Skip to main content
Premium Trial:

Request an Annual Quote

Liver Disease GWAS Highlights Genetic Overlap With, Differences From IBD

NEW YORK (GenomeWeb) – A new genome-wide association study suggests that a liver condition called primary sclerosing cholangitis (PSC) is likely a distinct disease from inflammatory bowel disease (IBD), despite the genetic and clinical overlap between the conditions. Roughly three-quarters of individuals with PSC also develop IBD, with around four-fifth of those IBD cases involving ulcerative colitis diagnoses.

The researchers did a genome-wide association study involving almost 4,800 individuals with PSC and close to 20,000 unaffected controls. Their research, reported in Nature Genetics today, led to four loci that have not been linked to the bile duct destroying condition in the past, bringing the tally of PSC-associated loci to nearly two dozen. One of these loci appeared to alter the levels of UBASH3A, a protein that regulates T-cell signaling in the immune system.

"We discovered that lower levels of the UBASH3A protein correlate with lower risk of PSC," co-corresponding author Carl Anderson, a researcher at the Wellcome Trust Sanger Institute, said in a statement. "A drug that could reduce the amount of UBASH3A may thus be helpful in treating people with PSC, so this gives pharmaceutical companies insight into biological systems to target."

The set of loci also included common genetic variants implicated in ulcerative colitis, in particular, though the genetic similarities did not fully account for the documented co-morbidity between PSC and IBD. Consequently, the team noted that future studies of PSC may benefit from separate analyses of individuals with or without IBD.

"If we want to understand bowel inflammation in PSC, we need to look at that specifically and compare it with a separate group of IBD patients without PSC, not merge the two groups and look at the average," co-corresponding author Konstantinos Lazaridis, a genomic hepatobiology researcher at the Mayo Clinic, said in the statement. "Our study suggests PSC is a separate disease to IBD, despite the many genetic and clinical commonalities."

Anderson, Lazaridis, and their colleagues began by comparing genotyping patterns in 2,871 individuals with PSC and 12,019 unaffected individuals, focusing on nearly 7.9 million directly genotyped or imputed SNPs. They carried 40 suspicious SNPs forward for further testing in another 1,925 individuals with PSC and more than 7,900 without, identifying significant PSC associations for variants at four new loci: SNPs in and around FOXP1, CCDC88B, and CLEC16A, as well as the locus in UBASH3A.

When the team took a closer look at the association involving the latter gene, it found that the variant with the strongest ties to PSC was previously described as an expression quantitative trait locus for UBASH3A.

Using data from prior GWAS involving tens of thousands of individuals with ulcerative colitis, Crohn's disease, or unaffected controls, the researchers also explored genetic overlap between PSC and IBD — an analysis that pointed to potential IBD-overlap for 14 of the 18 new and previously described PSC risk loci. In some cases, the apparent causal variants were the same for IBD- and PSC-associated loci, though suspected causal SNPs differed at other loci.

From these and other findings, the study's authors saw hints that the conditions may be distinct genetically, despite some overlap. As such, they wrote, "the biliary and intestinal inflammation seen specifically in PSC should be studied to advance our understanding of the disease and improve clinical outcome for patients with this devastating disorder."