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 SchrammMartina 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, Simon M. Rushbrook, Andre Franke, Tom H. Karlsen, Konstantinos N. Lazaridis, Carl A. Anderson

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; â 1/475% 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.

Original languageEnglish (US)
Pages (from-to)269-273
Number of pages5
JournalNature genetics
Volume49
Issue number2
DOIs
StatePublished - Jan 31 2017

ASJC Scopus subject areas

  • Genetics

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    Ji, S. G., 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., ... Anderson, C. A. (2017). Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nature genetics, 49(2), 269-273. https://doi.org/10.1038/ng.3745