, Volume 206, Issue 3, pp 491–499 | Cite as

Genome-wide association study of antipsychotic-induced parkinsonism severity among schizophrenia patients

  • Ana Alkelai
  • Lior Greenbaum
  • Amihai Rigbi
  • Kyra Kanyas
  • Bernard LererEmail author
Original Investigation



Antipsychotic-induced parkinsonism (AIP) is a severe adverse affect of neuroleptic treatment. Interindividual heterogeneity in AIP development and severity is associated with risk factors such as antipsychotic drug type, old age, and female gender. There is evidence for genetic predisposition to develop AIP but the variants that confer susceptibility or protection are mostly unknown.


To identify genes related to AIP susceptibility, we performed a pharmacogenomic genome-wide association study (GWAS) for AIP severity.


Three hundred ninety-seven American schizophrenia patients who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)-GWAS project were included in our analysis. Patients had been randomized to treatment with antipsychotic monotherapy for periods ranging from 2 weeks to 18 months during phase 1 of the CATIE trial. They were regularly assessed for AIP severity using the modified Simpson–Angus Scale (SAS). For statistical analysis, patients were dichotomized as cases (average SAS mean global score > 0.3 during CATIE phase 1, N = 199) or controls (average SAS mean global score 0, N = 198).


Using logistic regression and controlling for population stratification, age, gender, SAS score at baseline, and concomitant use of anticholinergic drugs, we identified several single-nucleotide polymorphisms associated with AIP severity. Although none reached the GWAS significance level of P < 4.2 × 10−7, some promising candidate genes for further research on genetic predisposition to AIP were identified including EPF1, NOVA1, and FIGN.


Our finding may contribute to understanding of the pathophysiology of AIP as well as to a priori identification of patients vulnerable for development of AIP.


Antipsychotic Genetics Schizophrenia Extrapyramidal symptoms Parkinsonism 



The principal investigators of the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) trial were Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., and Joseph P. McEvoy, M.D. The CATIE trial was funded by a grant from the National Institute of Mental Health (N01 MH900001) along with MH074027 (PI PF Sullivan). Genotyping was funded by Eli Lilly and Company.

Supplementary material

213_2009_1627_MOESM1_ESM.doc (56 kb)
Supplementary Table 1 (DOC 56 kb)


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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Ana Alkelai
    • 1
  • Lior Greenbaum
    • 1
  • Amihai Rigbi
    • 1
  • Kyra Kanyas
    • 1
  • Bernard Lerer
    • 1
    Email author
  1. 1.Biological Psychiatry Laboratory, Department of PsychiatryHadassah-Hebrew University Medical CenterJerusalemIsrael

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