Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

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

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalNature Genetics
DOIs
StateAccepted/In press - Dec 19 2016

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Sclerosing Cholangitis
Genetic Loci
Genome-Wide Association Study
Inflammatory Bowel Diseases
Ulcerative Colitis
Crohn Disease
Genome
Population Control
RNA Stability
Bile Ducts
Single Nucleotide Polymorphism
Alleles

ASJC Scopus subject areas

  • Genetics

Cite this

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. / The UK-PSC Consortium; The International IBD Genetics Consortium; The International PSC Study Group.

In: Nature Genetics, 19.12.2016.

Research output: Contribution to journalArticle

The UK-PSC Consortium ; The International IBD Genetics Consortium ; The International PSC Study Group. / Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. In: Nature Genetics. 2016.
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abstract = "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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