Genome-wide association mapping of loci for antipsychotic-induced extrapyramidal symptoms in mice.

Department of Genetics, University of North Carolina, Genomic Medicine Building, CB#7264, Chapel Hill, NC 27599-7264, USA.
Mammalian Genome (Impact Factor: 2.88). 12/2011; 23(5-6):322-35. DOI: 10.1007/s00335-011-9385-8
Source: PubMed

ABSTRACT Tardive dyskinesia (TD) is a debilitating, unpredictable, and often irreversible side effect resulting from chronic treatment with typical antipsychotic agents such as haloperidol. TD is characterized by repetitive, involuntary, purposeless movements primarily of the orofacial region. In order to investigate genetic susceptibility to TD, we used a validated mouse model for a systems genetics analysis geared toward detecting genetic predictors of TD in human patients. Phenotypic data from 27 inbred strains chronically treated with haloperidol and phenotyped for vacuous chewing movements were subject to a comprehensive genomic analysis involving 426,493 SNPs, 4,047 CNVs, brain gene expression, along with gene network and bioinformatic analysis. Our results identified ~50 genes that we expect to have high prior probabilities for association with haloperidol-induced TD, most of which have never been tested for association with human TD. Among our top candidates were genes regulating the development of brain motor control regions (Zic4 and Nkx6-1), glutamate receptors (Grin1 and Grin2a), and an indirect target of haloperidol (Drd1a) that has not been studied as well as the direct target, Drd2.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Mounting evidences have demonstrated the association of altered immune factors with neurodevelopmental and pathological progression of schizophrenia. However, whether immune factors play any role in the pathogenesis of tardive dyskinesia (TD) has been underexplored. To our best knowledge, ours is among the piloting studies examining the association of TNF alpha with extrapyramidal symptoms of schizophrenic patients so far.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 07/2014; · 4.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim: As the primary relevant tissue (brain) for psychiatric disorders is commonly not available, we aimed to investigate whether blood can be used as a proxy in methylation studies on the basis of two models. In the 'signature' model methylation-disease associations occur because a disease-causing factor affected methylation in the blood. In the 'mirror-site' model the methylation status in the blood is correlated with the corresponding disease-causing site in the brain. Materials, methods & results: Methyl-binding domain enrichment and next-generation sequencing of the blood, cortex and hippocampus from four haloperidol-treated and ten untreated C57BL/6 mice revealed high levels of correlation in methylation across tissues. Despite the treatment inducing a large number of methylation changes, this correlation remains high. Conclusion: Our results show that, consistent with the signature model, factors that affect brain processes (i.e., haloperidol) leave biomarker signatures in the blood and, consistent with the mirror-site model, the methylation status of many sites in the blood mirror those in the brain.
    Epigenomics 08/2013; 5(4):367-77. · 5.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    Genetics 11/2013; · 4.87 Impact Factor

Full-text (2 Sources)

Available from
May 31, 2014