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
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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