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Meta-analysis Uncovers Dozens of New Ulcerative Colitis Risk Variants

This article has been corrected to clarify that ulcerative colitis and Crohn's disease are forms of IBD not IBS.

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A meta-analysis appearing in the early, online edition of Nature Genetics has uncovered dozens of new regions of the genome with ties to ulcerative colitis.

An international research group led by investigators in the UK and Canada brought together data for tens of thousands of individuals with or without ulcerative colitis — a search that yielded 29 new loci. Between the new regions and those reported in the past, researchers now have 99 loci with potential links to the inflammatory bowel disease.

"This current study has more than doubled the number of confirmed ulcerative colitis susceptibility loci," co-corresponding author John Rioux, a researcher affiliated with the University of Montreal and the Montreal Heart Institute, who also is co-chair of the International IBD Genetics Consortium, and co-authors wrote, "and we estimate that 16 percent of ulcerative colitis heritability is explained by these loci."

Ulcerative colitis is a form of IBD characterized by inflammation of mucosal membranes in the colon, the researchers explained, noting that roughly one in every 250 individuals in European, North American, and Australasian populations are afflicted by the condition.

"The disease can be very severe in some patients resulting in life-threatening inflammation of the large bowel, and there is an increased risk of developing bowel cancer," Rioux said in a statement. "This is a really unpleasant and intrusive illness that typically affects young adults, and for which we presently have no known cure."

There is still much to be learned about the genetic patterns associated with the disease and their effects, the authors added, though several genetic loci have been linked to the disease, including some affecting immune response genes.

"Though the precise etiology is unknown," they noted, "the current hypothesis is a dysregulated mucosal immune response to commensal gut flora in genetically susceptible individuals."

In an effort to uncover more regions of the genome involved in the disease, the team did imputation and meta-analysis using data from six genome-wide association studies involving 6,687 affected and 19,718 unaffected individuals, all of European descent.

By focusing in on the 50 previously unreported loci that appeared most likely to influence ulcerative colitis, the researchers verified associations with 29 new risk loci in another set of 9,628 cases and 12,917 controls. A dozen of these loci had shown nominal associations in one or more past studies, they noted.

Overall, there are now 99 loci that are known or suspected of increasing ulcerative colitis risk based on this and other studies. Of these, 47 have been confirmed, they noted, including 28 that overlap with loci involved in Crohn's disease, another form of IBD, and 19 loci implicated in other immune-related disease.

The researchers attempted to pare down the list of genes in these regions to the top candidate genes using data on expression quantitative trait loci, gene interactions, linkage disequilibrium patterns, and more. Among the genes that were over-represented in these regions were some involved in cytokine signaling pathways, innate and adaptive immune function, and apoptosis, they reported.

The team also found transcription-related genes, as well as numerous genes from fatty acid and lipid metabolism pathways, MAP kinase signaling pathways, and other pathways not previously linked to inflammatory disease.

"Ultimately, we hope that unmasking the genetic processes that give rise to the disease will minimize the need for surgical outcomes, by opening the door for new therapies that can stop the disease in its tracks," Rioux said in a statement.

Still, those involved in the study emphasized that additional follow-up work, including association studies involving many more affected and unaffected individuals, will be needed to find the actual causal variants behind ulcerative colitis in European and other populations.

"[C]onfirmation of causality awaits detailed fine-mapping, expression, and function studies," they concluded. "Dense fine-mapping and large-scale re-sequencing studies are currently underway with the goal of identifying the causal variation within many of these loci."

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