Assessing the role of long-noncoding RNA in nucleus accumbens in subjects with alcohol dependence

Abstract

Recently, long noncoding RNA (lncRNA) were implicated in the etiology of alcohol dependence (AD). As lncRNA provide another layer of complexity to the transcriptome, assessing their expression in the brain is the first critical step towards understanding lncRNA functions in AD. To that end, we profiled the expression of lncRNA and protein coding genes (PCG) in nucleus accumbens (NAc) from 41 subjects with AD and 41 controls. At false discovery rate (FDR) of 5%, we identified 69 and 309 differentially expressed lncRNA and PCG genes, respectively. Using co-expression network analyses, we identified three lncRNA and five PCG modules significantly correlated with AD at Bonferroni adj. p≤0.05. To better understand lncRNA functions, we integrated the lncRNA and PCG hubs from the significant AD modules; at FDR of 5%, we identified 3 151 positive and 2 255 negative correlations supporting the functional role of lncRNA in the development of AD. Gene enrichment analysis revealed that PCG significantly correlated with lncRNA are, among others, enriched for neuronal and immune related processes. To highlight the mechanisms, by which genetic variants contribute to AD, we integrated lncRNA and PCG hubs with genome-wide SNP data. At FDR≤0.3, we identified 276 expression quantitative trait loci (eQTL), affecting the expression of 20 and 256 lncRNA and PCG hubs, respectively. Our study is the first to profile lncRNA expression in nucleus accumbens in a large postmortem alcohol brain sample and our results may provide novel insights into the regulation of the brain transcriptome across disease.

Network preservation reveals shared and unique biological processes associated with chronic alcohol abuse in NAc and PFC

“…Among these, the mesocorticolimbic system (MCL), which connects the ventral tegmental area (VTA) to the prefrontal cortex (PFC), and nucleus accumbens (NAc), has proven especially sensitive to alcohol-associated neuroadaptations [10][11][12]. Recent postmortem brain studies of AUD have focused on examining gene and microRNA (miRNA) expression as the biological intermediate between genetic variation and molecular function [13][14][15][16][17][18][19]. Studying mRNA and miRNA interactions may also reveal functional relationships that mediate the differential expression of risk AUD genes based on the role miRNAs play in the destabilization and degradation of their target genes [20].…”

Network Preservation Reveals Shared and Unique Biological Processes Associated with Chronic Alcohol Abuse in NAc and PFC

“…Among these, the mesocorticolimbic system (MCL), which connects the ventral tegmental area (VTA) to the prefrontal cortex (PFC), and nucleus accumbens (NAc), has proven especially sensitive to alcohol-associated neuroadaptations [10][11][12]. Recent postmortem brain studies of AUD have focused on examining gene and noncoding RNA expression as the biological intermediate between genetic variation and molecular function [13][14][15][16][17][18][19]. While single gene expression differences are continuously explored, network approaches, such as weighted gene coexpressed network analysis (WGCNA), allows genes with correlated expression to cluster into modules that then can be independently analyzed to identify dysregulated biological processes and molecular pathways underlying the etiology of AUD [20].…”