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Phenotype-specific enrichment of Mendelian disorder genes near GWAS regions across 62 complex traits

By Malika K Freund, Kathryn Burch, Huwenbo Shi, Nicholas Mancuso, Gleb Kichaev, Kristina M. Garske, David Z. Pan, Päivi Pajukanta, Gleb Pasaniuc, Valerie A. Arboleda

Posted 17 May 2018
bioRxiv DOI: 10.1101/324558 (published DOI: 10.1016/j.ajhg.2018.08.017)

Although recent studies provide evidence for a common genetic basis between complex traits and Mendelian disorders, a thorough quantification of their overlap in a phenotype-specific manner remains elusive. Here, we quantify the overlap of genes identified through large-scale genome-wide association studies (GWAS) for 62 complex traits and diseases with genes known to cause 20 broad categories of Mendelian disorders. We identify a significant enrichment of phenotypically-matched Mendelian disorder genes in GWAS gene sets. Further, we observe elevated GWAS effect sizes near phenotypically-matched Mendelian disorder genes. Finally, we report examples of GWAS variants localized at the transcription start site or physically interacting with the promoters of phenotypically-matched Mendelian disorder genes. Our results are consistent with the hypothesis that genes that are disrupted in Mendelian disorders are dysregulated by noncoding variants in complex traits, 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.

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