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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.
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
Validation of the microarray expression data using quantitative PCR.
S1_Table.docx (1628 kB)
(A) Results from the univariate mRNA analysis. The analysis was performed using multiple regression model implemented in the Number Cruncher Statistical Software (NCSSv.9). (B). Results from the univariate miRNA analysis. The analysis was performed using multiple regression model implemented in the Number Cruncher Statistical Software (NCSSv.9).
S2_Table.docx (29 kB)
(A) MRNA modules. MRNA module size and ME correlation to AD case-status (Class) and sample demographics with un-adjusted p-values. (B) MiRNA modules. MiRNA module size and ME correlation to AD case-status (Class) and sample demographics with un-adjusted p-values.
S3_Table.docx (53 kB)
(A) Candidate hub mRNA transcripts from top quartile of MM from 6 mRNA modules significantly correlated with AD case-status. P-values are unadjusted. (B) Candidate hub miRNA transcripts from top quartile of MM from 3 miRNA modules significantly correlated with AD case-status. P-values are unadjusted.
S4_Table.docx (20 kB)
(A) Shared gene sets enriched between significant modules associated with neuronal cell expression. (B) Shared gene sets enriched between significant modules associated with glial cell expression.
S5_Table.docx (14 kB)
Unique significant enriched a priori gene sets for the significant modules.
S6_Table.docx (610 kB)
The entire list of Pearson correlation coefficients resulting from the correlations of 461 mRNA hubs and 25 miRNA hubs.
S7_Table.docx (42 kB)
Significant negatively correlated miRNAs: mRNAs with bioinformatic support.
S8_Table.docx (54 kB)
(A) Table of the significant cis-eQTLs for the mRNA hubs at FDR ≤0.1. (B) Table of the significant cis-eQTLs for the miRNA hubs at FDR ≤0.1.
S9_Table.docx (24 kB)
Brain Sample Demographics.
S10_Table.docx (16 kB)
The table reports the individual expression values of the validated genes between the microarray and the PCR platforms.
S11_Table.xlsx (90 kB)
(A) Genotype calls for the mRNA hub genes. In the GEN file used by Gtool to convert between PED and GEN files, the genotypes are expressed as pairs of 1,2,0 where 1 corresponds to allele A from the GEN file and 2 corresponds to allele B. If none of the probabilities are over the calling threshold then the pair is unknown, 0 0. This should allow the conversion of indels and other biallelic structural variants from the 1000 Genomes. (B) Genotype calls for the miRNA hub genes.
S12_Table.docx (52 kB)
(A) List of the mRNA eQTLs identified in the Australian postmortem sample and tested for enrichment in COGA EA sample; Table abbreviations: chromosome (CHR), base pair position (BP), minor allele frequency (MAF) and Australian (AUS). (B) List of the miRNA eQTLs identified in the Australian postmortem sample and tested for enrichment in COGA EA sample. Table abbreviations: chromosome (CHR), base pair position (BP), minor allele frequency (MAF) and Australian (AUS).