Phenotype-Specific Enrichment of Mendelian Disorder Genes near GWAS Regions across 62 Complex Traits

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; Päivi Pajukanta; Bogdan Pasaniuc; Valerie A Arboleda

doi:10.1016/j.ajhg.2018.08.017

Phenotype-Specific Enrichment of Mendelian Disorder Genes near GWAS Regions across 62 Complex Traits

Am J Hum Genet. 2018 Oct 4;103(4):535-552. doi: 10.1016/j.ajhg.2018.08.017.

Authors

Affiliations

¹ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].
² Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
⁷ Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, 70210 Kuopio, Finland.
⁸ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].

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.

Keywords: GWAS; Hi-C; Mendelian; body mass index; common disease; complex traits; monogenic; polygenic; statistical genetics.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Female
Genetic Predisposition to Disease / genetics
Genome-Wide Association Study / methods
Humans
Male
Multifactorial Inheritance / genetics*
Phenotype
Polymorphism, Single Nucleotide / genetics*
Promoter Regions, Genetic / genetics
Quantitative Trait Loci / genetics*
Transcription Initiation Site / physiology

Abstract

Publication types

MeSH terms

Grants and funding