Poster 45
Presenter: William Valdar
Wednesday, 3:00 – 5:00pm
Crowley JJ*, Kim Y*, Lenarcic AB*, Quackenbush CR, Barrick CJ, Adkins DE, Shaw GS, Miller DR, Pardo-Manuel de Villena F, Sullivan PF, Valdar W Department of Genetics, University of North Carolina at Chapel Hill
Haloperidol is an efficacious antipsychotic drug that has serious, unpredictable motor side effects that limit its utility and cause non-compliance in many patients. We describe a diallel study to characterize the genome level genetic architecture of haloperidol response among eight mouse strains -- specifically, the founder strains of the Collaborative Cross. Treating at males and females with haloperidol and placebo, we measured changes in open field activity, inclined screen rigidity, orofacial movements, pre-pulse inhibition of the acoustic startle response, as well as plasma and brain drug level measurements, and body weight. To understand the genetic architecture of haloperidol response we developed a new statistical model linking heritable variation with causal treatment effects. Specifically, we adapt our existing Bayesian hierarchy for the diallel (Lenarcic et al, 2012) to measure genetic effects of treatment response, using counterfactual arguments (after Rubin, 2005). In doing so we decompose the effects of genetic background on haloperidol response into additive, inbred-specific, parent of origin, and epistatic effects, as well as sex-specific versions thereof. Our results provide the first quantitative description of the genetic architecture of haloperidol response in mice. The fact we also replicate estimates of genetic effects on body weight previously reported in an independent diallel experiment, strongly supports the robustness of our findings.