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  • 1
    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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  • 2
    Publication Date: 2018-01-11
    Description: Crohn’s disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene that conferred risk for CD (N2081D variant, P = 9.5 x 10 –10 ) or protection from CD (N551K variant, tagging R1398H-associated haplotype, P = 3.3 x 10 –8 ). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson’s disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases.
    Print ISSN: 1946-6234
    Electronic ISSN: 1946-6242
    Topics: Medicine
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