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

Sun-Gou Ji; Brian D Juran; Sören Mucha; Trine Folseraas; Luke Jostins; Espen Melum; Natsuhiko Kumasaka; Elizabeth J Atkinson; Erik M Schlicht; Jimmy Z Liu; Tejas Shah; Javier Gutierrez-Achury; Kirsten M Boberg; Annika Bergquist; Severine Vermeire; Bertus Eksteen; Peter R Durie; Martti Farkkila; Tobias Müller; Christoph Schramm; Martina Sterneck; Tobias J Weismüller; Daniel N Gotthardt; David Ellinghaus; Felix Braun; Andreas Teufel; Mattias Laudes; Wolfgang Lieb; Gunnar Jacobs; Ulrich Beuers; Rinse K Weersma; Cisca Wijmenga; Hanns-Ulrich Marschall; Piotr Milkiewicz; Albert Pares; Kimmo Kontula; Olivier Chazouillères; Pietro Invernizzi; Elizabeth Goode; Kelly Spiess; Carmel Moore; Jennifer Sambrook; Willem H Ouwehand; David J Roberts; John Danesh; Annarosa Floreani; Aliya F Gulamhusein; John E Eaton; Stefan Schreiber; Catalina Coltescu; Christopher L Bowlus; Velimir A Luketic; Joseph A Odin; Kapil B Chopra; Kris V Kowdley; Naga Chalasani; Michael P Manns; Brijesh Srivastava; George Mells; Richard N Sandford; Graeme Alexander; Daniel J Gaffney; Roger W Chapman; Gideon M Hirschfield; Mariza de Andrade; UK-PSC Consortium; International IBD Genetics Consortium; International PSC Study Group; Simon M Rushbrook; Andre Franke; Tom H Karlsen; Konstantinos N Lazaridis; Carl A Anderson

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

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

Authors

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

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.

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Alleles
Cholangitis, Sclerosing / genetics*
Colitis, Ulcerative / genetics
Genome-Wide Association Study / methods
Humans
Inflammatory Bowel Diseases / genetics*
Polymorphism, Single Nucleotide / genetics
RNA, Messenger / genetics
Risk Factors

Substances

Adaptor Proteins, Signal Transducing
RNA, Messenger
UBASH3A protein, human

Abstract

MeSH terms

Substances

Grants and funding