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Fine-mapping inflammatory bowel disease loci to single-variant resolution
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston MA, United States; Broad Institute of mit and Harvard, Cambridge MA, United States.
Örebro University, School of Medical Sciences. Department of Gastroenterology.ORCID iD: 0000-0003-0122-7234
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, United Kingdom.
Number of Authors: 46
2017 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 547, no 7662, 173-+ p.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, 173-+ p.
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: 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 

Available from: 2017-08-21 Created: 2017-08-21 Last updated: 2017-10-10Bibliographically approved

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CiteExportLink to record
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