MOLECULAR GENETICS OF TARDIVE DYSKINESIALerer B, Segman RH, Heresco-Levy U, Finkel B, Yakir A, Dorevich A, Shlaffman M, Lerner A, Greenberg D.Biological Psychiatry Unit, Hadassah -Hebrew University Medical Center, Jerusalem, Israel Tardive dyskinesia (TD) is a choreoathetotic movement disorder that develops in ~20% of patients chronically exposed to antipsychotic drugs that block dopamine D2 receptors. Known risk factors include age, gender and variables related to the duration, dose and potency of the antipsychotic drugs administered. These variables leave most of the inter-individual difference in susceptibility to TD unexplained, however. There is evidence from animal and human studies for a substantial genetic contribution to liability to TD but the genes involved are not known. The genetic basis of TD can be expected to be complex with multiple genetic factors as well as environmental influences contributing to expression of the phenotype. We have been screening a series of candidate genes in 53 chronic schizophrenia patients with TD who were on a stable antipsychotic dose for the three months preceding evaluation and were matched for variables such as age, gender, ethnic origin, smoking history and duration of antipsychotic treatment to 63 schizophrenia patients without TD. We found an excess of the dopamine D3 receptor glycine allele (DRD3gly) and of DRD3ser-gly and DRD3gly-gly genotypes in the patients with TD (Segman et al., Mol Psychiatry, 4:247-253, 1999). These findings confirmed the previous report of Steen et al. (Mol Psychiatry 2:139-145, 1997). We further demonstrated parametrically (by analysis of covariance, controlling for age at first antipsychotic treatment) that patients carrying genotypes with the DRD3gly allele had significantly higher Abnormal Involuntary Movement Scale (AIMS) total scores than those homozygous for the DRD3ser allele. Subsequently, Basile et al. (Neuropsychopharmacology 21:17-27, 1999) reported higher dyskinesia score in schizophrenia patients with TD homozygous for the DRD3gly allele. We genotyped the same group of patients for a functionally relevant cysteine to serine polymorphism in the 5-HT2C receptor gene (HT2CR). There was an excess of HT2CRser alleles in the patients with TD (27.1% vs. 14.6%, x2=4.1, df 1, p=.04; males and females combined) and in the female patients alone (32.6% vs. 17.2%, x2=3.6, df 1, p=.05). By ANCOVA (controlling for age at first antipsychotic treatment), there was a significant effect of HT2CR genotype on AIMS orofacial dyskinesia (AIMS-OFD) scores (F=3.47, df 2, p=.03). Planned comparisons showed higher AIMS-OFD scores in patients with the HT2CRcys-ser (p=.02) and HT2CRser-ser (p=.04) genotypes compared to patients homozygous for the wild type HT2CRcys-cys genotype. In a further ANCOVA in which the independent variables were carriage of DRD3gly or HT2CR-ser alleles, there was a significant main effect of both alleles on AIMS-OFD scores (p=.006 and p=.02 respectively) but no interaction. To evaluate the proportion of the variance in AIMS-OFD scores accounted for by demographic, clinical and genetic variables, we performed a stepwise multiple regression classifying patients according to carriage of DRD3gly or HT2CR-ser alleles. The overall proportion of the variance accounted for in the model was 20.8%. Age at first antipsychotic treatment accounted for 8.2% (p=.0001), gender for 3.7% (p=.02), DRD3gly for 4.6% (p=.02) and HT2CRser for 4.2% (p=.001). These findings indicate that both DRD3gly and HT2CRser alleles to contribute to susceptibility to TD in patients with chronic schizophrenia and are the first to demonstrate an additive contribution of two genes to vulnerability to this complex phenotype. Results will be presented for further candidate genes that have been examined and the possibility that TD susceptibility may mark a genetically distinct subtype of schizophrenia, will be considered (Supported in part by a grant from the Hadassit Applied Research Fund and by the Indian-Israeli Human Genome Research Program). 
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