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

Abstract

Inter-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 lines are mouse resources that capture substantial genetic diversity and can demonstrate expansive phenotypic variance in heritable traits. These populations may be utilized to discover candidate genes and gene networks that moderate ethanol consumption and other ethanol-related traits. To that end, we characterized ethanol consumption and preference and ethanol pharmacokinetics in the eight founder strains and ten CC strains in 12-hour drinking sessions during the dark phase of the light cycle. Ethanol 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 exceeding C57BL/6J, a strain frequently used to model ethanol binge drinking. Notably, we found evidence that sex moderated genetic effects on voluntary ethanol drinking. Collectively, this research may serve as a foundation for expanded genetic study of ethanol consumption in the CC/DO populations; moreover, we have identified reference strains with extreme consumption phenotypes that effectively represent polygenic models of hazardous ethanol use.

Heritable variation in locomotion, reward sensitivity and impulsive behaviors in a genetically diverse inbred mouse panel

“…We previously reported on heritable variation in ethanol consumption and preference in a sample of CC and founder strains 60 . Premature responding during the acquisition stage was positively correlated with ethanol intake (adjusted for body weight) assessed across sequential testing days (day 1 ( r [18] = 0.5, p < 0.05), 2 ( r [18] = 0.63, p < 0.001), and 3 ( r [18] = 0.62, p < 0.001)) in a two bottle choice modified drinking in the dark paradigm.…”

Gonadal Sex and Sex-Chromosome Complement Interact to Affect Ethanol Consumption in Adolescent Four Core Genotypes Mice

“…Ethanol-drinking phenotypes in mice show heritable variation as confirmed by recombinant inbred panel studies [151,152]. This has also been shown for DID in particular by way of selection experiments to generate “high DID” lines of mice via selection based on achieved BECs [70,71,73,80,84,153–156].…”

Genome‐wide association mapping of ethanol sensitivity in the Diversity Outbred mouse population

“…While this represents the first time the DO mice have been characterized for level of response to ethanol, others have studied the DO and related populations for additional ethanol‐related traits. For example, Hitzemann et al (2020) recently examined both chronic ethanol consumption and gene expression in the heterogeneous stock‐collaborative cross mice (HS‐CC, derived from the same eight founders as DO); Bagley et al (2021) measured heritability of ethanol consumption and pharmacokinetics in CC strains, and we are aware of ongoing work by Dr. Michael Miles to identify genes associated with ethanol consumption in DO mice. Collectively, these studies demonstrate the ways in the high genetic and phenotypic variation captured by these complementary mouse resources can be used to map genes and identify gene expression networks associated with ethanol‐relevant traits.…”