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Mendelian, Common Disease Links Detected From GWAS Data

NEW YORK (GenomeWeb) – Common genetic variants implicated in genome-wide association studies appear to be overrepresented at sites that may influence the activity of Mendelian disease genes, according to a study appearing online today in the American Journal of Human Genetics.

University of California, Los Angeles human genetics researchers Valerie Arboleda and Bogdan Pasaniuc led a team of investigators that compared results from 62 complex trait or disease GWAS to the suite of genes implicated in Mendelian diseases falling in 20 different categories. When they quantified the apparent overlap between these genes, they found that Mendelian disease genes were more likely than not to turn up at or near sites implicated in more common traits or conditions assessed by GWAS.

That overlap was particularly pronounced at sites containing GWAS variants with strong effect sizes or variants falling at sites related to gene regulation, the team reported. And shared genes were also more apt to turn up when the conditions being studied by GWAS were phenotypically related to those affected in the corresponding Mendelian disorder.

"Our results are consistent with the hypothesis that genes that are disrupted in Mendelian disorders are dysregulated by non-coding variants in complex traits," the authors wrote, "and demonstrate how leveraging findings from related Mendelian disorders and functional genomic datasets can prioritize genes that are putatively dysregulated by local and distal non-coding GWAS variants."

For their analysis, the researchers first assembled 20 Mendelian disorder gene sets, alongside the genes that were closest to risk SNPs unearthed in GWAS for 62 related traits or complex diseases. In addition to including risk variant-adjacent genes from coronary artery disease GWAS, for example, they looked at genes implicated in monogenic forms of cardiovascular disease and insulin disorders.

Across more than 1,200 comparisons, the team identified gene overlap in 77 of these Mendelian disease-GWAS pairings, including 50 phenotypically related Mendelian disease and GWAS conditions. In one case, the group saw overlap between inflammatory bowel disease and Mendelian conditions involving immune problems, while hemoglobin-related variants fell near genes contributing to Mendelian hematologic conditions.

"The remaining 27 pairs with significant overlap suggested shared biological mechanisms yet to be established between complex traits and Mendelian disorders," the authors wrote.

The researchers subsequently delved into these relationships with fine-mapping, regulatory, and functional analyses based on publicly available GWAS SNP effect size, transcription start site, GTEx, and chromatin interaction data. In the process, they saw GWAS variants at Mendelian gene transcription start sites, and identified a dozen GWAS variants acting as expression quantitative trait loci for Mendelian disorder-relevant genes.

Based on these and other data, the authors proposed that the apparent links between Mendelian disorders and common traits or conditions may lead to new treatment opportunities once the genetic overlap is explored more fully.

"Many drugs approved by the [US Food and Drug Administration] and developed by pharmaceutical companies are targeted toward the treatment of complex traits and diseases," they wrote. "[B]y identifying underlying links between Mendelian disorders and complex traits through their effects on the same biological genes and pathways, we can systematically and rationally target existing drugs for complex traits and diseases toward those with rare Mendelian disorders that largely do not have any rationally targeted treatments."

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