The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease
Open accessAbstract
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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“Population-based, genome-wide–association studies followed by subsequent meta-analysis of population-based, genome-wide–association studies and immunochip data have identified more than 160 loci linked to IBD susceptibility (Jostins et al., 2012).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Jostins et al., 2012
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“Examples include the role of complement in the pathogenesis of acute macular degeneration38, synaptic pruning in schizophrenia64 and autophagy in inflammatory bowel disease65.”
From A brief history of human disease genetics (2020) · cites this paper as [65]
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“The 71 regulators significantly overlap with genes genetically associated with inflammatory bowel disease44 (11 of 71, p<10-9).”
From Dynamic regulatory network controlling TH17 cell differentiation (2013) · cites this paper as [44]
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Self-citation
Metadata
- Authors
- The International IBD Genetics Consortium (IIBDGC), Jostins, L., Ripke, S., Weersma, R. K., Duerr, R. H., McGovern, D. P., Hui, K. Y., Lee, J. C., Philip Schumm, L., Sharma, Y., Anderson, C. A., Essers, J., Mitrovic, M., Ning, K., Cleynen, I., Theatre, E., Spain, S. L., Raychaudhuri, S., Goyette, P., Wei, Z., Abraham, C., Achkar, J.-P., Ahmad, T., Amininejad, L., Ananthakrishnan, A. N., Andersen, V., Andrews, J. M., Baidoo, L., Balschun, T., Bampton, P. A., Bitton, A., Boucher, G., Brand, S., Büning, C., Cohain, A., Cichon, S., D’Amato, M., De Jong, D., Devaney, K. L., Dubinsky, M., Edwards, C., Ellinghaus, D., Ferguson, L. R., Franchimont, D., Fransen, K., Gearry, R., Georges, M., Gieger, C., Glas, J., Haritunians, T., Hart, A., Hawkey, C., Hedl, M., Hu, X., Karlsen, T. H., Kupcinskas, L., Kugathasan, S., Latiano, A., Laukens, D., Lawrance, I. C., Lees, C. W., Louis, E., Mahy, G., Mansfield, J., Morgan, A. R., Mowat, C., Newman, W., Palmieri, O., Ponsioen, C. Y., Potocnik, U., Prescott, N. J., Regueiro, M., Rotter, J. I., Russell, R. K., Sanderson, J. D., Sans, M., Satsangi, J., Schreiber, S., Simms, L. A., Sventoraityte, J., Targan, S. R., Taylor, K. D., Tremelling, M., Verspaget, H. W., De Vos, M., Wijmenga, C., Wilson, D. C., Winkelmann, J., Xavier, R. J., Zeissig, S., Zhang, B., Zhang, C. K., Zhao, H., Silverberg, M. S., Annese, V., Hakonarson, H., Brant, S. R., Radford-Smith, G., Mathew, C. G., Rioux, J. D., Schadt, E. E., Daly, M. J., Franke, A., Parkes, M., Vermeire, S., Barrett, J. C., & Cho, J. H.
- Affiliations
- Wellcome Sanger Institute (GB)
- Broad Institute (US)
- University Medical Center Groningen (NL)
- University of Pittsburgh (US)
- Cedars-Sinai Medical Center (US)
- Yale University (US)
- University of Cambridge (GB)
- Harvard University (US)
- KU Leuven (BE)
- Guy's Hospital (GB)
- Montreal Heart Institute (CA)
- New Jersey Institute of Technology (US)
- Cleveland Clinic (US)
- Peninsula College of Medicine and Dentistry (GB)
- Université Libre de Bruxelles (BE)
- Regionshospitalet Viborg (DK)
- Royal Adelaide Hospital (AU)
- Christian-Albrechts-Universität zu Kiel (DE)
- Flinders University (AU)
- McGill University Health Centre (CA)
- Ludwig-Maximilians-Universität München (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Icahn School of Medicine at Mount Sinai (US)
- University Hospital Bonn (DE)
- Karolinska Institutet (SE)
- Torbay Hospital (GB)
- University of Auckland (NZ)
- Christchurch Hospital (NZ)
- University of Liège (BE)
- Helmholtz Munich (DE)
- St Mark's Hospital (GB)
- Queen's Medical Centre (GB)
- Brigham and Women's Hospital (US)
- Oslo University Hospital (NO)
- Emory University (US)
- Casa Sollievo della Sofferenza (IT)
- Ghent University Hospital (BE)
- The University of Western Australia (AU)
- Western General Hospital (GB)
- Townsville Hospital (AU)
- Newcastle University (GB)
- Ninewells Hospital (GB)
- Manchester Academic Health Science Centre (GB)
- Amsterdam UMC Location University of Amsterdam (NL)
- Royal Hospital for Children (GB)
- St Thomas' Hospital (GB)
- Hospital Clínic de Barcelona (ES)
- QIMR Berghofer Medical Research Institute (AU)
- F. Widjaja Inflammatory Bowel Disease Institute (US)
- Norfolk and Norwich University Hospital (GB)
- Leiden University Medical Center (NL)
- Institut für Humangenetik (DE)
- Mount Sinai Hospital (CA)
- Children's Hospital of Philadelphia (US)
- Johns Hopkins University (US)
- Corresponding author
- Cho, Judy H
- ORCID
- Ripke, Stephan
- Weersma, Rinse K.
- Duerr, Richard H.
- McGovern, Dermot P.
- Hui, Ken Y.
- Lee, James C.
- Sharma, Yashoda
- Anderson, Carl A.
- Ning, Kaida
- Cleynen, Isabelle
- Spain, Sarah L.
- Raychaudhuri, Soumya
- Wei, Zhi
- Abraham, Clara
- Achkar, Jean-Paul
- Ahmad, Tariq
- Amininejad, Leila
- Ananthakrishnan, Ashwin N.
- Andersen, Vibeke
- Andrews, Jane M.
- Baidoo, Leonard
- Bampton, Peter A.
- Bitton, Alain
- Boucher, Gabrielle
- Brand, Stephan
- Cohain, Ariella
- Cichon, Sven
- D’Amato, Mauro
- Dubinsky, Marla
- Edwards, Cathryn
- Ellinghaus, David
- Ferguson, Lynnette R.
- Franchimont, Denis
- Gearry, Richard
- Georges, Michel
- Gieger, Christian
- Haritunians, Talin
- Hart, Ailsa
- Hu, Xinli
- Karlsen, Tom H.
- Kugathasan, Subra
- Latiano, Anna
- Laukens, Debby
- Lees, Charlie W.
- Louis, Edouard
- Mansfield, John
- Mowat, Craig
- Newman, William
- Palmieri, Orazio
- Ponsioen, Cyriel Y.
- Prescott, Natalie J.
- Regueiro, Miguel
- Rotter, Jerome I.
- Russell, Richard K.
- Sanderson, Jeremy D.
- Sans, Miquel
- Schreiber, Stefan
- Simms, Lisa A.
- Targan, Stephan R.
- Taylor, Kent D.
- Verspaget, Hein W.
- Wijmenga, Cisca
- Winkelmann, Juliane
- Xavier, Ramnik J.
- Zeissig, Sebastian
- Zhang, Bin
- Zhao, Hongyu
- Silverberg, Mark S.
- Annese, Vito
- Hakonarson, Hakon
- Brant, Steven R.
- Mathew, Christopher G.
- Rioux, John D.
- Schadt, Eric E.
- Daly, Mark J.
- Parkes, Miles
- Barrett, Jeffrey C.
- Cho, Judy H
- Venue
- Nature
- Published
- 2012-10-31
- Volume
- 491
- Issue
- 7422
- Pages
- 119-124
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3491803
- OpenAlex
- W2143625465
- Cited by
- 4,722
- References
- 30
- Citations by year
- 2026: 169 · 2025: 221 · 2024: 303 · 2023: 296 · 2022: 314 · 2021: 345 · 2020: 360 · 2019: 384 · 2018: 374 · 2017: 404 · 2016: 444 · 2015: 422 · 2014: 424 · 2013: 247 · 2012: 13
- FWCI
- 43.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
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- Funders
- Crohn's and Colitis Foundation of America (DK062422)
- Leona M. and Harry B. Helmsley Charitable Trust
- Wellcome Trust (085475/Z/08/Z, 068545/Z/02), 085475, G0000934, 083948/Z/07/Z, 068545, 089120, 090532, 085475/B/08/Z, 098051)
- Crohn's and Colitis Foundation
- Cedars-Sinai Medical Center
- National Institute for Health and Care Research (NF-SI-0508-10299, NF-SI-0611-10219)
- British Heart Foundation (G0000934)
- Diabetes UK
- King's College London
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Fonds De La Recherche Scientifique - FNRS
- Fonds Wetenschappelijk Onderzoek
- Ministero della Salute
- Örebro Universitet
- Crohn's and Colitis UK (M11-1)
- Karolinska Institutet
- Universitetssjukhuset Örebro
- Svenska Läkaresällskapet
- Exzellenzclusters Entzündungsforschung
- Versus Arthritis (18475)
- National Institutes of Health (G0000934, UL1TR000124, UL1TR000005, 068545/Z/02, M01-RR00425, DK062429, TR000124, RR00425, DK-063491, DK 043351, PO1DK046763)
- U.S. Public Health Service (UL1 TR000124, DK062413, PO1DK046763)
- Inflammatory Bowel and Immunobiology Research Institute
- Medical Research Council (098051, 068545/Z/02, G0000934)
- National Health and Medical Research Council (G0000934)
- Helmholtz Zentrum München
- Münchner Zentrum für Gesundheitswissenschaften
- National Human Genome Research Institute (DK062429, DK062422)
- National Cancer Institute (CA141743, R01CA141743)
- National Institute of General Medical Sciences (T32-GM07205, T32GM007205)
- National Institute of Allergy and Infectious Diseases (AI 062773, R01AI062773)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK076984, DK063491, DK-06-2423, (DK043351, R01DK083756, P01DK046763, DK062429, DK062413, DK062420, R01DK055731, R21DK084554, R03DK076984, DK062429-S1, DK062418, DK 83756, DK062431, DK062422, K23DK097142, DK062432, U01DK062418, DK084554, U01DK062420, M01-RR00425, U01DK062429, U24DK062429, U01DK062413, U01DK062422, P30DK063491, U01DK062432, P30DK043351, U01DK062431, U01DK062423)
- National Institute of Child Health and Human Development
- National Center for Research Resources (M01RR000425, M01-RR00425)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- inflammatory bowel disease, Crohn's disease, ulcerative colitis, host-microbe interactions, mycobacterial infection, immune-mediated diseases, ankylosing spondylitis, psoriasis, genetic susceptibility loci, balancing selection, directional selection, gene co-expression network
- MeSH terms
- Colitis, Ulcerative, Crohn Disease, Haplotypes, Humans, Mycobacterium, Mycobacterium Infections, Mycobacterium tuberculosis, Phenotype, Reproducibility of Results, Inflammatory Bowel Diseases, Genome, Human, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Host-Pathogen Interactions, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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