Differential Expression of miR-130a in Postmortem Prefrontal Cortex of Subjects with Alcohol Use Disorders.
BACKGROUND
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.


METHODS
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.


RESULTS
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 allPvalues 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.,ITPR2andATP1A2) of miRNA130a were mainly responsible for regulating ion channel function.


CONCLUSIONS
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.
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA ; VA Medical Center, VA Connecticut Healthcare System, West Haven, CT, USA.
Fan
F
Wang
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA ; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA ; Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA ; VA Medical Center, VA Connecticut Healthcare System, West Haven, CT, USA.
Joel
J
Gelernter
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA ; VA Medical Center, VA Connecticut Healthcare System, West Haven, CT, USA.
Huiping
H
Zhang
alcohol use disorders; expression microarray; microRNA; postmortem prefrontal cortex