Mammalian Genome

, Volume 23, Issue 5, pp 322–335

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

  • James J. Crowley
  • Yunjung Kim
  • Jin Peng Szatkiewicz
  • Amanda L. Pratt
  • Corey R. Quackenbush
  • Daniel E. Adkins
  • Edwin van den Oord
  • Molly A. Bogue
  • Hyuna Yang
  • Wei Wang
  • David W. Threadgill
  • Fernando Pardo-Manuel de Villena
  • Howard L. McLeod
  • Patrick F. Sullivan
Article

DOI: 10.1007/s00335-011-9385-8

Cite this article as:
Crowley, J.J., Kim, Y., Szatkiewicz, J.P. et al. Mamm Genome (2012) 23: 322. doi:10.1007/s00335-011-9385-8

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.

Supplementary material

335_2011_9385_MOESM1_ESM.doc (4.2 mb)
Supplementary material 1 (DOC 4320 kb)

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • James J. Crowley
    • 1
    • 2
  • Yunjung Kim
    • 1
  • Jin Peng Szatkiewicz
    • 1
  • Amanda L. Pratt
    • 1
  • Corey R. Quackenbush
    • 1
  • Daniel E. Adkins
    • 3
  • Edwin van den Oord
    • 3
  • Molly A. Bogue
    • 4
  • Hyuna Yang
    • 4
  • Wei Wang
    • 5
  • David W. Threadgill
    • 6
  • Fernando Pardo-Manuel de Villena
    • 1
  • Howard L. McLeod
    • 2
  • Patrick F. Sullivan
    • 1
    • 7
  1. 1.Department of GeneticsUniversity of North CarolinaChapel HillUSA
  2. 2.Institute for Pharmacogenomics and Individualized TherapyUniversity of North CarolinaChapel HillUSA
  3. 3.Center for Biomarker Research & Personalized MedicineVirginia Commonwealth UniversityRichmondUSA
  4. 4.The Jackson LaboratoryBar HarborUSA
  5. 5.Department of Computer ScienceUniversity of North CarolinaChapel HillUSA
  6. 6.Department of GeneticsNorth Carolina State UniversityRaleighUSA
  7. 7.Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden

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