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

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

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-nucleoti...

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Main Authors: Sung, Min Kyung, Bang, Hyoeun, Choi, Jung Kyoon
Format: Online
Language:English
Published: Korea Genome Organization 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330252/
id pubmed-4330252
recordtype oai_dc
spelling pubmed-43302522015-02-22 Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases Sung, Min Kyung Bang, Hyoeun Choi, Jung Kyoon Original Article 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 to understand their phenotypic contribution. In this work, we studied epistatic interactions associated with three common diseases using Korea Association Resource (KARE) data: type 2 diabetes mellitus (DM), hypertension (HT), and coronary artery disease (CAD). We showed that epistatic single-nucleotide polymorphisms (SNPs) were enriched in enhancers, as well as in DNase I footprints (the Encyclopedia of DNA Elements [ENCODE] Project Consortium 2012), which suggested that the disruption 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 discovered using DNase I profiles and Cap Analysis Gene Expression (CAGE). Assigned genes were significantly enriched in known disease associated gene sets, which were explored based on the literature, suggesting that this approach is useful for detecting relevant affected genes. In our knowledge-based epistatic network, the three diseases share many associated genes and are also closely related with each other through many epistatic interactions. These findings elucidate the genetic basis of the close relationship between DM, HT, and CAD. Korea Genome Organization 2014-12 2014-12-31 /pmc/articles/PMC4330252/ /pubmed/25705156 http://dx.doi.org/10.5808/GI.2014.12.4.181 Text en Copyright © 2014 by the Korea Genome Organization http://creativecommons.org/licenses/by-nc/3.0/ It is identical to the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/).
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Sung, Min Kyung
Bang, Hyoeun
Choi, Jung Kyoon
spellingShingle Sung, Min Kyung
Bang, Hyoeun
Choi, Jung Kyoon
Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases
author_facet Sung, Min Kyung
Bang, Hyoeun
Choi, Jung Kyoon
author_sort Sung, Min Kyung
title Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases
title_short Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases
title_full Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases
title_fullStr Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases
title_full_unstemmed Understanding Epistatic Interactions between Genes Targeted by Non-coding Regulatory Elements in Complex Diseases
title_sort understanding epistatic interactions between genes targeted by non-coding regulatory elements in complex diseases
description 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 to understand their phenotypic contribution. In this work, we studied epistatic interactions associated with three common diseases using Korea Association Resource (KARE) data: type 2 diabetes mellitus (DM), hypertension (HT), and coronary artery disease (CAD). We showed that epistatic single-nucleotide polymorphisms (SNPs) were enriched in enhancers, as well as in DNase I footprints (the Encyclopedia of DNA Elements [ENCODE] Project Consortium 2012), which suggested that the disruption 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 discovered using DNase I profiles and Cap Analysis Gene Expression (CAGE). Assigned genes were significantly enriched in known disease associated gene sets, which were explored based on the literature, suggesting that this approach is useful for detecting relevant affected genes. In our knowledge-based epistatic network, the three diseases share many associated genes and are also closely related with each other through many epistatic interactions. These findings elucidate the genetic basis of the close relationship between DM, HT, and CAD.
publisher Korea Genome Organization
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330252/
_version_ 1613188971059216384

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