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Antipsychotic-induced vacuous chewing movements and extrapyramidal side effects are highly heritable in mice.

Crowley JJ, Adkins DE, Pratt AL, Quackenbush CR, van den Oord EJ, Moy SS, Wilhelmsen KC, Cooper TB, Bogue MA, McLeod HL, Sullivan PF - Pharmacogenomics J. (2010)

Bottom Line: As expected, haloperidol caused marked changes in VCMs, activity in the open field and extrapyramidal symptoms (EPS).The heritability of a composite phenotype was ∼0.9 after incorporation of the longitudinal nature of the design.Murine VCMs are a face valid animal model of antipsychotic-induced TD, and heritability estimates from this study support the feasibility of mapping of susceptibility loci for VCMs.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7264, USA. crowley@unc.edu

ABSTRACT
Pharmacogenomics is yet to fulfill its promise of manifestly altering clinical medicine. As one example, a predictive test for tardive dyskinesia (TD) (an adverse drug reaction consequent to antipsychotic exposure) could greatly improve the clinical treatment of schizophrenia but human studies are equivocal. A complementary approach is the mouse-then-human design in which a valid mouse model is used to identify susceptibility loci, which are subsequently tested in human samples. We used inbred mouse strains from the Mouse Phenome Project to estimate the heritability of haloperidol-induced activity and orofacial phenotypes. In all, 159 mice from 27 inbred strains were chronically treated with haloperidol (3 mg kg(-1) per day via subdermal slow-release pellets) and monitored for the development of vacuous chewing movements (VCMs; the mouse analog of TD) and other movement phenotypes derived from open-field activity and the inclined screen test. The test battery was assessed at 0, 30, 60, 90 and 120 days in relation to haloperidol exposure. As expected, haloperidol caused marked changes in VCMs, activity in the open field and extrapyramidal symptoms (EPS). Unexpectedly, factor analysis demonstrated that these measures were imprecise assessments of a latent construct rather than discrete constructs. The heritability of a composite phenotype was ∼0.9 after incorporation of the longitudinal nature of the design. Murine VCMs are a face valid animal model of antipsychotic-induced TD, and heritability estimates from this study support the feasibility of mapping of susceptibility loci for VCMs.

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Heritability estimatesA) Heritability estimates for each dependent variable (square root transformation) at five time points (baseline and 30, 60, 90, and 120 days). B) Heritability estimates of change in phenotype from baseline (√timet – √time0). C) Heritability estimates for response trajectories of change scores. D) Heritability of factor analysis of response trajectories.
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Figure 3: Heritability estimatesA) Heritability estimates for each dependent variable (square root transformation) at five time points (baseline and 30, 60, 90, and 120 days). B) Heritability estimates of change in phenotype from baseline (√timet – √time0). C) Heritability estimates for response trajectories of change scores. D) Heritability of factor analysis of response trajectories.

Mentions: The study of 27 inbred mouse strains allowed calculation of heritability for VCMs, EPS, and activity measures. We estimated heritability for these phenotypic data in four progressive ways. Figure 3a shows heritability estimates at five time points for the nine phenotypes (square root transformations of raw data). Strong genetic effects are evident for virtually all phenotypes. To isolate the impact of exposure to haloperidol, Figure 3b depicts the heritabilities of haloperidol-induced change scores (√timet – √time0). Heritabilities are considerably lower but generally > 0.4. Change scores can be unreliable and reflect error variance 26, particularly if the variables in the change score calculation are correlated. For example, the correlations of time0 with time30 measures were high for the activity (~0.6) and VCM measures (~0.5) but near zero for EPS (−0.07). For all correlated measures, the heritability of change scores is markedly lower but not for the uncorrelated EPS measure. Thus, the estimates in Figure 3b appear to be artifactually low. Figure 3c provides an improved estimation of phenotype-level heritability via analysis of change trajectories. The heritability of seven phenotypes exceeded 75% (all except center time and stereotopy).


Antipsychotic-induced vacuous chewing movements and extrapyramidal side effects are highly heritable in mice.

Crowley JJ, Adkins DE, Pratt AL, Quackenbush CR, van den Oord EJ, Moy SS, Wilhelmsen KC, Cooper TB, Bogue MA, McLeod HL, Sullivan PF - Pharmacogenomics J. (2010)

Heritability estimatesA) Heritability estimates for each dependent variable (square root transformation) at five time points (baseline and 30, 60, 90, and 120 days). B) Heritability estimates of change in phenotype from baseline (√timet – √time0). C) Heritability estimates for response trajectories of change scores. D) Heritability of factor analysis of response trajectories.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3117923&req=5

Figure 3: Heritability estimatesA) Heritability estimates for each dependent variable (square root transformation) at five time points (baseline and 30, 60, 90, and 120 days). B) Heritability estimates of change in phenotype from baseline (√timet – √time0). C) Heritability estimates for response trajectories of change scores. D) Heritability of factor analysis of response trajectories.
Mentions: The study of 27 inbred mouse strains allowed calculation of heritability for VCMs, EPS, and activity measures. We estimated heritability for these phenotypic data in four progressive ways. Figure 3a shows heritability estimates at five time points for the nine phenotypes (square root transformations of raw data). Strong genetic effects are evident for virtually all phenotypes. To isolate the impact of exposure to haloperidol, Figure 3b depicts the heritabilities of haloperidol-induced change scores (√timet – √time0). Heritabilities are considerably lower but generally > 0.4. Change scores can be unreliable and reflect error variance 26, particularly if the variables in the change score calculation are correlated. For example, the correlations of time0 with time30 measures were high for the activity (~0.6) and VCM measures (~0.5) but near zero for EPS (−0.07). For all correlated measures, the heritability of change scores is markedly lower but not for the uncorrelated EPS measure. Thus, the estimates in Figure 3b appear to be artifactually low. Figure 3c provides an improved estimation of phenotype-level heritability via analysis of change trajectories. The heritability of seven phenotypes exceeded 75% (all except center time and stereotopy).

Bottom Line: As expected, haloperidol caused marked changes in VCMs, activity in the open field and extrapyramidal symptoms (EPS).The heritability of a composite phenotype was ∼0.9 after incorporation of the longitudinal nature of the design.Murine VCMs are a face valid animal model of antipsychotic-induced TD, and heritability estimates from this study support the feasibility of mapping of susceptibility loci for VCMs.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7264, USA. crowley@unc.edu

ABSTRACT
Pharmacogenomics is yet to fulfill its promise of manifestly altering clinical medicine. As one example, a predictive test for tardive dyskinesia (TD) (an adverse drug reaction consequent to antipsychotic exposure) could greatly improve the clinical treatment of schizophrenia but human studies are equivocal. A complementary approach is the mouse-then-human design in which a valid mouse model is used to identify susceptibility loci, which are subsequently tested in human samples. We used inbred mouse strains from the Mouse Phenome Project to estimate the heritability of haloperidol-induced activity and orofacial phenotypes. In all, 159 mice from 27 inbred strains were chronically treated with haloperidol (3 mg kg(-1) per day via subdermal slow-release pellets) and monitored for the development of vacuous chewing movements (VCMs; the mouse analog of TD) and other movement phenotypes derived from open-field activity and the inclined screen test. The test battery was assessed at 0, 30, 60, 90 and 120 days in relation to haloperidol exposure. As expected, haloperidol caused marked changes in VCMs, activity in the open field and extrapyramidal symptoms (EPS). Unexpectedly, factor analysis demonstrated that these measures were imprecise assessments of a latent construct rather than discrete constructs. The heritability of a composite phenotype was ∼0.9 after incorporation of the longitudinal nature of the design. Murine VCMs are a face valid animal model of antipsychotic-induced TD, and heritability estimates from this study support the feasibility of mapping of susceptibility loci for VCMs.

Show MeSH
Related in: MedlinePlus