PT  - JOURNAL ARTICLE
AU  - Malika Kumar Freund
AU  - Kathryn Burch
AU  - Huwenbo Shi
AU  - Nicholas Mancuso
AU  - Gleb Kichaev
AU  - Kristina M. Garske
AU  - David Z. Pan
AU  - Päivi Pajukanta
AU  - Gleb Pasaniuc
AU  - Valerie A. Arboleda
TI  - Phenotype-specific enrichment of Mendelian disorder genes near GWAS regions across 62 complex traits
AID  - 10.1101/324558
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 324558
4099  - http://biorxiv.org/content/early/2018/05/17/324558.short
4100  - http://biorxiv.org/content/early/2018/05/17/324558.full
AB  - 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.