Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis

Abstract

Much evidence from studies in humans and animals supports the hypothesis that alcohol addiction is a complex disease with both hereditary and environmental influences. Molecular determinants of excessive alcohol consumption are difficult to study in humans. However, several rodent models show a high or low degree of alcohol preference, which provides a unique opportunity to approach the molecular complexities underlying the genetic predisposition to drink alcohol. Microarray analyses of brain gene expression in three selected lines, and six isogenic strains of mice known to differ markedly in voluntary alcohol consumption provided >4.5 million data points for a meta-analysis. A total of 107 arrays were obtained and arranged into six experimental data sets, allowing the identification of 3,800 unique genes significantly and consistently changed between all models of high or low amounts of alcohol consumption. Several functional groups, including mitogen-activated protein kinase signaling and transcription regulation pathways, were found to be significantly overrepresented and may play an important role in establishing a high level of voluntary alcohol drinking in these mouse models. Data from the general meta-analysis was further filtered by a congenic strain microarray set, from which cis-regulated candidate genes for an alcohol preference quantitative trait locus on chromosome 9 were identified: Arhgef12, Carm1, Cryab, Cox5a, Dlat, Fxyd6, Limd1, Nicn1, Nmnat3, Pknox2, Rbp1, Sc5d, Scn4b, Tcf12, Vps11, and Zfp291 and four ESTs. The present study demonstrates the use of (i) a microarray meta-analysis to analyze a behavioral phenotype (in this case, alcohol preference) and (ii) a congenic strain for identification of cis regulation.alcoholism ͉ gene expression ͉ microarray

Voluntary ethanol consumption in 22 inbred mouse strains

“…The utility of this strategy is provided by recent work that employed a meta-analysis of microarray data from different genetic models of high and low alcohol consumption in their analysis of alcohol preference (Mulligan et al, 2006). This analysis identified genes covering a range of cellular pathways, such as cellular homeostasis and neuronal function, as well as genes with uncharacterized functions.…”

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).…”

Alcohol dependence is associated with the ZNF699 gene, a human locus related to Drosophila hangover, in the Irish affected sib pair study of alcohol dependence (IASPSAD) sample

“…In a separate comparison of expression data between a B6.D2 congenic line and the B6 background, Zfp291 showed reduced expression in high ethanol-consuming lines. 36 Zfp291 contains a U1 subclass ZNF domain characteristic of RNA binding proteins 37 and maps to the strongest alcohol preference QTL in B6-and D2-derived populations, found on mouse chromosome 9. We are following up the present study in several ways.…”