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Genotyping, Fine Mapping Identifies Single-Variant Resolution Loci for IBD

NEW YORK (GenomeWeb) – An international research team has found a total of 94 inflammatory bowel disease loci through high-density genotyping and fine mapping.

Inflammatory bowel diseases (IBDs) are a group of chronic debilitating disorders of the gastrointestinal tract with two subtypes, ulcerative colitis and Crohn's disease. More than 1.4 million Americans are affected by IBDs and they have an estimated direct healthcare cost of $6.3 billion per year, the researchers noted.

"So far, 200 genomic loci have been associated with IBD, but only a handful have been conclusively ascribed to a specific causal variant with direct insight into the underlying disease biology," the researchers wrote in a paper describing the work and published today in Nature.

Overall, the researchers found that disease loci were associated with both IBD subtypes, but many more were strongly associated with Crohn's disease.

The researchers genotyped 67,852 individuals of European ancestry — 18,967 individuals with Crohn's disease, 14,628 with ulcerative colitis, and 34,257 healthy controls — using the Illumina ImmunoChip. They performed quality control by comparing to a dataset from the 1000 Genome Project reference panel. The team applied three complementary Bayesian fine-mapping methods to identify independent association within a region. They then analyzed all associations mapped to single variants.

Overall, the team concluded that their results were "concordant with an existing fine-mapping method" since 67 of 68 credible sets in single-signal regions overlapped.

Of the 94 disease loci they found, the investigators pinpointed 18 associations to a single causal variant with greater than 95 percent certainty, and an additional 27 associations to a single variant with greater than 50 percent certainty. These 45 variants are significantly enriched for protein-coding changes, direct disruption of transcription-factor binding sites, and tissue-specific epigenetic marks. The researchers also found that within the 94 disease loci, they defined 139 independent associations. Of those, 79 signals were more strongly associated with Crohn's disease while 23 were more strongly associated with ulcerative colitis.

They noted that "resolving multiple independent associations may often help target the causal gene more precisely." As an example, they state that the SMAD3 locus hosts a nonsynonymous variant and a variant disrupting the conserved-factor binding site which they believe "unambiguously [articulates] a role in disease and [provides] an allelic series for further experimental inquiry."

However, the investigators did write that the resolution of fine mapping is currently limited by the small sample sizes from non-European groups, such as East Asian, South Asian, Middle Eastern, and African. "Ultimately this effort will be aided by more substantial investment in genotyping non-European population samples and by developing and applying more robust trans-ethnic fine-mapping algorithms," they added.