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Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
journal contribution
posted on 2019-10-22, 11:53 authored by L Jostins, S Ripke, RK Weersma, RH Duerr, DP McGovern, KY Hui, JC Lee, LP Schumm, Y Sharma, CA Anderson, J Essers, M Mitrovic, K Ning, I Cleynen, E Theatre, SL Spain, S Raychaudhuri, P Goyette, Z Wei, C Abraham, J-P Achkar, T Ahmad, L Amininejad, AN Ananthakrishnan, V Andersen, JM Andrews, L Baidoo, T Balschun, PA Bampton, A Bitton, G Boucher, S Brand, C Büning, A Cohain, S Cichon, M D'Amato, D De Jong, KL Devaney, M Dubinsky, C Edwards, D Ellinghaus, LR Ferguson, D Franchimont, K Fransen, R Gearry, M Georges, C Gieger, J Glas, T Haritunians, A Hart, C Hawkey, M Hedl, X Hu, TH Karlsen, L Kupcinskas, S Kugathasan, A Latiano, D Laukens, IC Lawrance, CW Lees, E Louis, G Mahy, J Mansfield, AR Morgan, C Mowat, W Newman, O Palmieri, CY Ponsioen, U Potocnik, NJ Prescott, M Regueiro, JI Rotter, RK Russell, JD Sanderson, M Sans, J Satsangi, S Schreiber, LA Simms, J Sventoraityte, SR Targan, KD Taylor, M Tremelling, HW Verspaget, M De Vos, C Wijmenga, DC Wilson, J Winkelmann, RJ Xavier, S Zeissig, B Zhang, CK Zhang, H Zhao, International IBD Genetics Consortium (IIBDGC), MS Silverberg, V Annese, H Hakonarson, SR Brant, G Radford-Smith, CG Mathew, JD Rioux, EE Schadt, MJ Daly, A Franke, M Parkes, S Vermeire, JC Barrett, JH ChoCrohn'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.
Funding
We thank all the subjects who contributed samples and the physicians and nursing staff who helped with recruitment globally. UK case collections were supported by the National Association for Colitis and Crohn’s disease; Wellcome Trust grant 098051 (L.J., C.A.A., J.C.B.); Medical Research Council UK; the Catherine McEwan Foundation; an NHS Research Scotland career fellowship (R.K.R.); Peninsula College of Medicine and Dentistry, Exeter; the National Institute for Health Research, through the Comprehensive Local Research Network, and through Biomedical Research Centre awards to Guy’s & Saint Thomas’ National Health Service Trust, King’s College London, Addenbrooke’s Hospital, University of Cambridge School of Clinical Medicine and to the University of Manchester and Central Manchester Foundation Trust. The British 1958 Birth Cohort DNA collection was funded by Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02, and the UK National Blood Service controls by the Wellcome Trust. The Wellcome Trust Case Control Consortium projects were supported by Wellcome Trust grants 083948/Z/07/Z, 085475/B/08/Z and 085475/Z/08/Z. North American collections and data processing were supported by funds to the National Institute of Diabetes, Digestive and Kidney diseases (NIDDK) IBD Genetics Consortium, which is funded by the following grants: DK062431 (S.R.B.), DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 (J.D.R.), DK062423 (M.S.S.), DK062413 (D.P.M.), DK076984 (M.J.D.), DK084554 (M.J.D. and D.P.M.) and DK062429 (J.H.C.). Additional funds were provided by funding to J.H.C. (DK062429-S1 and Crohn’s & Colitis Foundation of America, Senior Investigator Award (5-2229)) and R.H.D. (CA141743). K.Y.H. is supported by the National Institutes of Health (NIH) MSTP TG T32GM07205 training award. Cedars-Sinai is supported by USPHS grant PO1DK046763 and the Cedars-Sinai F. Widjaja Inflammatory Bowel and Immunobiology Research Institute Research Funds, Nationa
History
Citation
Nature, 2012, 491 (7422), pp. 119-124Author affiliation
/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Health SciencesVersion
- AM (Accepted Manuscript)
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NaturePublisher
Nature Research (part of Springer Nature)eissn
1476-4687Acceptance date
2012-09-12Copyright date
2012Available date
2019-10-22Publisher DOI
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https://www.nature.com/articles/nature11582Notes
Refer to Web version on PubMed Central for supplementary material.Language
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Colitis, UlcerativeCrohn DiseaseGenetic Predisposition to DiseaseGenome, HumanGenome-Wide Association StudyHaplotypesHost-Pathogen InteractionsHumansInflammatory Bowel DiseasesMycobacteriumMycobacterium InfectionsMycobacterium tuberculosisPhenotypePolymorphism, Single NucleotideReproducibility of Results
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