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

Mohammed Mamdani; Vernell Williamson; Gowon O McMichael; Tana Blevins; Fazil Aliev; Amy Adkins; Laura Hack; Tim Bigdeli; Andrew D van der Vaart; Bradley Todd Web; Silviu-Alin Bacanu; Gursharan Kalsi; Kenneth S Kendler; Michael F Miles; Danielle Dick; Brien P Riley; Catherine Dumur; Vladimir I Vladimirov; Collaborative Study on Genetics of Alcohol (COGA) Consortium

doi:10.1371/journal.pone.0137671

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

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

Mohammed Mamdani, Vernell Williamson, Gowon O McMichael, Tana Blevins, Fazil Aliev, Amy Adkins, Laura Hack, Tim Bigdeli, Andrew D van der Vaart, Bradley Todd Web, …

PloS one, Vol.10(9), pp.e0137671-e0137671

2015

DOI: 10.1371/journal.pone.0137671

PMCID: PMC4575063

PMID: 26381263

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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.

Alcoholism - genetics

Alcoholism - metabolism

Astrocytes - metabolism

Female

Gene Expression Profiling

Gene Regulatory Networks

Humans

Male

MicroRNAs - genetics

MicroRNAs - metabolism

Middle Aged

Neurons - metabolism

Nucleus Accumbens - metabolism

Quantitative Trait Loci

RNA, Messenger - genetics

RNA, Messenger - metabolism

Signal Transduction - physiology

Transcriptome

Up-Regulation

Details

Title: Subtitle: Integrating mRNA and miRNA Weighted Gene Co-Expression Networks with eQTLs in the Nucleus Accumbens of Subjects with Alcohol Dependence
Creators: Mohammed Mamdani - Virginia Commonwealth University
Vernell Williamson - Virginia Commonwealth University
Gowon O McMichael - Virginia Commonwealth University
Tana Blevins - Virginia Commonwealth University
Fazil Aliev - Virginia Commonwealth University
Amy Adkins - Virginia Commonwealth University
Laura Hack - Virginia Commonwealth University
Tim Bigdeli - Virginia Commonwealth University
Andrew D van der Vaart - Virginia Commonwealth University
Bradley Todd Web - Virginia Commonwealth University
Silviu-Alin Bacanu - Virginia Commonwealth University
Gursharan Kalsi - Department of Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, London SE5 8AF, United Kingdom.
Kenneth S Kendler - Virginia Commonwealth University
Michael F Miles - Virginia Commonwealth University
Danielle Dick - Virginia Commonwealth University
Brien P Riley - Virginia Commonwealth University
Catherine Dumur - Virginia Commonwealth University
Vladimir I Vladimirov - Virginia Commonwealth University
Collaborative Study on Genetics of Alcohol (COGA) Consortium
Contributors: Samuel Kuperman (Contributor) - University of Iowa, Psychiatry
Resource Type: Journal article
Publication Details: PloS one, Vol.10(9), pp.e0137671-e0137671
DOI: 10.1371/journal.pone.0137671
PMID: 26381263
PMCID: PMC4575063
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Grant note: P20 AA017828 / NIAAA NIH HHS K02AA018755 / NIAAA NIH HHS U01HG004438 / NHGRI NIH HHS U10AA008401 / NIAAA NIH HHS VIVU10AA008401 / NIAAA NIH HHS 1R21AA022717 / NIAAA NIH HHS U10 AA008401 / NIAAA NIH HHS P50AA022537 / NIAAA NIH HHS U01 HG004438 / NHGRI NIH HHS HHSN268200782096C / NHGRI NIH HHS T32 MH020030 / NIMH NIH HHS R21 AA022717 / NIAAA NIH HHS R21 AA022749 / NIAAA NIH HHS 5T32MH020030 / NIMH NIH HHS K02 AA018755 / NIAAA NIH HHS R01 AA020634 / NIAAA NIH HHS P20AA017828 / NIAAA NIH HHS R28 AA012725 / NIAAA NIH HHS P50 AA022537 / NIAAA NIH HHS
Language: English
Date published: 2015
Academic Unit: Psychiatry
Record Identifier: 9984293656702771

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