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Differentially co-expressed genes in postmortem prefrontal cortex of individuals with alcohol use disorders: influence on alcohol metabolism-related pathways.

ABSTRACT: Chronic alcohol consumption may induce gene expression alterations in brain reward regions such as the prefrontal cortex (PFC), modulating the risk of alcohol use disorders (AUDs). Transcriptome profiles of 23 AUD cases and 23 matched controls (16 pairs of males and 7 pairs of females) in postmortem PFC were generated using Illumina's HumanHT-12 v4 Expression BeadChip. Probe-level differentially expressed genes and gene modules in AUD subjects were identified using multiple linear regression and weighted gene co-expression network analyses. The enrichment of differentially co-expressed genes in alcohol dependence-associated genes identified by genome-wide association studies (GWAS) was examined using gene set enrichment analysis. Biological pathways overrepresented by differentially co-expressed genes were uncovered using DAVID bioinformatics resources. Three AUD-associated gene modules in males [Module 1 (561 probes mapping to 505 genes): r = 0.42, P(correlation) = 0.020; Module 2 (815 probes mapping to 713 genes): r = 0.41, P(correlation) = 0.020; Module 3 (1,446 probes mapping to 1,305 genes): r = -0.38, P(correlation) = 0.030] and one AUD-associated gene module in females [Module 4 (683 probes mapping to 652 genes): r = 0.64, P(correlation) = 0.010] were identified. Differentially expressed genes mapped by significant expression probes (P(nominal) ? 0.05) clustered in Modules 1 and 2 were enriched in GWAS-identified alcohol dependence-associated genes [Module 1 (134 genes): P = 0.028; Module 2 (243 genes): P = 0.004]. These differentially expressed genes, including ALDH2, ALDH7A1, and ALDH9A1, are involved in cellular functions such as aldehyde detoxification, mitochondrial function, and fatty acid metabolism. Our study revealed differentially co-expressed genes in postmortem PFC of AUD subjects and demonstrated that some of these differentially co-expressed genes participate in alcohol metabolism.

SUBMITTER: Zhang H

PROVIDER: S-EPMC4185230 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Differentially co-expressed genes in postmortem prefrontal cortex of individuals with alcohol use disorders: influence on alcohol metabolism-related pathways.

Zhang Huiping H Wang Fan F Xu Hongqin H Liu Yawen Y Liu Jin J Zhao Hongyu H Gelernter Joel J

Human genetics 20140730 11

Chronic alcohol consumption may induce gene expression alterations in brain reward regions such as the prefrontal cortex (PFC), modulating the risk of alcohol use disorders (AUDs). Transcriptome profiles of 23 AUD cases and 23 matched controls (16 pairs of males and 7 pairs of females) in postmortem PFC were generated using Illumina's HumanHT-12 v4 Expression BeadChip. Probe-level differentially expressed genes and gene modules in AUD subjects were identified using multiple linear regression and ...[more]

PMID: 25073604

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Project description:Emerging evidence suggests that neuroadaptations to alcohol may result from chronic alcohol consumption-induced expression changes of microRNAs (miRNAs) and their target genes. Studies with animal or cell culture models have demonstrated that ethanol exposure leads to miRNA expression alterations. However, there is limited information on miRNA expression in the brains of subjects with alcohol use disorders (AUDs). The present study aimed to analyze expression changes of miRNAs and their target genes in postmortem prefrontal cortex (PFC) of AUD subjects.Genome-wide miRNA and mRNA expression was examined in postmortem PFC of 23 European Australia AUD cases and 23 matched controls using the Illumina HumanHT-12 v4 Expression BeadChip array, which targets 43,270 coding transcripts and 3,961 non-coding transcripts (including 574 miRNA transcripts). Multiple linear regression analysis and permutation test were performed to identify differentially expressed miRNAs and their target mRNAs. Target gene prediction, Gene Set Enrichment Analysis (GESA), and DAVID functional annotation clustering analysis were applied to identify AUD-associated gene sets and biological modules.Two miRNAs and 787 coding genes were differentially expressed in the PFC of AUD cases [miR-130a (downregulated): Ppermutation=0.023, miR-604 (upregulated): Ppermutation=0.019, coding genes: 1.6×10-5?Ppermutation?0.05; but all P values did not survive multiple-testing correction]. GESA showed that the 202 predicted target genes of miR-130a were highly enriched in differentially expressed genes (Pnominal<0.001), but not the 116 predicted target genes of miR-604 (Pnominal=0.404). DAVID functional clustering further revealed that the hub target genes (e.g., ITPR2 and ATP1A2) of miRNA130a were mainly responsible for regulating ion channel function.This study provides evidence that downregulation of miR-130a may lead to altered expression of a number of genes in the PFC of AUD subjects. Further studies are warranted to confirm these findings in replication samples and other reward-related brain regions.

Dataset Information

Differentially co-expressed genes in postmortem prefrontal cortex of individuals with alcohol use disorders: influence on alcohol metabolism-related pathways.

Publications

Differentially co-expressed genes in postmortem prefrontal cortex of individuals with alcohol use disorders: influence on alcohol metabolism-related pathways.

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