Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence

Authors

Mohammed Mamdani, Virginia Commonwealth UniversityFollow
Vernell Williamson, Virginia Commonwealth UniversityFollow
Gowon O. McMichael, Virginia Commonwealth UniversityFollow
Tana Blevins, Virginia Commonwealth UniversityFollow
Fazil Aliev, Virginia Commonwealth UniversityFollow
Amy Adkins, Virginia Commonwealth UniversityFollow
Laura Hack, Virginia Commonwealth UniversityFollow
Tim Bigdeli, Virginia Commonwealth UniversityFollow
Andrew D. van der Vaart, Virginia Commonwealth UniversityFollow
Bradley Todd Web, Virginia Commonwealth UniversityFollow
Silviu-Alin Bacanu, Virginia Commonwealth UniversityFollow
Gursharan Kalsi, Virginia Commonwealth University
COGA Consortium
Kenneth S. Kendler, Virginia Commonwealth UniversityFollow
Michael F. Miles, Virginia Commonwealth UniversityFollow
Danielle Dick, Virginia Commonwealth UniversityFollow
Brien P. Riley, Virginia Commonwealth UniversityFollow
Catherine Dumur, Virginia Commonwealth UniversityFollow
Vladimir I. Vladimirov, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2015

Journal/Book/Conference Title

PLOS ONE

Volume

10

Issue

9

DOI of Original Publication

10.1371/journal.pone.0137671

Comments

Originally published at http://dx.doi.org/10.1371/journal.pone.0137671

Date of Submission

April 2016

Abstract

Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.

Rights

Copyright: © 2015 Mamdani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Is Part Of

VCU Psychiatry Publications