Cited by 392Liver Diseases and ImmunityGenetic Associations and EpidemiologyInflammatory Bowel Disease

Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

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The UK-PSCSC Consortium, Liu, Jimmy Z, The International IBD Genetics Consortium, The International PSC Study Group, Hov, Johannes Roksund, Folseraas, Trine, Ellinghaus, Eva, Rushbrook, Simon M +79 more·2013·Nature Genetics

Abstract

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
Venue
Nature Genetics
Published
2013-04-21
Volume
45
Issue
6
Pages
670-675
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W2130462669
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
Locations
  • Nature Genetics (publishedVersion)
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  • Apollo
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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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