Genetics of Adverse Reactions to Haloperidol in a Mouse Diallel: A Drug–Placebo Experiment and Bayesian Causal Analysis

Abstract

Haloperidol is an efficacious antipsychotic drug that has serious, unpredictable motor side effects that limit its utility and cause noncompliance 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, prepulse 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: prepulse inhibition showed additivity and epistasis in about equal proportions (26.1% and 23.7%); there was evidence of nonreciprocal epistasis in pretreatment 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.

Determinants of QTL mapping power in the realized Collaborative Cross

“…treated and vehicle-treated strain replicates [e.g., Festing (2010); Crowley et al (2014)] and recombinant inbred lines such as the CC are uniquely able to combine such definitions with QTL mapping [e.g., Mosedale et al (2017) and also, in flies, Kislukhin et al (2013); Najarro et al (2015)]. Similarly, strain-specific phenotypic variance ideally requires replicates (Rönnegård and Valdar 2011;Ayroles et al 2015).…”

A diallel of the mouse Collaborative Cross founders reveals strong strain-specific maternal effects on litter size

“…For all 62 genetic inbred and hybrid crosses, we recorded the following information: mated pairs, wean dates, litter size at weaning, including total and sex-specific counts (File S1). This diallel cross was originally designed and maintained for the generation of F1 mice for several experimental projects (Koturbash et al 2011;Aylor et al 2011;Mathes et al 2011;Kelada et al 2012;Didion et al 2012;Collaborative Cross Consortium 2012;Calaway et al 2013;Crowley et al 2014;Phillippi et al 2014;Odet et al 2015;Crowley et al 2015;Morgan et al 2016;Percival et al 2016;Shorter et al 2017;Oreper et al 2017;Maurizio et al 2018). As a result, certain reproductive measurements such as time between litters and maximum number of offspring per cross were necessarily biased by experimental breeding requirements.…”

Animal models of bipolar mania: The past, present and future

“…An example of this type of strategy has identified new mechanisms common to bipolar and addiction disorders that could be recapitulated in a mouse model (Le-Niculescu et al, 2008). Collaborative Cross and Diversity Outbred mice may also help in our understanding of how genetics contributes to differential treatment responses, such as in the case of haloperidol response (Crowley et al, 2014). Thus, the major advantage of using these mice to investigate disease relevant phenotypes and treatment response is to study the continuous and more complete spectrum of the behavior by maximizing the genetic and phenotype variance, eventually moving the field from the classical approach of the simple presence or absence of an intended phenotype.…”