Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.
Ji S-G., Juran BD., Mucha S., Folseraas T., Jostins L., Melum E., Kumasaka N., Atkinson EJ., Schlicht EM., Liu JZ., Shah T., Gutierrez-Achury J., Boberg KM., Bergquist A., Vermeire S., Eksteen B., Durie PR., Farkkila M., Müller T., Schramm C., Sterneck M., Weismüller TJ., Gotthardt DN., Ellinghaus D., Braun F., Teufel A., Laudes M., Lieb W., Jacobs G., Beuers U., Weersma RK., Wijmenga C., Marschall H-U., Milkiewicz P., Pares A., Kontula K., Chazouillères O., Invernizzi P., Goode E., Spiess K., Moore C., Sambrook J., Ouwehand WH., Roberts DJ., Danesh J., Floreani A., Gulamhusein AF., Eaton JE., Schreiber S., Coltescu C., Bowlus CL., Luketic VA., Odin JA., Chopra KB., Kowdley KV., Chalasani N., Manns MP., Srivastava B., Mells G., Sandford RN., Alexander G., Gaffney DJ., Chapman RW., Hirschfield GM., de Andrade M., Rushbrook SM., Franke A., Karlsen TH., Lazaridis KN., Anderson CA.
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.