hospital Research Foundation
National Institute for Health Research (NIHR) Biomedical Research Centre
German Federal Ministry of Education and Research (SysInflame grant) 01ZX1306A
DFG Excellence Cluster 306
Foundation for Experimental Medicine (Zurich, Switzerland)
European Union DK062413 AI067068 U54DE023789-01 305479
Leona M. and Harry B. Helmsley Charitable Trust
P30DK43351
U01DK062432
R01DK64869
DK062429
DK062422
DK092235
DK106593
2017-08-212017-08-212018-09-06Bibliographically approved