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

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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.

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Acknowledgments

The mice used in this study were acquired as part of the Mouse Phenome Project, an ongoing international collaborative effort headquartered at The Jackson Laboratory (Bar Harbor, ME, USA). This work was supported by the Pharmacogenetics Research Network (U01 GM63340, PI Dr. McLeod), a NIMH/NHGRI Center of Excellence for Genome Sciences grant (P50 MH90338, PIs Drs. Fernando Pardo-Manuel de Villena and Sullivan), and the Mouse Behavioral Phenotyping Laboratory (NICHD P30 HD03110, PI Dr. Joseph Piven). Dr. Sullivan was supported by MH080403, MH077139, and MH074027.

Disclosures

The authors have no biomedical financial interests or potential conflicts of interest to disclose.

Online Resources

Phenotypic data from this project are available online via the Mouse Phenome Database (MPD; http://www.jax.org/phenome).

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Authors and Affiliations

  1. Department of Genetics, University of North Carolina, Genomic Medicine Building, CB#7264, Chapel Hill, NC, 27599-7264, USA

    James J. Crowley, Yunjung Kim, Jin Peng Szatkiewicz, Amanda L. Pratt, Corey R. Quackenbush, Fernando Pardo-Manuel de Villena & Patrick F. Sullivan

  2. Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA

    James J. Crowley & Howard L. McLeod

  3. Center for Biomarker Research & Personalized Medicine, Virginia Commonwealth University, Richmond, VA, USA

    Daniel E. Adkins & Edwin van den Oord

  4. The Jackson Laboratory, Bar Harbor, ME, USA

    Molly A. Bogue & Hyuna Yang

  5. Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA

    Wei Wang

  6. Department of Genetics, North Carolina State University, Raleigh, NC, USA

    David W. Threadgill

  7. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Patrick F. Sullivan

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  1. James J. Crowley
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  2. Yunjung Kim
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  3. Jin Peng Szatkiewicz
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  12. Fernando Pardo-Manuel de Villena
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Correspondence to James J. Crowley.

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Crowley, J.J., Kim, Y., Szatkiewicz, J.P. et al. Genome-wide association mapping of loci for antipsychotic-induced extrapyramidal symptoms in mice. Mamm Genome 23, 322–335 (2012). https://doi.org/10.1007/s00335-011-9385-8

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