Genome-wide association for methamphetamine sensitivity in an advanced intercross mouse line.

Abstract

Sensitivity to the locomotor stimulant effects of methamphetamine (MA) is a heritable trait that utilizes neurocircuitry also associated with the rewarding effects of drugs. We used the power of a C57BL/6J × DBA/2J F(2) intercross (n = 676) and the precision of a C57BL/6J × DBA/2J F(8) advanced intercross line (Aap: B6, D2-G8; or F(8) AIL; n = 552) to identify and narrow quantitative trait loci (QTLs) associated with sensitivity to the locomotor stimulant effects of MA. We used the program QTLRel to simultaneously map QTL in the F(2) and F(8) AIL mice. We identified six genome-wide significant QTLs associated with locomotor activity at baseline and seven genome-wide significant QTLs associated with MA-induced locomotor activation. The average per cent decrease in QTL width between the F(2) and the integrated analysis was 65%. Additionally, these QTLs showed a distinct temporal specificity within each session that allowed us to further refine their locations, and identify one QTL with a 1.8-LOD support interval of 1.47 Mb. Next, we utilized publicly available bioinformatics resources to exploit strain-specific sequence data and strain- and region-specific expression data to identify candidate genes. These results illustrate the power of AILs in conjunction with sequence and gene expression data to investigate the genetic underpinnings of behavioral and other traits.