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Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease
Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England..
Harvard Univ, Massachusetts Gen Hosp, Sch Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA.;Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
Univ Groningen, Dept Gastroenterol & Hepatol, NL-9700 RB Groningen, Netherlands..
Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15261 USA.;Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA..ORCID iD: 0000-0001-6586-3905
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2012 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 491, no 7422, 119-124 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2012. Vol. 491, no 7422, 119-124 p.
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Medical Genetics Rheumatology and Autoimmunity
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URN: urn:nbn:se:oru:diva-58704DOI: 10.1038/nature11582ISI: 000310434500042PubMedID: 23128233OAI: oai:DiVA.org:oru-58704DiVA: diva2:1127727
Available from: 2017-07-18 Created: 2017-07-18 Last updated: 2017-07-18

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Duerr, Richard H.Lee, James C.Anderson, Carl A.Spain, Sarah L.Andersen, VibekeCichon, SvenD'Amato, MauroGearry, RichardGieger, ChristianLatiano, AnnaLaukens, DebbyNewman, WilliamPalmieri, OrazioPotocnik, UrosPrescott, Natalie J.Schreiber, StefanWijmenga, CiscaWinkelmann, JulianeMathew, Christopher G.Rioux, John D.Franke, AndreVermeire, SeverineBarrett, Jeffrey C.Halfvarson, Jonas
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