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Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Lookup NU author(s): Dr John Mansfield


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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.

Publication metadata

Author(s): Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Buning C, Cohain A, Cichon S, D'Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu XL, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao HY, Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD, Schadt EE, Daly MJ, Franke A, Parkes M, Vermeire S, Barrett JC, Cho JH, Int IBD Genetics Consortium IIBDGC

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2012

Volume: 491

Issue: 7422

Pages: 119-124

Print publication date: 31/10/2012

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group


DOI: 10.1038/nature11582


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Funder referenceFunder name
Central Manchester Foundation Trust
Crohn's and Colitis Foundation of America
Else Kroner-Fresenius-Stiftung (Else Kroner-Exzellenzstipendium)
European Community (5th PCRDT)
German Ministry of Education and Research through the National Genome Research Network
Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition
Karolinska Institutet
National Association for Colitis and Crohn's disease
National Health and Medical Research Council, Australia
National Institute for Health Research, through the Comprehensive Local Research Network
National Institute of Diabetes, Digestive and Kidney diseases (NIDDK) IBD Genetics Consortium
Popgen biobank, through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ` Inflammation at Interfaces'
Swedish National Program for IBD Genetics
UK National Blood Service
Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine
Biomedical ResearchCentre
Catherine McEwan Foundation
Cedars-Sinai F. Widjaja Inflammatory Bowel and Immunobiology Research Institute Research Funds
German Federal Ministry of Education and Research (BMBF)
Helmholtz Zentrum Munchen-German Research Center for Environmental Health
Helmsley Foundation
Ihre Foundation
Juvenile Diabetes Research Foundation (JDRF)
King's College London
Medical Research Council UK
National Human Genome Research Institute (NHGRI)
National Institute of Child Health and Human Development (NICHD)
NHS Research Scotland career fellowship
NIDDK, National Institute of Allergy and Infectious Diseases (NIAID)
Orebro University Hospital Research Foundation
Peninsula College of Medicine and Dentistry, Exeter
Royal Brisbane and Women's Hospital Foundation
Saint Thomas' NationalHealth Service Trust
State of Bavaria
Swedish Medical Research Council
Swedish Organization for IBD
Swedish Society of Medicine
University of Manchester
068545/Z/02Wellcome Trust grant
085475/Z/08/ZWellcome Trust
098051Wellcome Trust
083948/Z/07/ZWellcome Trust
085475/B/08/ZWellcome Trust
918.66.620Netherlands Organization for Scientific Research
90.700.281Netherlands Organization for Scientific Research
BR 1912/6-1DFG
BSIK03009Celiac Disease Consortium
DK063491Southern California Diabetes and Endocrinology Research Grant (DERC)
FR 2821/2-1DFG
G0000934Medical Research Council
GR-2008-1144485Italian Ministry of Health
M01-RR00425National Center for Research Resources (NCRR)
MSTP TG T32GM07205National Institutes of Health (NIH)
U01 DK062418
UL1 TR000124-01UCLA/Cedars-Sinai/Harbor/Drew Clinical and Translational Science Institute (CTSI)