Patterns of Gene Expression in the Frontal Cortex Discriminate Alcoholic from Nonalcoholic Individuals

Abstract

Alcohol dependence is characterized by tolerance, physical dependence, and craving. The neuroadaptations underlying these effects of chronic alcohol abuse are likely due to altered gene expression. Previous gene expression studies using human post-mortem brain demonstrated that several gene families were altered by alcohol abuse. However, most of these changes in gene expression were small. It is not clear if gene expression profiles have sufficient power to discriminate control from alcoholic individuals and how consistent gene expression changes are when a relatively large sample size is examined. In the present study, microarray analysis (B47 000 elements) was performed on the superior frontal cortex of 27 individual human cases (14 well characterized alcoholics and 13 matched controls). A partial least squares statistical procedure was applied to identify genes with altered expression levels in alcoholics. We found that genes involved in myelination, ubiquitination, apoptosis, cell adhesion, neurogenesis, and neural disease showed altered expression levels. Importantly, genes involved in neurodegenerative diseases such as Alzheimer's disease were significantly altered suggesting a link between alcoholism and other neurodegenerative conditions. A total of 27 genes identified in this study were previously shown to be changed by alcohol abuse in previous studies of human post-mortem brain. These results revealed a consistent re-programming of gene expression in alcohol abusers that reliably discriminates alcoholic from non-alcoholic individuals.

Neurotoxic Consequences of Chronic Alcohol Withdrawal: Expression Profiling Reveals Importance of Gender Over Withdrawal Severity

“…The 10 most up or downregulated named sequences are included in Table 1 (for a complete list of EtOH-regulated genes, see Supplementary Table 1). Several genes involved in protein secretion or degradation/ubiquitination were among the most highly differentially expressed (Table 1), indicating one pathway activated by chronic EtOH exposure and withdrawal also previously identified by us (Schafer et al, 2001) and others (Liu et al, 2005). Many genes identified with significantly different expression levels have been identified previously as regulated by EtOH, or in a variety of models of neurodegenerative diseases (eg adenylate cyclase 7 and Ncr1, also see Supplementary Table 4 in supporting information online for additional characterization of concordance).…”

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

“…Genetic analyses have an important role in identifying many immune-related genes associated with alcohol abuse in both rodents and humans (Kimpel et al, 2007;Liu et al, 2006;Mulligan et al, 2006). Validating several candidate genes from these studies (including Cd14, Il1ra, and Il6) through single-gene null mutations in mice confirmed that knockout of each gene resulted in decreased alcohol consumption on a two-bottle choice test (Blednov et al, 2012).…”

Proteomic Approaches and Identification of Novel Therapeutic Targets for Alcoholism

“…Proteomic techniques have evolved rapidly over the past few years, and the integration and interpretation of the huge amounts of data obtained from such studies are complicated by many factors. It has been shown that the magnitude of changes in brain gene and protein expression induced by alcohol exposure is less pronounced than in other diseases (Bull et al, 2001;Liu et al, 2006;Smith, 2002). Therefore, to avoid the possibility that individual diversity could overshadow the discrete differences underlying alcohol-related disorders, expression data for a large number of proteins should be combined and interpreted with rigorous appropriate statistical tests and bioinformatics.…”