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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
- 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;
- Rushbrook, Simon M;
- Franke, Andre;
- Karlsen, Tom H;
- Lazaridis, Konstantinos N;
- Anderson, Carl A
- et al.
Published Web Location
https://doi.org/10.1038/ng.3745Abstract
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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