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Nat Genet. 2017 Feb;49(2):269-273. doi: 10.1038/ng.3745. Epub 2016 Dec 19.

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.

Author information

1
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
2
Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
3
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
4
Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
5
Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
6
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
7
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
8
Christ Church, University of Oxford, St Aldates, Oxford, UK.
9
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
10
Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
11
Department of Gastroenterology and Hepatology, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
12
Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.
13
Department of Gastroenterology, University Hospital Leuven, Leuven, Belgium.
14
Snyder Institute for Chronic Diseases, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
15
Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
16
Helsinki University and Helsinki University Hospital, Clinic of Gastroenterology, Helsinki, Finland.
17
Department of Internal Medicine, Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany.
18
1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
19
Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
20
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
21
Integrated Research and Treatment Center-Transplantation (IFB-tx), Hannover Medical School, Hannover, Germany.
22
Department of Internal Medicine 1, University Hospital of Bonn, Bonn, Germany.
23
Department of Medicine, University Hospital of Heidelberg, Heidelberg, Germany.
24
Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany.
25
Department of Medicine I, University Medical Center, Regensburg, Germany.
26
Clinic of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
27
Institute of Epidemiology and Biobank PopGen, University Hospital Schleswig-Holstein, Kiel, Germany.
28
Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
29
Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
30
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
31
Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
32
Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
33
Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.
34
Department of Medicine, University of Helsinki, Helsinki, Finland.
35
AP-HP Hôpital Saint Antoine, Department of Hepatology, UPMC University Paris 6, Paris, France.
36
Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
37
Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
38
NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
39
INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
40
Department of Hematology, University of Cambridge, Cambridge, UK.
41
NHS Blood and Transplant, Cambridge, UK.
42
NHS Blood and Transplant-Oxford Centre, John Radcliffe Hospital, Oxford, UK.
43
Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
44
Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy.
45
Department for General Internal Medicine, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
46
Liver Centre, Toronto Western Hospital, Toronto, Ontario, Canada.
47
Division of Gastroenterology and Hepatology, University of California at Davis, Davis, California, USA.
48
Gastroenterology and Hepatology Section, Virginia Commonwealth University, Richmond, Virginia, USA.
49
Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
50
Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
51
Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, Washington, USA.
52
Indiana University School of Medicine, Indianapolis, Indiana, USA.
53
Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK.
54
Department of Medicine, Division of Hepatology, University of Cambridge, Cambridge, UK.
55
Department of Translational Gastroenterology, Oxford University Hospitals NHS Trust, Oxford, UK.
56
Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK.
57
University of Toronto and Liver Center, Toronto Western Hospital, Toronto, Ontario, Canada.

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.

PMID:
27992413
PMCID:
PMC5540332
DOI:
10.1038/ng.3745
[Indexed for MEDLINE]
Free PMC Article

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