Journal
NATURE
Volume 547, Issue 7662, Pages 173-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/nature22969
Keywords
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Categories
Funding
- 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
- Swedish Research Council [2010-2976, 2013-3862, 521 2011 2764]
- 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
- Orebro 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]
- Chief Scientist Office [ETM/137] Funding Source: researchfish
- Crohn's and Colitis UK [M14-5] Funding Source: researchfish
- Medical Research Council [G0800759, MR/M00533X/1, G0600329] Funding Source: researchfish
- Wellcome Trust [098759/Z/12/Z] Funding Source: Wellcome Trust
- MRC [G0800759, MR/M00533X/1, G0600329] Funding Source: UKRI
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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.
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