Association of dopaminergic and serotonergic genes with tardive dyskinesia in patients with chronic schizophrenia.

Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal side effect profile of atypical antipsychotic drugs. We evaluated candidate dopamine and serotonin genes for association with drug-induced TD. We examined three polymorphisms in the dopamine D2 receptor gene (DRD2), two sites in the 3' region of the dopamine transporter (DAT) gene, two sites in the promoter and coding region of the dopamine D4 (DRD4) receptor gene, as well as polymorphic sites in the serotonin 6 receptor gene, the serotonin transporter gene and the tryptophan hydroxylase gene, for association with TD susceptibility. Schizophrenic patients with (n=59) and without TD (n=63), matched for antipsychotic drug exposure and other relevant variables, were studied. No significant associations were found. Within the limitations imposed by the size of the clinical sample, these findings suggest that the above polymorphic loci do not contribute significantly to risk for TD. Further examination of loci that yielded positive results at a trend level and investigation of other candidate genetic loci coding for antipsychotic drug targets is warranted.

Association between the dopamine transporter gene and posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a chronic anxiety disorder that follows exposure to extreme events. A large twin study of Vietnam veterans had demonstrated a significant genetic contribution to chronic PTSD upon exposure to combat.(1,2) The underlying genes, however, have not been described. Given previous findings of abnormal dopamine (DA) function in PTSD, and given the putative effect of dopamine neurotransmission in shaping the responses to stress in animals, this study examined the association of the dopamine transporter (DAT) SLC6A3 3' variable number tandem repeat (VNTR) polymorphism with PTSD. The study evaluated 102 chronic PTSD patients and 104 carefully-documented trauma survivors (TS) who did not develop PTSD. Significant excess of 9 repeat allele was observed among PTSD patients (43% vs 30.5% in TS controls; chi(2) = 6.3, df = 1, P = 0.012). An excess of 9 repeat homozygous genotype was also observed in PTSD (20.43% in PTSD vs 9.47% in TS controls; chi(2) = 6.11, df = 2, P < 0.047). These findings suggest that genetically determined changes in dopaminergic reactivity may contribute to the occurrence of PTSD among trauma survivors.

Preferential transmission of interleukin-1 receptor antagonist alleles in attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, where family data support substantial heritability.(1) To date, association studies focussed mainly on genes regulating dopaminergic neurotransmission.(2)Interleukin-1 (IL-1) activity in the brain has been implicated with differentiation of dopaminergic neurons(3,4) and modulation of central monoaminergic reactivity.(5) We investigated the role of interleukin-1 receptor antagonist (IL-1Ra) gene variable number tandem repeat (VNTR) polymorphism,(6) in a sample of 86 children with DSM-IV ADHD and their parents. Transmission disequilibrium analysis showed increased transmission of the IL-1Ra 4-repeat allele (chi(2) = 4.07, P = 0.04) and decreased transmission of the 2-repeat allele (chi(2) = 4.59, P = 0.03) to affected children. The 4-repeat allele was associated with a significantly increased risk for ADHD (chi(2) = 4.46, df 1, P = 0.035, RR = 1.292, 95% CI 1.01-1.66). The IL-1Ra 2-repeat allele was associated with a significantly decreased risk for ADHD (chi(2) = 4.65, df 1, P = 0.03, RR = 0.763, 95% CI 0.59-0.98). If replicated, this finding may point to a role for brain cytokine activity in the etiopathogenesis of ADHD.

Association between the serotonin 2A receptor gene and tardive dyskinesia in chronic schizophrenia.

Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers.(1) Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal effects profile of atypical antipsychotic drugs.(2) We examined the association of three polymorphisms in the 5-HT2A receptor gene (HTR2A) with TD susceptibility--T102C(3) and his452tyr(4) in the coding region and A-1438G(5) in the promoter--in matched schizophrenia patients with (n = 59, SCZ-TD-Y) and without TD (n = 62, SCZ-TD-N) and normal control subjects (n = 96). The T102C and the A-1438G polymorphisms are in complete linkage disequilibrium but not his452tyr. There was a significant excess of 102C and -1438G alleles (62.7%) in the SCZ-TD-Y patients compared to SCZ-TD-N patients (41.1%) and controls (45.9%; chi(2) = 12.8, df = 2, P = 0.002; SCZ-TD-Y vs SCZ-TD-N, chi(2) = 11.4, df = 1, P = 0.0008, OR 2.41, 95% CI 1.43-3.99) and of 102CC and -1438GG genotypes (SCZ-TD-Y 42.4%, SCZ-TD-N, 16.1%, controls 20.8%, chi(2) = 13.3, df = 4, P = 0.01). The 102CC and the -1438GG genotypes were associated with significantly higher AIMS trunk dyskinesia scores (F = 3.9; df = 2, 116; P = 0.02) and more incapacitation (F = 5.0; df = 2, 115; P = 0.006). The his452tyr polymorphism showed no association with TD. These findings suggest that the 5-HT2A receptor gene is significantly associated with susceptibility to TD in patients with chronic schizophrenia. Previously reported association of the T102C and A-1438G polymorphisms with schizophrenia(6) may reflect association of a sub-group of patients with a susceptibility to abnormal involuntary movements related to antipsychotic drug exposure.

Association between the serotonin 2C receptor gene and tardive dyskinesia in chronic schizophrenia: additive contribution of 5-HT2Cser and DRD3gly alleles to susceptibility.

RATIONALE: Tardive dyskinesia (TD) is a longterm adverse effect of dopamine receptor blockers. The dopamine D3 receptor gene (DRD3) ser9gly polymorphism has been previously associated with susceptibility to TD. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extra-pyramidal effects profile of atypical antipsychotic drugs. OBJECTIVES: To examine the association of a functional polymorphism in the 5-HT2C receptor gene (HT2CR) with TD and the joint contribution of HT2CR and DRD3 to susceptibility. METHODS: Case control association analysis of allele and genotype frequencies among schizophrenia patients with (n=55) and without TD (n=60), matched for antipsychotic drug exposure and other relevant variables, and normal control subjects (n=97). Parametric analyses of the contribution of 5-HT2Cser and DRD3gly alleles to dyskinesia scores. RESULTS: We found a significant excess of 5-HT2Cser alleles in schizophrenia patients with TD (27.2%) compared to patients without TD (14.6%) and normal controls (14.2%; chi2=6.4, df 2, P=0.03) which was due to the female patients (chi2=8.6, df 2, P=0.01). Among the female TD patients there was an excess of cys-ser and ser-ser genotypes (chi2= 11.9, df 4, P=0.02). Analysis of covariance (ANCOVA), controlling for age at first antipsychotic treatment, revealed a significant effect of 5-HT2C genotype on orofacial dyskinesia (OFD) scores (F=3.47, df 2, P=.03). In a stepwise multiple regression analysis, 5-HT2C and DRD3 genotype (5-HT2Cser and DRD3gly allele carriage) respectively contributed 4.2% and 4.7% to the variance in OFD scores. CONCLUSIONS: These findings support a small but significant contribution of the HT2CR and DRD3 to susceptibility to TD, which is additive in nature.