TY - JOUR
T1 - Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease
AU - Australia and New Zealand IBDGC
AU - Belgium Genetic Consortium
AU - Initiative on Crohn and Colitis
AU - NIDDK IBDGC
AU - United Kingdom IBDGC
AU - Wellcome Trust Case Control Consortium
AU - The International IBD Genetics Consortium (IIBDGC)
AU - for The International IBD Genetics Consortium (IIBDGC)
AU - Jostins, Luke
AU - Ripke, Stephan
AU - Weersma, Rinse K.
AU - Duerr, Richard H.
AU - McGovern, Dermot P.
AU - Hui, Ken Y.
AU - Lee, James C.
AU - Philip Schumm, L.
AU - Sharma, Yashoda
AU - Anderson, Carl A.
AU - Essers, Jonah
AU - Mitrovic, Mitja
AU - Ning, Kaida
AU - Cleynen, Isabelle
AU - Theatre, Emilie
AU - Spain, Sarah L.
AU - Raychaudhuri, Soumya
AU - Goyette, Philippe
AU - Wei, Zhi
AU - Abraham, Clara
AU - Achkar, Jean Paul
AU - Ahmad, Tariq
AU - Amininejad, Leila
AU - Ananthakrishnan, Ashwin N.
AU - Andersen, Vibeke
AU - Andrews, Jane M.
AU - Baidoo, Leonard
AU - Balschun, Tobias
AU - Bampton, Peter A.
AU - Bitton, Alain
AU - Boucher, Gabrielle
AU - Brand, Stephan
AU - Büning, Carsten
AU - Cohain, Ariella
AU - Cichon, Sven
AU - D'Amato, Mauro
AU - De Jong, Dirk
AU - Devaney, Kathy L.
AU - Dubinsky, Marla
AU - Edwards, Cathryn
AU - Ellinghaus, David
AU - Ferguson, Lynnette R.
AU - Franchimont, Denis
AU - Fransen, Karin
AU - Gearry, Richard
AU - Georges, Michel
AU - Gieger, Christian
AU - Glas, Jürgen
AU - Haritunians, Talin
AU - Hart, Ailsa
PY - 2012/11/1
Y1 - 2012/11/1
N2 - 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. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. 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.
AB - 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. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. 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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U2 - 10.1038/nature11582
DO - 10.1038/nature11582
M3 - Article
C2 - 23128233
AN - SCOPUS:84868336049
SN - 0028-0836
VL - 491
SP - 119
EP - 124
JO - Nature
JF - Nature
IS - 7422
ER -