Phenotype-Specific Enrichment of Mendelian Disorder Genes Near GWAS Regions Across 62 Complex Traits

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2018 Oct 6

PMID 30290150

Citations 56

Authors

Malika Kumar Freund

Kathryn S Burch

Huwenbo Shi

Nicholas Mancuso

Gleb Kichaev

Kristina M Garske

David Z Pan

Zong Miao

Karen L Mohlke

Markku Laakso

Paivi Pajukanta

Bogdan Pasaniuc

Valerie A Arboleda

Affiliations

Soon will be listed here.

Abstract

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 have quantified the overlap of genes identified through large-scale genome-wide association studies (GWASs) for 62 complex traits and diseases with genes containing mutations known to cause 20 broad categories of Mendelian disorders. We identified a significant enrichment of genes linked to phenotypically matched Mendelian disorders in GWAS gene sets; of the total 1,240 comparisons, a higher proportion of phenotypically matched or related pairs (n = 50 of 92 [54%]) than phenotypically unmatched pairs (n = 27 of 1,148 [2%]) demonstrated significant overlap, confirming a phenotype-specific enrichment pattern. Further, we observed elevated GWAS effect sizes near genes linked to phenotypically matched Mendelian disorders. Finally, we report examples of GWAS variants localized at the transcription start site or physically interacting with the promoters of genes linked to phenotypically matched Mendelian disorders. Our results are consistent with the hypothesis that genes that are disrupted in Mendelian disorders are dysregulated by non-coding 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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