Abstract
Chronic alcohol abuse has been linked to the disruption of executive function and allostatic conditioning of reward response dysregulation in the mesocorticolimbic pathway (MCL). Here, we analyzed genome-wide mRNA and miRNA expression from matched cases with alcohol dependence (AD) and controls (n = 35) via gene network analysis to identify unique and shared biological processes dysregulated in the prefrontal cortex (PFC) and nucleus accumbens (NAc). We further investigated potential mRNA/miRNA interactions at the network and individual gene expression levels to identify the neurobiological mechanisms underlying AD in the brain. By using genotyped and imputed SNP data, we identified expression quantitative trait loci (eQTL) uncovering potential genetic regulatory elements for gene networks associated with AD. At a Bonferroni corrected p≤0.05, we identified significant mRNA (NAc = 6; PFC = 3) and miRNA (NAc = 3; PFC = 2) AD modules. The gene-set enrichment analyses revealed modules preserved between PFC and NAc to be enriched for immune response processes, whereas genes involved in cellular morphogenesis/localization and cilia-based cell projection were enriched in NAc modules only. At a Bonferroni corrected p≤0.05, we identified significant mRNA/miRNA network module correlations (NAc = 6; PFC = 4), which at an individual transcript level implicated miR-449a/b as potential regulators for cellular morphogenesis/localization in NAc. Finally, we identified eQTLs (NAc: mRNA = 37, miRNA = 9; PFC: mRNA = 17, miRNA = 16) which potentially mediate alcohol's effect in a brain region-specific manner. Our study highlights the neurotoxic effects of chronic alcohol abuse as well as brain region specific molecular changes that may impact the development of alcohol addiction.
Highlights
Alcohol use disorder (AUD) is a debilitating psychiatric illness with negative health, economic, and social consequences for nearly 15.1 million affected adults worldwide [1]
We successfully identified gene networks and biological processes from both brain regions that were validated by previous alcohol dependence (AD) studies as well implicated a novel biological process and gene family as potentially important for the development of AD
While our sample size could be perceived as a limitation, we mitigated this by utilizing weighted gene co-expression network analysis (WGCNA) to aggregate differentially expressed genes into biologically relevant modules with single expression values, effectively increasing our power to detect significant AD associations within a multivariate framework
Summary
Alcohol use disorder (AUD) is a debilitating psychiatric illness with negative health, economic, and social consequences for nearly 15.1 million affected adults worldwide [1]. The neurobiological framework for understanding how benign, recreational alcohol use leads to AUD follows various hypotheses [3,4,5], with the most commonly accepted being the cyclical model of addiction [6]. This hypothesis provides valuable insight into the functional specialization of different brain regions that underlie behavioral maladaptations associated with AUD [7]. 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]. While postmortem brain expression differences alone are insufficient to infer a causal relationship between AUD and neurobiological function, the integration of genetic information via expression quantitative trait loci (eQTL) analysis can help elucidate the regulatory mechanisms by which genetic variants associated with AUD impact gene expression [22]
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