Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis
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Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.
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- Authors
- The UK-PSCSC Consortium, Liu, J. Z., The International IBD Genetics Consortium, The International PSC Study Group, Hov, J. R., Folseraas, T., Ellinghaus, E., Rushbrook, S. M., Doncheva, N. T., Andreassen, O. A., Weersma, R. K., Weismüller, T. J., Eksteen, B., Invernizzi, P., Hirschfield, G. M., Gotthardt, D. N., Pares, A., Ellinghaus, D., Shah, T., Juran, B. D., Milkiewicz, P., Rust, C., Schramm, C., Müller, T., Srivastava, B., Dalekos, G., Nöthen, M. M., Herms, S., Winkelmann, J., Mitrovic, M., Braun, F., Ponsioen, C. Y., Croucher, P. J. P., Sterneck, M., Teufel, A., Mason, A. L., Saarela, J., Leppa, V., Dorfman, R., Alvaro, D., Floreani, A., Onengut-Gumuscu, S., Rich, S. S., Thompson, W. K., Schork, A. J., Næss, S., Thomsen, I., Mayr, G., König, I. R., Hveem, K., Cleynen, I., Gutierrez-Achury, J., Ricaño-Ponce, I., van Heel, D., Björnsson, E., Sandford, R. N., Durie, P. R., Melum, E., Vatn, M. H., Silverberg, M. S., Duerr, R. H., Padyukov, L., Brand, S., Sans, M., Annese, V., Achkar, J.-P., Boberg, K. M., Marschall, H.-U., Chazouillères, O., Bowlus, C. L., Wijmenga, C., Schrumpf, E., Vermeire, S., Albrecht, M., Rioux, J. D., Alexander, G., Bergquist, A., Cho, J., Schreiber, S., Manns, M. P., Färkkilä, M., Dale, A. M., Chapman, R. W., Lazaridis, K. N., Franke, A., Anderson, C. A., & Karlsen, T. H.
- Affiliations
- Wellcome Sanger Institute (GB)
- Oslo University Hospital (NO)
- National Health Service (GB)
- University of Oslo (NO)
- University Medical Center Groningen (NL)
- University of Calgary (CA)
- Humanitas University (IT)
- University of Toronto (CA)
- University Hospital Heidelberg (DE)
- Mayo Clinic (US)
- Pomeranian Medical University (PL)
- University Medical Center Hamburg-Eppendorf (DE)
- Medizinische Hochschule Hannover (DE)
- University of Cambridge (GB)
- University of Thessaly (GR)
- University of Bonn (DE)
- Amsterdam UMC Location University of Amsterdam (NL)
- Johannes Gutenberg University Mainz (DE)
- University of Alberta (CA)
- University of Helsinki (FI)
- Hospital for Sick Children (CA)
- University of Padua (IT)
- University of California San Diego (US)
- Christian-Albrechts-Universität zu Kiel (DE)
- Norwegian University of Science and Technology (NO)
- Mount Sinai Hospital (CA)
- Karolinska University Hospital (SE)
- Hospital Quirón Teknon (ES)
- Casa Sollievo della Sofferenza (IT)
- Cleveland Clinic (US)
- Sahlgrenska University Hospital (SE)
- Assistance Publique – Hôpitaux de Paris (FR)
- Universitätsmedizin Greifswald (DE)
- Helsinki University Hospital (FI)
- John Radcliffe Hospital (GB)
- Corresponding author
- Anderson, Carl A
- Karlsen, Tom H
- ORCID
- Liu, Jimmy Z
- Hov, Johannes Roksund
- Folseraas, Trine
- Ellinghaus, Eva
- Rushbrook, Simon M
- Doncheva, Nadezhda T
- Andreassen, Ole A
- Weersma, Rinse K
- Weismüller, Tobias J
- Eksteen, Bertus
- Invernizzi, Pietro
- Hirschfield, Gideon M
- Gotthardt, Daniel Nils
- Ellinghaus, David
- Milkiewicz, Piotr
- Schramm, Christoph
- Müller, Tobias
- Nöthen, Markus M
- Herms, Stefan
- Winkelmann, Juliane
- Braun, Felix
- Ponsioen, Cyriel Y
- Croucher, Peter J P
- Sterneck, Martina
- Teufel, Andreas
- Mason, Andrew L
- Saarela, Janna
- Dorfman, Ruslan
- Alvaro, Domenico
- Floreani, Annarosa
- Rich, Stephen S
- Thompson, Wesley K
- Schork, Andrew J
- Thomsen, Ingo
- König, Inke R
- Hveem, Kristian
- Cleynen, Isabelle
- Ricaño-Ponce, Isis
- Sandford, Richard N
- Melum, Espen
- Silverberg, Mark S
- Duerr, Richard H
- Padyukov, Leonid
- Brand, Stephan
- Sans, Miquel
- Annese, Vito
- Achkar, Jean-Paul
- Boberg, Kirsten Muri
- Marschall, Hanns-Ulrich
- Chazouillères, Olivier
- Bowlus, Christopher L
- Wijmenga, Cisca
- Rioux, John D
- Alexander, Graeme
- Bergquist, Annika
- Cho, Judy
- Schreiber, Stefan
- Manns, Michael P
- Färkkilä, Martti
- Dale, Anders M
- Chapman, Roger W
- Lazaridis, Konstantinos N
- Anderson, Carl A
- Karlsen, Tom H
- Venue
- Nature Genetics
- Published
- 2013-04-21
- Volume
- 45
- Issue
- 6
- Pages
- 670-675
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3667736
- OpenAlex
- W2130462669
- Semantic Scholar
- 5d263bd3c0585dca079840c633880f04b00abc48
- Cited by
- 391
- References
- 61
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 23 · 2023: 24 · 2022: 33 · 2021: 28 · 2020: 30 · 2019: 23 · 2018: 23 · 2017: 42 · 2016: 35 · 2015: 40 · 2014: 39 · 2013: 20
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- University of Maribor digital library (University of Maribor) (publishedVersion, other-oa)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- ORBi (University of Liège) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- University of Thessaly Institutional Repository (University of Thessaly) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Lithuanian University of Health Sciences (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Apollo
- WOS
- Funders
- Yale University
- Cleveland Clinic
- Helsingin Yliopisto
- University of Pittsburgh
- Norges Teknisk-Naturvitenskapelige Universitet
- Queen Mary University of London
- Wellcome Trust (FP7/2007–2013, 098051, 091745)
- University of Alberta
- National Institute for Health and Care Research (FP7/2007–2013)
- European Commission (262055)
- Deutsche Forschungsgemeinschaft (FR 2821/2-1, FP7/2007–2013, 01EO0802)
- Rijksuniversiteit Groningen
- Università degli Studi di Padova
- University of Toronto
- KU Leuven
- Karolinska Institutet
- Landspítali Háskólasjúkrahús
- Universität zu Lübeck
- Sapienza Università di Roma
- Université de Montréal
- Universitetet i Oslo
- Medizinischen Hochschule Hannover (01EO0802)
- Technische Universität München
- Universitat de Barcelona
- Hospital for Sick Children
- Rheinische Friedrich-Wilhelms-Universität Bonn
- Pomorski Uniwersytet Medyczny W Szczecinie
- Assistance publique-Hôpitaux de Paris
- University of Thessaly
- Akershus Universitetssykehus
- Institut de Cardiologie de Montréal
- Terveyden ja hyvinvoinnin laitos
- Université de Paris
- National Institutes of Health (UL1TR000005)
- University of California, Davis
- University of California, San Diego
- Graduate School of Public Health, University of Pittsburgh
- Lerner Research Institute, Cleveland Clinic
- Barts and The London School of Medicine and Dentistry
- Sahlgrenska Akademin
- Department of Medicine, University of Toronto
- Universitätsklinikum Hamburg-Eppendorf
- Helmholtz Zentrum München
- National Cancer Institute (R01CA141743)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK062420, U01DK062423)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Keywords
- primary sclerosing cholangitis, genetic susceptibility loci, pleiotropy, inflammatory bowel disease, autoimmune disease comorbidity, HLA complex, genetic architecture, network analysis, bile duct fibrosis
- MeSH terms
- Gene Frequency, Humans, Risk Factors, Cholangitis, Sclerosing, Linkage Disequilibrium, Case-Control Studies, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci, Genetic Pleiotropy, Genotyping Techniques
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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.
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