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


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


METHODS
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).


RESULTS
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 x 10(-7), some promising candidate genes for further research on genetic predisposition to AIP were identified including EPF1, NOVA1, and FIGN.


CONCLUSIONS
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.
Alkelai
Ana
A
Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Ein Karem, Jerusalem 91120, Israel.
Greenbaum
Lior
L
Rigbi
Amihai
A
Kanyas
Kyra
K
Lerer
Bernard
B
D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D016032:Randomized Controlled Trials as Topic; D012559:Schizophrenia / Q000188:drug therapy*; D012720:Severity of Illness Index; D014481:United States; D055815:Young Adult
D014150:Antipsychotic Agents
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