title: Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.
abstract: 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.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Sun-Gou
authors.identifier: http://orcid.org/0000-0001-8652-6318
authors.initials: SG
authors.lastname: Ji
authors.affiliation: Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Juran
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Mucha
authors.affiliation: Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Trine
authors.initials: T
authors.lastname: Folseraas
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Christ Church, University of Oxford, St Aldates, Oxford, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Jostins
authors.affiliation: Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Espen
authors.initials: E
authors.lastname: Melum
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Natsuhiko
authors.initials: N
authors.lastname: Kumasaka
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Atkinson
authors.affiliation: Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Erik M
authors.initials: EM
authors.lastname: Schlicht
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Jimmy Z
authors.initials: JZ
authors.lastname: Liu
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Tejas
authors.initials: T
authors.lastname: Shah
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Javier
authors.initials: J
authors.lastname: Gutierrez-Achury
authors.affiliation: Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Boberg
authors.affiliation: Department of Gastroenterology and Hepatology, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Bergquist
authors.affiliation: Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.|Department of Gastroenterology, University Hospital Leuven, Leuven, Belgium.
authors.forename: Severine
authors.initials: S
authors.lastname: Vermeire
authors.affiliation: Snyder Institute for Chronic Diseases, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Bertus
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authors.affiliation: Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Peter R
authors.initials: PR
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authors.affiliation: Helsinki University and Helsinki University Hospital, Clinic of Gastroenterology, Helsinki, Finland.
authors.forename: Martti
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authors.affiliation: Department of Internal Medicine, Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Tobias
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authors.lastname: Müller
authors.affiliation: 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christoph
authors.initials: C
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authors.affiliation: Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Sterneck
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.|Integrated Research and Treatment Center-Transplantation (IFB-tx), Hannover Medical School, Hannover, Germany.|Department of Internal Medicine 1, University Hospital of Bonn, Bonn, Germany.
authors.forename: Tobias J
authors.initials: TJ
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authors.affiliation: Department of Medicine, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Gotthardt
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Ellinghaus
authors.affiliation: Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Braun
authors.affiliation: Department of Medicine I, University Medical Center, Regensburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Teufel
authors.affiliation: Clinic of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Mattias
authors.initials: M
authors.lastname: Laudes
authors.affiliation: Institute of Epidemiology and Biobank PopGen, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: Institute of Epidemiology and Biobank PopGen, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Jacobs
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.affiliation: Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Milkiewicz
authors.affiliation: Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.
authors.forename: Albert
authors.identifier: http://orcid.org/0000-0002-5413-9687
authors.initials: A
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authors.affiliation: Department of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Kimmo
authors.initials: K
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authors.affiliation: AP-HP Hôpital Saint Antoine, Department of Hepatology, UPMC University Paris 6, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Chazouillères
authors.affiliation: Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.affiliation: Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Goode
authors.affiliation: Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
authors.forename: Kelly
authors.initials: K
authors.lastname: Spiess
authors.affiliation: NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Carmel
authors.initials: C
authors.lastname: Moore
authors.affiliation: INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Department of Hematology, University of Cambridge, Cambridge, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sambrook
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.|NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Department of Hematology, University of Cambridge, Cambridge, UK.|NHS Blood and Transplant, Cambridge, UK.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|NHS Blood and Transplant-Oxford Centre, John Radcliffe Hospital, Oxford, UK.|Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Roberts
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.|NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: John
authors.initials: J
authors.lastname: Danesh
authors.affiliation: Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy.
authors.forename: Annarosa
authors.initials: A
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authors.affiliation: Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Aliya F
authors.initials: AF
authors.lastname: Gulamhusein
authors.affiliation: Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Eaton
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.|Department for General Internal Medicine, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
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authors.affiliation: Liver Centre, Toronto Western Hospital, Toronto, Ontario, Canada.
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authors.initials: C
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authors.affiliation: Division of Gastroenterology and Hepatology, University of California at Davis, Davis, California, USA.
authors.forename: Christopher L
authors.initials: CL
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authors.affiliation: Gastroenterology and Hepatology Section, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Velimir A
authors.initials: VA
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authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
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authors.initials: JA
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authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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authors.initials: KB
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authors.affiliation: Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, Washington, USA.
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authors.initials: KV
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authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Naga
authors.initials: N
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authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.|Integrated Research and Treatment Center-Transplantation (IFB-tx), Hannover Medical School, Hannover, Germany.
authors.forename: Michael P
authors.initials: MP
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authors.affiliation: Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
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authors.initials: B
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authors.affiliation: Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.|Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK.
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authors.affiliation: Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
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authors.affiliation: Department of Medicine, Division of Hepatology, University of Cambridge, Cambridge, UK.
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authors.lastname: Alexander
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
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authors.initials: DJ
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authors.affiliation: Department of Translational Gastroenterology, Oxford University Hospitals NHS Trust, Oxford, UK.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Chapman
authors.affiliation: Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK.|University of Toronto and Liver Center, Toronto Western Hospital, Toronto, Ontario, Canada.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.affiliation: Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Rushbrook
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Konstantinos N
authors.initials: KN
authors.lastname: Lazaridis
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Anderson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000483:Alleles; D015209:Cholangitis, Sclerosing / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D012333:RNA, Messenger; C423262:UBASH3A protein, human