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., UK-PSC Consortium ., International IBD Genetics Consortium ., International PSC Study Group ., 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.

DOI

10.1038/ng.3745

Type

Journal article

Publication Date

2017-02-01T00:00:00+00:00

Volume

49

Pages

269 - 273

Total pages

4

Addresses

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

Keywords

UK-PSC Consortium, International IBD Genetics Consortium, International PSC Study Group, Humans, Cholangitis, Sclerosing, Colitis, Ulcerative, Inflammatory Bowel Diseases, Adaptor Proteins, Signal Transducing, RNA, Messenger, Risk Factors, Polymorphism, Single Nucleotide, Alleles, Genome-Wide Association Study

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