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

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...

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Vydáno v:	PloS one Ročník 10; číslo 9; s. e0137671
Hlavní autoři:	Mamdani, Mohammed, Williamson, Vernell, McMichael, Gowon O., Blevins, Tana, Aliev, Fazil, Adkins, Amy, Hack, Laura, Bigdeli, Tim, D. van der Vaart, Andrew, Web, Bradley Todd, Bacanu, Silviu-Alin, Kalsi, Gursharan, Kendler, Kenneth S., Miles, Michael F., Dick, Danielle, Riley, Brien P., Dumur, Catherine, Vladimirov, Vladimir I.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 18.09.2015 Public Library of Science (PLoS)
Témata:	Alcoholism Alcoholism - genetics Alcoholism - metabolism Alcohols Analysis Astrocytes - metabolism Bioinformatics Biology Brain Brain research Cell adhesion & migration Chronic fatigue syndrome Complications and side effects Consortia Correlation Correlation analysis Drug dependence Drug use Enrichment Etiology Female Gene expression Gene Expression Profiling Gene Regulatory Networks Gene set enrichment analysis Genes Genetic analysis Genetic aspects Genetics Genomes Humans Male MAP kinase Messenger RNA MicroRNA MicroRNAs MicroRNAs - genetics MicroRNAs - metabolism Middle Aged miRNA Mitochondria Modules Network hubs Neurons - metabolism Neurosciences Nuclei Nucleus accumbens Nucleus Accumbens - metabolism Oxidative phosphorylation Phosphorylation Physiological aspects Psychiatry Quantitative Trait Loci Ribonucleic acid RNA RNA, Messenger - genetics RNA, Messenger - metabolism Signal Transduction - physiology Signaling Studies Toxicology Transcriptome Up-Regulation United States United States > US Virginia
ISSN:	1932-6203, 1932-6203
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Membership of COGA Consortium is provided in the Acknowledgments. Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: VIV. Performed the experiments: MM GOM T. Blevins. Analyzed the data: VIV MM VW FA SAB. Wrote the paper: MM VIV VW CD BPR KSK MM DD ADV GK. GWAS p-values: COGA. Generated the genotype data and performed the QC analysis: BTW AA LH T. Bigdeli BPR.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0137671