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

Abstract

1Although recent studies provide evidence for a common genetic basis between complex traits 2 and Mendelian disorders, a thorough quantification of their overlap in a phenotype-specific 3 manner remains elusive. Here, we quantify the overlap of genes identified through large-scale 4 genome-wide association studies (GWAS) for 62 complex traits and diseases with genes known 5 to cause 20 broad categories of Mendelian disorders. We identify a significant enrichment of 6 phenotypically-matched Mendelian disorder genes in GWAS gene sets. Further, we observe 7 elevated GWAS effect sizes near phenotypically-matched Mendelian disorder genes. Finally, we 8 report examples of GWAS variants localized at the transcription start site or physically 9 interacting with the promoters of phenotypically-matched Mendelian disorder genes. Our results 1 0 are consistent with the hypothesis that genes that are disrupted in Mendelian disorders are 1 1 dysregulated by noncoding variants in complex traits, and demonstrate how leveraging findings 1 2 from related Mendelian disorders and functional genomic datasets can prioritize genes that are 1 3 putatively dysregulated by local and distal non-coding GWAS variants.

A brief history of human disease genetics

“…In these cases, mechanistic inference depends on connecting association signals to their downstream targets (see below). For many traits, there is clear convergence between common-variant association signals and genes implicated in monogenic forms of the same disease, as well as enrichment of GWAS signals in regulatory elements specifically active in cell types consistent with known disease biology 60,61 . This provides reassurance that, even as the number of association signals for a given disease proliferates, the genetic associations uncovered will coalesce around molecular and cellular processes with a core role in pathogenesis 62,63 .…”

Genomic Analysis in the Age of Human Genome Sequencing

“…First, the transition to WGS as a universal technology will detect variants regardless of location and frequency, making the codingnoncoding and rare-common distinctions unnecessary from a technical perspective. Furthermore, several studies have demonstrated a more complex, mixed genetic architecture of both common and rare disease even though optimal study designs for traits of different genetic architectures remain a matter of debate (Castel et al, 2018;Freund et al, 2018;Niemi et al, 2018;Weiner et al, 2017). Finally, a more refined understanding of functional effects of genetic variants challenges the simple coding-noncoding classification that often carries implicit assumptions that coding variants cause gene knockouts or disrupt protein structure, whereas noncoding variants fine-tune transcription levels.…”

Whole-Exome Sequencing Reveals a Rare Missense Variant in SLC16A9 in a Pedigree with Early-Onset Gout

“…At SLC16A9, the observed association with gout was restricted to the lower Polynesian ancestry group (rs12356193, P � 0.006) [11]. Of note, the relationship between GWAS signals and genes underlying Mendelian phenotypes has been observed [47,48].…”