Genetics of Adverse Reactions to Haloperidol in a Mouse Diallel: A Drug-Placebo Experiment and Bayesian Causal Analysis
James J. Crowley, Yunjung Kim, Alan B. Lenarcic, Corey R. Quackenbush, Cordelia J. Barrick, Daniel E. Adkins, Ginger S. Shaw, Darla R. Miller, Fernando Pardo-Manuel de Villena, Patrick F. Sullivan, William Valdar

Abstract

Haloperidol is an efficacious antipsychotic drug that has serious, unpredictable motor side effects that limit its utility and cause non-compliance in many patients. Using a drug-placebo diallel of the eight founder strains of the Collaborative Cross and their F1 hybrids, we characterized aggregate effects of genetics, sex, parent-of-origin and their combinations on haloperidol response. Treating matched pairs of both sexes with drug or placebo, we measured changes in the following: open field activity; inclined screen rigidity; orofacial movements; pre-pulse inhibition of the acoustic startle response; plasma and brain drug level measurements; and body weight. To understand the genetic architecture of haloperidol response we introduce new statistical methodology linking heritable variation with causal effect of drug treatment. Our new estimators, Difference-of-Models and Multiple Impute Matched Pairs, are motivated by the Neyman-Rubin potential outcomes framework and extend our existing Bayesian hierarchical model for the diallel (Lenarcic et al, 2012). Drug-induced rigidity after chronic treatment was affected by mainly additive genetics and parent-of-origin effects (accounting for 28% and 14.8% of the variance), with NZO/HILtJ and 129S1/SvlmJ contributions tending to increase this side-effect. Locomotor activity after acute treatment, by contrast, was more affected by strain-specific inbreeding (12.8%). In addition to drug response phenotypes, we examined diallel effects on behavior before treatment and found not only effects of additive genetics (10.2%-53.2%) but also strong effects of epistasis (10.64%-25.2%). In particular, pre-pulse inhibition showed additivity and epistasis in about equal proportion (26.1% and 23.7%); there was evidence of non-reciprocal epistasis in pre-treatment activity and rigidity; and we estimated a range of effects on body weight that replicate those found in our previous work. Our results provide the first quantitative description of the genetic architecture of haloperidol response in mice, and indicate that additive, dominance-like inbreeding, and parent-of-origin effects contribute strongly to treatment effect heterogeneity for this drug.

  • Received August 27, 2013.
  • Accepted October 14, 2013.