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Saturday, March 10, 2012

Quantitative trait loci for sensitivity to ethanol intoxication in a C57BL/6J 3 129S1/SvImJ inbred mouse cross

Individual variation in sensitivity to acute ethanol (EtOH) challenge is associated with alcohol drinking
and is a predictor of alcohol abuse. Previous studies have shown that the C57BL/6J (B6) and 129S1/SvImJ (S1) inbred mouse strains differ in responses on certain measures of acute EtOH intoxication.

To gain insight into
genetic factors contributing to these differences, we performed quantitative trait locus (QTL) analysis of measures of EtOH-induced ataxia (accelerating rotarod), hypothermia,and loss of righting reflex (LORR) duration in a B6 9 S1 F2 population.

We confirmed that S1 showed
greater EtOH-induced hypothermia (specifically at a high
dose) and longer LORR compared to B6. QTL analysis revealed several additive and interacting loci for various phenotypes, as well as examples of genotype interactions with sex.

QTLs for different EtOH phenotypes were largely
non-overlapping, suggesting separable genetic influences on these behaviors. The most compelling main-effect QTLs were for hypothermia on chromosome 16 and for LORR on
chromosomes 4 and 6. Several QTLs overlapped with loci repeatedly linked to EtOH drinking in previous mouse studies.

The architecture of the traits we examined was
complex but clearly amenable to dissection in future studies. Using integrative genomics strategies, plausible functional and positional candidates may be found.

Uncovering candidate genes associated with variation in
these phenotypes in this population could ultimately shed light on genetic factors underlying sensitivity to EtOH intoxication and risk for alcoholism in humans.

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