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

Sun-Gou Ji¹, Brian D Juran², Sören Mucha³, Trine Folseraas^{4

5

6}, Luke Jostins^{7

8}, Espen Melum^{4

5}, Natsuhiko Kumasaka¹, Elizabeth J Atkinson⁹, Erik M Schlicht², Jimmy Z Liu¹, Tejas Shah¹, Javier Gutierrez-Achury¹, Kirsten M Boberg^{4

6

10}, Annika Bergquist¹¹, Severine Vermeire^{12

13}, Bertus Eksteen¹⁴, Peter R Durie¹⁵, Martti Farkkila¹⁶, Tobias Müller¹⁷, Christoph Schramm¹⁸, Martina Sterneck¹⁹, Tobias J Weismüller^{20

21

22}, Daniel N Gotthardt²³, David Ellinghaus³, Felix Braun²⁴, Andreas Teufel²⁵, Mattias Laudes²⁶, Wolfgang Lieb²⁷, Gunnar Jacobs²⁷, Ulrich Beuers²⁸, Rinse K Weersma²⁹, Cisca Wijmenga³⁰, Hanns-Ulrich Marschall³¹, Piotr Milkiewicz³², Albert Pares³³, Kimmo Kontula³⁴, Olivier Chazouillères³⁵, Pietro Invernizzi³⁶, Elizabeth Goode³⁷, Kelly Spiess³⁷, Carmel Moore^{38

39}, Jennifer Sambrook^{39

40}, Willem H Ouwehand^{1

38

40

41}, David J Roberts^{38

42

43}, John Danesh^{1

38

39}, Annarosa Floreani⁴⁴, Aliya F Gulamhusein², John E Eaton², Stefan Schreiber^{3

45}, Catalina Coltescu⁴⁶, Christopher L Bowlus⁴⁷, Velimir A Luketic⁴⁸, Joseph A Odin⁴⁹, Kapil B Chopra⁵⁰, Kris V Kowdley⁵¹, Naga Chalasani⁵², Michael P Manns^{20

21}, Brijesh Srivastava³⁷, George Mells^{37

53}, Richard N Sandford³⁷, Graeme Alexander⁵⁴, Daniel J Gaffney¹, Roger W Chapman⁵⁵, Gideon M Hirschfield^{56

57}, Mariza de Andrade⁹; UK-PSC Consortium; International IBD Genetics Consortium; International PSC Study Group; Simon M Rushbrook³⁷, Andre Franke³, Tom H Karlsen^{4

5

6

10}, Konstantinos N Lazaridis², Carl A Anderson¹

Affiliations

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.

PMID: 27992413
PMCID: PMC5540332
DOI: 10.1038/ng.3745

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

Sun-Gou Ji et al. Nat Genet. 2017 Feb.

. 2017 Feb;49(2):269-273.

doi: 10.1038/ng.3745. Epub 2016 Dec 19.

Authors

Affiliations

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.

PMID: 27992413
PMCID: PMC5540332
DOI: 10.1038/ng.3745

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 (r_G) between PSC and ulcerative colitis (UC) (r_G = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (r_G = 0.04) (P = 2.55 × 10^-15). UC and CD were genetically more similar to each other (r_G = 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.

PubMed Disclaimer

Conflict of interest statement

Competing Financial Interests

The authors declare no competing financial interests.

Figures

Figure 1. Odds ratios (and their 95% confidence intervals) for PSC, UC and CD across the 6 PSC associated SNPs demonstrating strong evidence for a shared causal variant (maximum posterior probability > 0.8)
PSC ORs were taken from the GWAS and replication meta-analysis. UC and CD ORs were obtained from the latest association studies conducted by the International IBD Genetics Consortium. Heterogeneity of odds tests were carried out using Cochran’s Q test. A failure to detect significant heterogeneity of odds does not necessarily indicate that effect sizes are equivalent because power to detect heterogeneity varies across SNPs.

**Figure 2. Genome-wide genetic correlation between PSC (and its subphenotypes), CD and UC**
Genetic correlations (and their 95% confidence intervals) were calculated using a bivariate extension of the linear mixed model implemented in GCTA (**Online Methods**). PSC has a lower genetic correlation with both CD and UC than the two inflammatory bowel diseases have to each other. PSC is genetically more correlated to UC than it is to CD and this is consistent across the PSC subphenotypes.

See this image and copyright information in PMC

References

1. Boonstra K, et al. Primary sclerosing cholangitis is associated with a distinct phenotype of inflammatory bowel disease. Inflammatory Bowel Diseases. 2012;18:2270–2276. - PubMed
1. Tischendorf JJW, Hecker H, Kruger M, Manns MP, Meier PN. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: A single center study. American Journal of Gastroenterology. 2007;102:107–114. - PubMed
1. Karlsen TH, Kaser A. Deciphering the Genetic Predisposition to Primary Sclerosing Cholangitis. Seminars in Liver Disease. 2011;31:188–207. - PubMed
1. Karlsen TH, Schrumpf E, Boberg KM. Update on primary sclerosing cholangitis. Digestive and Liver Disease. 2010;42:390–400. - PubMed
1. Bergquist A, et al. Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis. Clinical gastroenterology and hepatology. 2008;6:939–943. - PubMed

Methods-only References

1. Chapman RWG, et al. Primary Sclerosing Cholangitis - a Review of Its Clinical-Features, Cholangiography, and Hepatic Histology. Gut. 1980;21:870–877. - PMC - PubMed
1. Yimam KK, Bowlus CL. Diagnosis and classification of primary sclerosing cholangitis. Autoimmunity Reviews. 2014;13:445–450. - PubMed
1. Mailman MD, et al. The NCBI dbGaP database of genotypes and phenotypes. Nature Genetics. 2007;39:1181–1186. - PMC - PubMed
1. Bellenguez C, et al. A robust clustering algorithm for identifying problematic samples in genome-wide association studies. Bioinformatics. 2012;28:134–135. - PMC - PubMed
1. Price AL, et al. Principal components analysis corrects for stratification in genome-wide association studies. Nature genetics. 2006;38:904–909. - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Methods-only References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources