Analysis of whole genome-transcriptomic organization in brain to identify genes associated with alcoholism

Abstract

Alcohol exposure triggers changes in gene expression and biological pathways in human brain. We explored alterations in gene expression in the Pre-Frontal Cortex (PFC) of 65 alcoholics and 73 controls of European descent, and identified 129 genes that showed altered expression (FDR < 0.05) in subjects with alcohol dependence. Differentially expressed genes were enriched for pathways related to interferon signaling and Growth Arrest and DNA Damage-inducible 45 (GADD45) signaling. A coexpression module (thistle2) identified by weighted gene co-expression network analysis (WGCNA) was significantly correlated with alcohol dependence, alcohol consumption, and AUDIT scores. Genes in the thistle2 module were enriched with genes related to calcium signaling pathways and showed significant downregulation of these pathways, as well as enrichment for biological processes related to nicotine response and opioid signaling. A second module (brown4) showed significant upregulation of pathways related to immune signaling. Expression quantitative trait loci (eQTLs) for genes in the brown4 module were also enriched for genetic associations with alcohol dependence and alcohol consumption in large genome-wide studies included in the Psychiatric Genetic Consortium and the UK Biobank’s alcohol consumption dataset. By leveraging multi-omics data, this transcriptome analysis has identified genes and biological pathways that could provide insight for identifying therapeutic targets for alcohol dependence.

Alcohol use disorder causes global changes in splicing in the human brain

“…In the past few years, there have been several studies on alcohol-induced changes in gene expression in the brain. For example, gene expression profiling on the prefrontal cortex identified 129 altered genes in patients with AUD 16 . Likewise, microarray analysis detected 163 differentially expressed genes in the superior frontal cortex in AUD 8 .…”

“…Postmortem human brain samples were obtained from the New South Wales Tissue Resource Centre at the University of Sydney and have been previously characterized 16 . Briefly, diagnosis of alcohol use disorder (AUD) was based on DSM-IV and was confirmed by physician interviews, review of hospital medical records, questionnaires to next-of-kin, and from pathology, radiology, and neuropsychology reports.…”

“…RNA sequencing was performed as described recently 16 . The total RNA was extracted using mirVana™ miRNA Isolation Kit, with phenol (#AM1560, Thermo Fisher Scientific).…”

Transcriptome Analysis of Alcohol Drinking in Non-Dependent and Dependent Mice Following Repeated Cycles of Forced Swim Stress Exposure

“…Examination of human postmortem brain tissue and animal models for AUD have demonstrated biologically coordinated changes in gene expression throughout several cell-types and areas of the CNS. Specific groups of evolutionarily conserved protein-coding and non-coding gene expression networks are associated with lifetime consumption of alcohol [3,4], suggesting chronic neuroadaptations proportional to substance use. Despite the valuable contributions of postmortem human brain to understanding the neurobiological impact of long-term alcohol use [5], not all of the psychological and pathophysiological measures are appropriately measured or rigorously controlled in human samples.…”

Convergent evidence for predispositional effects of brain gray matter volume on alcohol consumption

“…Given the wide prevalence of alcohol use across the world (73), it will likely be impossible to ever definitively confirm in human adults that alcohol use is not confounding these results. Notably, none of the identified genes (C16orf93, CWF19L1, C18orf8) have been found to be differentially expressed in the frontal cortex of donors with alcoholism (74,75). Our analyses are also limited by the omission of the insula from the geneexpression data, precluding a comparison of the gene-expression correlates between the insula and frontal cortex.…”