Transcriptomics and the genetics of alcohol consumption in mice
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Alcoholism is a complex disease determined by both genetic and environmental components that exerts a devastating economic and social impact worldwide. The complexity of this disease makes the elucidation of candidate genes for the susceptibility to alcoholism difficult in human populations, however, mouse model systems replicate many aspects of the disease and represent an excellent system for the investigation of the genetic contributions to alcoholism. One component of alcoholism that can be investigated in mouse models is the predisposition to high alcohol consumption. Selectively bred and inbred mice differ markedly in the level of voluntary alcohol intake using a two-bottle choice paradigm. The phenotype of voluntary alcohol consumption in mice is a complex trait and a genetic comparison between mouse models with similar levels of alcohol intake should identify genes that contribute to the predisposition for alcohol consumption. Three different studies were completed at the University of Texas and candidate genes involved in the predisposition to high alcohol consumption in mice were identified through the use of brain transcriptome analysis. In the first study, 3,800 transcripts were identified that were divergent between 3 selected lines and 6 isogenic strains of mice known to differ in voluntary alcohol consumption. This list was filtered to reveal candidate genes associated with alcohol preference on mouse chromosome 9: Arhgef12, Carm1, Cryab, Cox5a, Dlat, Fxyd6, Limd1, Nicn1, Nmnat3, Pknox2, Rbp1, Sc5d, Scn4b, Tcf12, Vps11, Zfp291. In the second study, analysis of voluntary alcohol intake and brain gene expression between two closely related inbred mouse substrains separated for nearly fifty years revealed divergent alcohol consumption as well as genetic variation between the substrains. Finally, the third study revealed dominant and overdominant patterns of expression in an F1 hybrid that voluntarily consumed more alcohol than either inbred parental strain. The microarray datasets analyzed here represent an important first step in the elucidation of the genetic determinants of high alcohol consumption in mice and will be influential in the discovery of genes that play a role in vulnerability to alcoholism in humans.