Chronic Alcohol Tolerance in Mice with Human GCKR Gene Variant

Department

Institute for Behavioral Genetics, Department of Integrative Physiology, University of Colorado Boulder

Document Type

Poster

Publication Date

4-17-2026

Abstract

Genome-wide association studies (GWAS) of alcohol-related behaviors have identified a non synonymous single nucleotide polymorphism (SNP), rs1260326, in the human glucokinase regulatory protein gene (GCKR). This SNP produces a proline-to-leucine substitution at position 446 (P446L), where the proline (P) allele is associated with increased alcohol consumption and is considered a risk allele. The biological mechanisms underlying this association remain unclear. CRISPR knock-in mice carrying the Gckr 446P or 446L alleles on a C57BL/6J background were assessed for alcohol-related behaviors. Voluntary alcohol consumption and preference were measured using a 24-hour two-bottle choice paradigm. Initial alcohol sensitivity was evaluated using loss of righting reflex, balance beam, and stationary dowel tests. Chronic tolerance development is being examined following two weeks of voluntary alcohol consumption, with alcohol-induced ataxia assessed using the stationary dowel test. Gckr brain expression is being evaluated using in situ hybridization. Female PP and PL mice consumed and preferred alcohol significantly more than LL mice, consistent with human GWAS findings. No genotype-dependent differences in alcohol consumption were observed in males. Initial sensitivity measures showed minimal genotypic differences. Preliminary data suggest potential chronic tolerance development following extended alcohol exposure; however, genotype comparisons are ongoing due to limited sample sizes. The Gckr P446L mouse model recapitulates human sex-specific genetic associations with alcohol consumption and provides a translational framework for investigating liver–brain mechanisms contributing to alcohol use risk. Key Words: SNP rs1260326, GCKR, alcohol consumption, chronic tolerance, mouse model

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