Congenic dissection of a major QTL for methamphetamine sensitivity implicates epistasis

Abstract

We previously used the C57BL/6J (B6) × A/J mouse chromosome substitution strain (CSS) panel to identify a major quantitative trait locus (QTL) on chromosome 11 influencing methamphetamine (MA)-induced locomotor activity. We then made an F(2) cross between CSS-11 and B6 and narrowed the locus (Bayes credible interval: 79-109 Mb) which was inherited dominantly and accounted for 14% of the phenotypic variance in the CSS panel. In the present study, we created congenic and subcongenic lines possessing heterozygous portions of this QTL to narrow the interval. We identified one line (84-96 Mb) that recapitulated the QTL, thus narrowing the region to 12 Mb. This interval also produced a small decrease in locomotor activity following prior saline treatment. When we generated subcongenic lines spanning the entire 12-Mb region, the phenotypic difference in MA sensitivity abruptly disappeared, suggesting an epistatic mechanism. We also evaluated the rewarding properties of MA (2 mg/kg, i.p.) in the 84- to 96-Mb congenic line using the conditioned place preference (CPP) test. We replicated the locomotor difference in the MA-paired CPP chamber yet observed no effect of genotype on MA-CPP, supporting the specificity of this QTL for MA-induced locomotor activity under these conditions. Lastly, to aid in prioritizing candidate genes responsible for this QTL, we used the Affymetrix GeneChip(®) Mouse Gene 1.0ST Array to identify genes containing expression QTLs (eQTL) in the striatum of drug-naÏve, congenic mice. These findings highlight the difficulty of using congenic lines to fine map QTLs and illustrate how epistasis may thwart such efforts.