Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases

Abstract

Genome-wide association studies have proven the highly polygenic architecture of complex diseases or traits; therefore,single-locus-based methods are usually unable to detect all involved loci, especially when individual loci exert small effects. Moreover, the majority of associated single-nucleotide polymorphisms resides in non-coding regions, making it difficult tounderstand their phenotypic contribution. In this work, we studied epistatic interactions associated with three commondiseases using Korea Association Resource (KARE) data: type 2 diabetes mellitus (DM), hypertension (HT), and coronary arterydisease (CAD). We showed that epistatic single-nucleotide polymorphisms (SNPs) were enriched in enhancers, as well as inDNase I footprints (the Encyclopedia of DNA Elements [ENCODE] Project Consortium 2012), which suggested that thedisruption of the regulatory regions where transcription factors bind may be involved in the disease mechanism. Accordingly,to identify the genes affected by the SNPs, we employed whole-genome multiple-cell-type enhancer data which discoveredusing DNase I profiles and Cap Analysis Gene Expression (CAGE). Assigned genes were significantly enriched in known diseaseassociated gene sets, which were explored based on the literature, suggesting that this approach is useful for detectingrelevant affected genes. In our knowledge-based epistatic network, the three diseases share many associated genes and arealso closely related with each other through many epistatic interactions. These findings elucidate the genetic basis of theclose relationship between DM, HT, and CAD.