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Consortium Takes Array-Based Mapping Approach to Find Functional Variants Behind IBD

COLD SPRING HARBOR, NY (GenomeWeb) – Members of a consortium focused on finding genetic culprits underlying inflammatory bowel disease, or IBD, are demonstrating the utility of using a dense, array-based genotyping approach to fine map loci linked to the conditions in genome-wide association studies.

At the Biology of Genomes meeting here this week, Hailiang Huang, a researcher affiliated with Massachusetts General Hospital and the Broad Institute, described the Immunochip-centered strategy that the International IBD Genetics Consortium is taking to fine map loci linked to Crohn's disease and/or ulcerative colitis.

Huang said that in their effort to narrow in on functional variants within the 163 IBD-associated loci detected by prior GWAS, he and his colleagues genotype batches of samples collected by the IBD consortium at some 200,000 variants apiece using Immunochip, a custom array that focuses on 186 main sites implicated in autoimmunity and inflammation.

The researchers subject that array data to typical quality control analyses as well as additional data cleaning steps, Huang noted, before they perform an imputation and analysis step using several Bayesian fine-mapping algorithms aimed at producing a minimal set of variants showing independent IBD association signals.

By applying this approach to samples from 18,603 individuals with Crohn's disease, 14,307 individuals with ulcerative colitis, and 33,938 unaffected controls, for example, the researchers have already refined 171 IBD-associated signals in 103 regions of the genome, Huang said.

At almost two dozen loci, for instance, they narrowed in on lone variants showing ties to Crohn's disease- or ulcerative colitis. Another 54 sites were trimmed down to five or fewer suspicious variants and signals at 54 more IBD-associated sites were localized to 5,000 or fewer bases.

Huang also presented evidence suggesting the dense genotyping take on the fine mapping method compares favorably with sequencing-based processes for pruning down variants in linkage disequilibrium with one another.

He noted that additional advances are likely needed to continue refining and interpreting causal variants in IBD, including those that may overlap with expression quantitative trait loci or other regulatory sites.

Nevertheless, in the abstract for the Biology of Genomes presentation, Huang and his co-authors noted in their presentation abstract that results so far "suggest that genetic mapping, beginning with GWAS discovery, given high-density genotype information and extremely large samples, can effectively narrow in on many common variant signals and provide a much stronger basis for integration with functional data in order to elucidate the mechanisms of disease."