Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease
Open accessAbstract
Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10−15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10−15). Our study represents a substantial advance in understanding of the genetics of PSC.
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References 52 · Cited by 357
- Authors
- The UK-PSC Consortium, Ji, S.-G., The International IBD Genetics Consortium, The International PSC Study Group, Juran, B. D., Mucha, S., Folseraas, T., Jostins, L., Melum, E., Kumasaka, N., Atkinson, E. J., Schlicht, E. M., Liu, J. Z., Shah, T., Gutierrez-Achury, J., Boberg, K. M., Bergquist, A., Vermeire, S., Eksteen, B., Durie, P. R., Farkkila, M., Müller, T., Schramm, C., Sterneck, M., Weismüller, T. J., Gotthardt, D. N., Ellinghaus, D., Braun, F., Teufel, A., Laudes, M., Lieb, W., Jacobs, G., Beuers, U., Weersma, R. K., Wijmenga, C., Marschall, H.-U., Milkiewicz, P., Pares, A., Kontula, K., Chazouillères, O., Invernizzi, P., Goode, E., Spiess, K., Moore, C., Sambrook, J., Ouwehand, W. H., Roberts, D. J., Danesh, J., Floreani, A., Gulamhusein, A. F., Eaton, J. E., Schreiber, S., Coltescu, C., Bowlus, C. L., Luketic, V. A., Odin, J. A., Chopra, K. B., Kowdley, K. V., Chalasani, N., Manns, M. P., Srivastava, B., Mells, G., Sandford, R. N., Alexander, G., Gaffney, D. J., Chapman, R. W., Hirschfield, G. M., de Andrade, M., Rushbrook, S. M., Franke, A., Karlsen, T. H., Lazaridis, K. N., & Anderson, C. A.
- Affiliations
- Wellcome Sanger Institute (GB)
- Mayo Clinic (US)
- Oslo University Hospital (NO)
- Karolinska University Hospital (SE)
- University of Calgary (CA)
- University of Helsinki (FI)
- University Medical Center Hamburg-Eppendorf (DE)
- University Hospital Bonn (DE)
- University Hospital Heidelberg (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- University Hospital Regensburg (DE)
- University Hospital Schleswig-Holstein (DE)
- Amsterdam UMC Location University of Amsterdam (NL)
- University Medical Center Groningen (NL)
- Medical University of Warsaw (PL)
- Assistance Publique – Hôpitaux de Paris (FR)
- University of Cambridge (GB)
- NHS Blood and Transplant (GB)
- University of Padua (IT)
- Toronto Western Hospital (CA)
- Virginia Commonwealth University (US)
- University of Pittsburgh (US)
- Swedish Medical Center (US)
- Medizinische Hochschule Hannover (DE)
- University of Toronto (CA)
- Corresponding author
- Lazaridis, Konstantinos N
- Anderson, Carl A
- ORCID
- Ji, Sun-Gou
- Mucha, Sören
- Folseraas, Trine
- Melum, Espen
- Kumasaka, Natsuhiko
- Atkinson, Elizabeth J
- Liu, Jimmy Z
- Boberg, Kirsten M
- Bergquist, Annika
- Eksteen, Bertus
- Müller, Tobias
- Schramm, Christoph
- Sterneck, Martina
- Weismüller, Tobias J
- Gotthardt, Daniel N
- Ellinghaus, David
- Braun, Felix
- Teufel, Andreas
- Lieb, Wolfgang
- Beuers, Ulrich
- Weersma, Rinse K
- Wijmenga, Cisca
- Marschall, Hanns-Ulrich
- Milkiewicz, Piotr
- Pares, Albert
- Kontula, Kimmo
- Chazouillères, Olivier
- Invernizzi, Pietro
- Goode, Elizabeth
- Moore, Carmel
- Ouwehand, Willem H
- Roberts, David J
- Danesh, John
- Floreani, Annarosa
- Gulamhusein, Aliya F
- Eaton, John E
- Schreiber, Stefan
- Bowlus, Christopher L
- Luketic, Velimir A
- Odin, Joseph A
- Kowdley, Kris V
- Chalasani, Naga
- Manns, Michael P
- Mells, George
- Sandford, Richard N
- Alexander, Graeme
- Gaffney, Daniel J
- Chapman, Roger W
- Hirschfield, Gideon M
- Rushbrook, Simon M
- Karlsen, Tom H
- Lazaridis, Konstantinos N
- Anderson, Carl A
- Venue
- Nature Genetics
- Published
- 2016-12-19
- Volume
- 49
- Issue
- 2
- Pages
- 269-273
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5540332
- OpenAlex
- W2563442740
- Semantic Scholar
- c36827ca14d4231ffa1ea21576c07266f8570f53
- Cited by
- 357
- References
- 52
- Citations by year
- 2026: 22 · 2025: 44 · 2024: 79 · 2023: 44 · 2022: 28 · 2021: 28 · 2020: 41 · 2019: 28 · 2018: 24 · 2017: 18
- FWCI
- 16.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by-nc-sa)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by-nc-sa)
- UCL Discovery (University College London) (submittedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Padua Research Archive (University of Padova) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-sa)
- Apollo
- Funders
- Genome Canada
- NHS Blood and Transplant
- Wellcome Trust (098759/Z/12/Z, UK10K, 098051)
- National Institute for Health and Care Research (NF-SI-0512-10165, NF-SI-0510-10214, RP-PG-0310-1002, RP-PG-0310-1004, NF-SI-0513-10151)
- British Heart Foundation (G0800270, SP/09/002, RG/08/014/24067, RG/09/012/28096)
- Deutsche Forschungsgemeinschaft (01ZX1306A, SFB 841, 01EY1103)
- Bundesministerium für Bildung und Forschung (01ZX1306A, 01EY1103)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Kwanjeong Educational Foundation
- Ministerio de Ciencia e Innovación
- Exzellenzclusters Entzündungsforschung
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
- Center for Individualized Medicine, Mayo Clinic
- NIHR BioResource
- Canadian Institutes of Health Research
- Medical Research Council (MR/L003120/1, 098051, G0800270, MC_PC_15018)
- Instituto de Salud Carlos III
- Helse Sør-Øst RHF (2015024)
- NIHR Cambridge Biomedical Research Centre
- National Institute on Aging (RC2AG036495, RC4AG039029, U01AG009740)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK084960)
- 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, inflammatory bowel disease, ulcerative colitis, Crohn's disease, genetic susceptibility loci, UBASH3A, genetic correlation, bile duct diseases
- MeSH terms
- Alleles, Colitis, Ulcerative, Humans, Risk Factors, RNA, Messenger, Cholangitis, Sclerosing, Inflammatory Bowel Diseases, Polymorphism, Single Nucleotide, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study
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