Publication Date:
2012-11-07
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491803/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491803/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jostins, Luke -- Ripke, Stephan -- Weersma, Rinse K -- Duerr, Richard H -- McGovern, Dermot P -- Hui, Ken Y -- Lee, James C -- Schumm, L Philip -- Sharma, Yashoda -- Anderson, Carl A -- Essers, Jonah -- Mitrovic, Mitja -- Ning, Kaida -- Cleynen, Isabelle -- Theatre, Emilie -- Spain, Sarah L -- Raychaudhuri, Soumya -- Goyette, Philippe -- Wei, Zhi -- Abraham, Clara -- Achkar, Jean-Paul -- Ahmad, Tariq -- Amininejad, Leila -- Ananthakrishnan, Ashwin N -- Andersen, Vibeke -- Andrews, Jane M -- Baidoo, Leonard -- Balschun, Tobias -- Bampton, Peter A -- Bitton, Alain -- Boucher, Gabrielle -- Brand, Stephan -- Buning, Carsten -- Cohain, Ariella -- Cichon, Sven -- D'Amato, Mauro -- De Jong, Dirk -- Devaney, Kathy L -- Dubinsky, Marla -- Edwards, Cathryn -- Ellinghaus, David -- Ferguson, Lynnette R -- Franchimont, Denis -- Fransen, Karin -- Gearry, Richard -- Georges, Michel -- Gieger, Christian -- Glas, Jurgen -- Haritunians, Talin -- Hart, Ailsa -- Hawkey, Chris -- Hedl, Matija -- Hu, Xinli -- Karlsen, Tom H -- Kupcinskas, Limas -- Kugathasan, Subra -- Latiano, Anna -- Laukens, Debby -- Lawrance, Ian C -- Lees, Charlie W -- Louis, Edouard -- Mahy, Gillian -- Mansfield, John -- Morgan, Angharad R -- Mowat, Craig -- Newman, William -- Palmieri, Orazio -- Ponsioen, Cyriel Y -- Potocnik, Uros -- Prescott, Natalie J -- Regueiro, Miguel -- Rotter, Jerome I -- Russell, Richard K -- Sanderson, Jeremy D -- Sans, Miquel -- Satsangi, Jack -- Schreiber, Stefan -- Simms, Lisa A -- Sventoraityte, Jurgita -- Targan, Stephan R -- Taylor, Kent D -- Tremelling, Mark -- Verspaget, Hein W -- De Vos, Martine -- Wijmenga, Cisca -- Wilson, David C -- Winkelmann, Juliane -- Xavier, Ramnik J -- Zeissig, Sebastian -- Zhang, Bin -- Zhang, Clarence K -- Zhao, Hongyu -- International IBD Genetics Consortium (IIBDGC) -- Silverberg, Mark S -- Annese, Vito -- Hakonarson, Hakon -- Brant, Steven R -- Radford-Smith, Graham -- Mathew, Christopher G -- Rioux, John D -- Schadt, Eric E -- Daly, Mark J -- Franke, Andre -- Parkes, Miles -- Vermeire, Severine -- Barrett, Jeffrey C -- Cho, Judy H -- 068545/Z/02/Wellcome Trust/United Kingdom -- 083948/Z/07/Z/Wellcome Trust/United Kingdom -- 085475/B/08/Z/Wellcome Trust/United Kingdom -- 085475/Z/08/Z/Wellcome Trust/United Kingdom -- 089120/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- AI062773/AI/NIAID NIH HHS/ -- CA141743/CA/NCI NIH HHS/ -- CZB/4/540/Chief Scientist Office/United Kingdom -- DK043351/DK/NIDDK NIH HHS/ -- DK062413/DK/NIDDK NIH HHS/ -- DK062420/DK/NIDDK NIH HHS/ -- DK062422/DK/NIDDK NIH HHS/ -- DK062423/DK/NIDDK NIH HHS/ -- DK062429/DK/NIDDK NIH HHS/ -- DK062429-S1/DK/NIDDK NIH HHS/ -- DK062431/DK/NIDDK NIH HHS/ -- DK062432/DK/NIDDK NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK076984/DK/NIDDK NIH HHS/ -- DK084554/DK/NIDDK NIH HHS/ -- DK83756/DK/NIDDK NIH HHS/ -- ETM/137/Chief Scientist Office/United Kingdom -- ETM/75/Chief Scientist Office/United Kingdom -- G0000934/British Heart Foundation/United Kingdom -- G0600329/Medical Research Council/United Kingdom -- G0800675/Medical Research Council/United Kingdom -- G0800759/Medical Research Council/United Kingdom -- G1002033/Medical Research Council/United Kingdom -- K23 DK097142/DK/NIDDK NIH HHS/ -- M01-RR00425/RR/NCRR NIH HHS/ -- P01 DK046763/DK/NIDDK NIH HHS/ -- P01DK046763/DK/NIDDK NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 CA141743/CA/NCI NIH HHS/ -- R01 DK055731/DK/NIDDK NIH HHS/ -- T32 GM007205/GM/NIGMS NIH HHS/ -- T32GM07205/GM/NIGMS NIH HHS/ -- U01 DK062418/DK/NIDDK NIH HHS/ -- U01 DK062420/DK/NIDDK NIH HHS/ -- U01 DK062422/DK/NIDDK NIH HHS/ -- U01 DK062429/DK/NIDDK NIH HHS/ -- U01 DK062431/DK/NIDDK NIH HHS/ -- U01 DK062432/DK/NIDDK NIH HHS/ -- UL1 TR000005/TR/NCATS NIH HHS/ -- UL1 TR000124/TR/NCATS NIH HHS/ -- UL1 TR000124-01/TR/NCATS NIH HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2012 Nov 1;491(7422):119-24. doi: 10.1038/nature11582.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23128233" target="_blank"〉PubMed〈/a〉
Keywords:
Colitis, Ulcerative/genetics/immunology/microbiology/physiopathology
;
Crohn Disease/genetics/immunology/microbiology/physiopathology
;
Genetic Predisposition to Disease/*genetics
;
Genome, Human/genetics
;
*Genome-Wide Association Study
;
Haplotypes/genetics
;
*Host-Pathogen Interactions/genetics/immunology
;
Humans
;
Inflammatory Bowel Diseases/*genetics/immunology/*microbiology/physiopathology
;
Mycobacterium/*immunology/pathogenicity
;
Mycobacterium Infections/genetics/microbiology
;
Mycobacterium tuberculosis/immunology/pathogenicity
;
Phenotype
;
Polymorphism, Single Nucleotide/genetics
;
Reproducibility of Results
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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