Heritability of ethanol consumption and pharmacokinetics in a genetically diverse panel of Collaborative Cross mouse strains and their inbred founders

Abstract

BackgroundInter-individual variation in voluntary ethanol consumption and ethanol response is partially influenced by genetic variation. Discovery of the genes and allelic variants that affect these phenotypes may clarify the etiology and pathophysiology of problematic alcohol use, including alcohol use disorder. Genetically diverse mouse populations also demonstrate heritable variation in ethanol consumption and can be utilized to discover the genes and gene networks that influence this trait. The Collaborative Cross (CC) recombinant inbred strains, Diversity Outbred (DO) population and their eight founder strains are complementary mouse resources that capture substantial genetic diversity and can demonstrate expansive phenotypic variation in heritable traits. These populations may be utilized to discover candidate genes and gene networks that moderate ethanol consumption and other ethanol-related traits. MethodsWe characterized ethanol consumption, preference and pharmacokinetics in the eight founder strains and ten CC strains in 12-hour drinking sessions during the dark phase of the circadian cycle. ResultsEthanol consumption was found to be substantially heritable, both early in ethanol access and over a chronic intermittent access schedule. Ethanol pharmacokinetics were also found to be heritable; however, no association between strain-level ethanol consumption and pharmacokinetics was detected. The PWK/PhJ strain was found to be the highest drinking strain, with consumption substantially exceeding C57BL/6J, a strain commonly used as a model of "high" or "binge" drinking. Notably, we found strong evidence that sex moderated genetic effects on voluntary ethanol drinking. ConclusionsCollectively, this research may serve as a foundation for expanded genetic study of ethanol consumption in the CC/DO and related populations; moreover, we have identified reference strains with extreme consumption phenotypes that effectively represent polygenic models of hazardous ethanol use.