Journal
NATURE
Volume 491, Issue 7422, Pages 119-124Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11582
Keywords
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Categories
Funding
- National Association for Colitis and Crohn's disease
- Wellcome Trust [098051, 083948/Z/07/Z, 085475/B/08/Z, 085475/Z/08/Z]
- Medical Research Council UK
- Catherine McEwan Foundation
- NHS Research Scotland career fellowship
- Peninsula College of Medicine and Dentistry, Exeter
- National Institute for Health Research, through the Comprehensive Local Research Network
- Biomedical ResearchCentre
- Saint Thomas' NationalHealth Service Trust
- King's College London
- Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine
- University of Manchester
- Central Manchester Foundation Trust
- Medical Research Council [G0000934]
- Wellcome Trust grant [068545/Z/02]
- UK National Blood Service
- National Institute of Diabetes, Digestive and Kidney diseases (NIDDK) IBD Genetics Consortium
- National Institutes of Health (NIH) [MSTP TG T32GM07205]
- USPHS [PO1DK046763]
- Cedars-Sinai F. Widjaja Inflammatory Bowel and Immunobiology Research Institute Research Funds
- National Center for Research Resources (NCRR) [M01-RR00425]
- UCLA/Cedars-Sinai/Harbor/Drew Clinical and Translational Science Institute (CTSI) [UL1 TR000124-01]
- Southern California Diabetes and Endocrinology Research Grant (DERC) [DK063491]
- Helmsley Foundation
- Crohn's and Colitis Foundation of America
- Netherlands Organization for Scientific Research [90.700.281, 918.66.620]
- Celiac Disease Consortium [BSIK03009]
- German Ministry of Education and Research through the National Genome Research Network
- Popgen biobank, through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ` Inflammation at Interfaces'
- DFG [FR 2821/2-1, BR 1912/6-1]
- Else Kroner-Fresenius-Stiftung (Else Kroner-Exzellenzstipendium)
- Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition
- Italian Ministry of Health [GR-2008-1144485]
- Swedish Society of Medicine
- Ihre Foundation
- Orebro University Hospital Research Foundation
- Karolinska Institutet
- Swedish National Program for IBD Genetics
- Swedish Organization for IBD
- Swedish Medical Research Council
- Royal Brisbane and Women's Hospital Foundation
- National Health and Medical Research Council, Australia
- European Community (5th PCRDT)
- NIDDK, National Institute of Allergy and Infectious Diseases (NIAID)
- National Human Genome Research Institute (NHGRI)
- National Institute of Child Health and Human Development (NICHD)
- Juvenile Diabetes Research Foundation (JDRF)
- Helmholtz Zentrum Munchen-German Research Center for Environmental Health
- German Federal Ministry of Education and Research (BMBF)
- State of Bavaria
- [DK062431]
- [DK062422]
- [DK062420]
- [DK062432]
- [DK062423]
- [DK062413]
- [DK076984]
- [DK084554]
- [DK062429]
- [DK062429-S1]
- [CA141743]
- [DK83756]
- [AI062773]
- [DK043351]
- [U01 DK062418]
- MRC [G0800759, G1002033, G0800675, G0600329] Funding Source: UKRI
- Chief Scientist Office [CZB/4/540, ETM/75, ETM/137] Funding Source: researchfish
- Crohn's and Colitis UK [M11-1] Funding Source: researchfish
- Medical Research Council [G0800759, G0800675, G0600329, G1002033] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10299, NF-SI-0611-10219] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [18475] Funding Source: researchfish
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Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations(1). Genome-wide association studies and subsequent meta-analyses of these two diseases(2,3) as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy(4), in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases(5). Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
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