Association of the ZFPM2 gene with antipsychotic-induced parkinsonism in schizophrenia patients

Rationale Antipsychotic-induced parkinsonism (AIP) is a severe adverse affect of antipsychotic drug treatment. Recently, our group performed a genome-wide association study (GWAS) for AIP severity, and identified several potential AIP risk variants. Objectives The aim of this study was to validate our original AIP-GWAS susceptibility variants and to understand their possible function. Methods We conducted a validation study of 15 single-nucleotide polymorphisms (SNPs) in an independent sample of 178 US schizophrenia patients treated for at least a month with typical or atypical antipsychotics. Then, a sample of 49 Jewish Israeli Parkinson's disease (PD) patients with available neuroimaging ([ ¹²³I]-FP-CIT-SPECT) data was analyzed, to study association of confirmed AIP SNPs with level of dopaminergic deficits in the putamen. Results Using logistic regression and controlling for possible confounders, we found nominal association of the intronic SNP, rs12678719, in the Zinc Finger Protein Multitype 2 (ZFPM2) gene with AIP (62 affected/116 unaffected), in the whole sample (p=0.009; P=5.97×10 ^-5 in the GWAS), and in the African American sub-sample (N=111; p=0.002). The same rs12678719-G AIP susceptibility allele was associated with lower levels of dopami-nergic neuron related ligand binding in the contralateral putamen of PD patients (p=0.026). Conclusions Our preliminary findings support association of the ZFPM2 SNP, rs12678719, with AIP. At the functional level, this variant is associated with deficits in the nigrostriatal pathway in PD patients that may be related to latent subclinical deficits among AIP-prone individuals with schizophrenia. Further validation studies in additional populations are required.