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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.

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

Published Web Location

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.

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