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IBD gene suspects narrowed with fine-mapping strategy
Researchers have used a high resolution fine-mapping strategy to separate specific genetic variants likely to play a causal role in inflammatory bowel disease from other variants in the same genomic region.
These findings could lead to the discovery of new drug targets and more effective treatments for IBD, the investigators concluded.
“We have taken the biggest ever data set for IBD and applied careful statistics to narrow down to the individual genetic variants involved,” Jeffrey C. Barrett, D. Phil, a medical genomics researcher at the Wellcome Trust Sanger Institute, said in a press release. “Now we have a clearer picture of which genes do and do not play a role in the disease. We are zooming in on the genetic culprits of IBD.”
While 200 genetic loci associated with IBD have been identified in genome-wide association studies, few specific functional variants have been conclusively implicated. Therefore, Barrett and colleagues used high-density genotyping in 67,852 individuals of European ancestry (33,595 with IBD) to produce a high-resolution map of 94 IBD loci. Ultimately, they “pinpointed” 18 genetic IBD associations to a single causal variant with more than 95% certainty, and another 27 associations to a single variant with more than 50% certainty.
Among these variants, 13 were enriched for protein-coding changes, three for direct disruption of transcription-factor binding sites, and 10 for tissue-specific epigenetic marks. These last 10 variants also showed “enrichment in specific immune cells among associations stronger in Crohn’s disease and in gut mucosa among associations stronger in ulcerative colitis,” the researchers wrote.
“An issue with studying complex diseases is that it can be hard to move from genetic associations, usually including many genetic variants of similar evidence, to knowing exactly which variants are involved,” Hailiang Huang, PhD, of the Massachusetts General Hospital and Broad Institute of MIT and Harvard, said in the press release. “We need to be careful in deciding when we are sure we have the right variant. This new technique helps us to pinpoint which genetic variants are implicated in IBD with greater confidence.”
“These results will help towards rational drug discovery for complex human diseases like IBD, and possibly for the development of personalized medicine by finding biomarkers for more effective prescription of existing drugs,” Michel Georges, MD, PhD, of the GIGA Institute at the University of Liège, added. – by Adam Leitenberger
Disclosures: The researchers report no relevant financial disclosures.