Dopamine D3 receptor variant and tardive dyskinesia

Rietschel, Marcella; Krauss, Herbert H.; Müller, Daniel J.; Schulze, Thomas G.; Knapp, Michael; Marwinski, Konrad; Maroldt, A.; Paus, Sebastian; Grünhage, F; Propping, Peter; Maier, Wolfgang; Held, Tilo; Nöthen, Markus M.

doi:10.1007/pl00007536

Cited by 64 publications

(46 citation statements)

References 19 publications

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“…This was not true of DRD3 which, intriguingly, was found to be associated with TD by our group 4 and by Basile et al 5 and is a widely although not universally replicated genetic association with TD. [9][10][11] On the other hand, there was a significant age effect of HTR2A for which there was a disparity between our findings 2 and those of Basile et al 3 As noted, the sample examined by Basile et al 3 was two decades younger, on average, than our sample. There is considerable evidence from post-mortem and neuroimaging studies that brain serotonin receptor density, particularly 5-HT2A receptor density, is reduced with age (reviewed in Cidis Meltzer et al 12 ).…”

Section: Agecontrasting

confidence: 70%

Age and the relationship of dopamine D3, serotonin 2C and serotonin 2A receptor genes to abnormal involuntary movements in chronic schizophrenia

Segman¹,

Lerer²

2002

Mol Psychiatry

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trols was within Hardy-Weinberg equilibrium. Odds ratio (OD) and their 95% confidence intervals were calculated to evaluate effects of different genotypes. We found a difference in the frequency of A/G alleles between the total amount of patients studied and controls which comes close to statistical significance ( 2 = 3.440; P = 0.063). The genotype distributions differed significantly in patients with AD compared to the controls ( 2 = 8.68; P = 0.013). The frequency of individuals who carried two copies of the Val allele was significantly increased in patients than in controls ( 2 = 6.202; P = 0.013, odds ratio: 1.994, 95% CI 1.15-3.46), suggesting that homozygosity for the Val allele confers an increased risk for AD.In order to examine the possible interaction between AD and APOE, we genotyped the 130 AD patients and we found 65 carrying the ⑀4 allele of APOE gene. There was no significant difference in the distribution of allele frequencies between the two groups ( 2 = 0.090, df = 1, P = 0.76) ( Table 1), and we concluded that possible effects of Val on susceptibility to AD might be independent from the APOE genotype. These data are in agreement with a recent observation of association of another BDNF gene polymorphism (C270T in the 5ЈUTR) to late onset AD in the Japanese population. 9 Further studies are needed to confirm the relationship of two polymorphisms including a possible linkage disequilibrium.In conclusion these results make the BDNF an important candidate gene for susceptibility of AD and might provide a baseline to rationalize the use of neurotrophins as possible therapeutic agents in specific human neurodegenerative diseases. 2 This receptor is implicated in the mechanism of action of atypical antipsychotic drugs that have a lower propensity to induce TD. Our positive findings were for the silent T102C polymorphism in the coding region and the A-1438G polymorphism in the promoter, which were in complete linkage disequilibrium in our sample. Patients with TD had a significant excess of 102C and −1438G alleles and of 102CC and −1438GG genotypes compared to patients without TD and normal control subjects. Patients carrying the 102CC and −1438GG genotypes had significantly higher scores on the sub-scales of the Abnormal Involuntary Movements Scale (AIMS) that measure dyskinetic trunk movements and degree of incapacitation. M VentrigliaIn the same issue of Molecular Psychiatry, Basile et al, 3 to whom we had communicated our unpublished findings, reported no allelic or genotypic association of the same polymorphisms in HTR2A with TD. Their patients carrying 102CC and −1438GG genotypes did not have higher AIMS total scores than patients homozygous for the wild-type allele. AIMS sub-scale scores were not reported. This disparity contrasts with similar findings of the two groups in the same patient samples in regard to association of the dopamine D3 receptor gene (DRD3) with TD. 4,5 Among the demographic and clinical factors that have been associated with individual susceptibility to TD, age is the mos...

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Section: Agecontrasting

confidence: 70%

Age and the relationship of dopamine D3, serotonin 2C and serotonin 2A receptor genes to abnormal involuntary movements in chronic schizophrenia

Segman¹,

Lerer²

2002

Mol Psychiatry

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“…Recently, a genotypic association between the DRD3 receptor polymorphism and a susceptibility to neuroleptic-induced motor disturbances such as tardive dyskinesia and akathisia in schizophrenic patients was obtained in a number of studies [9][10][11][12] except for one. 13 Furthermore, the association between the DRD3 polymorphism and a schizoaffective variant of schizophrenia was reported. 14 The identification of vulnerability genes for schizophrenia is compounded by the wide range of phenotypic variability postulated in this illness and it has recently been suggested that in genetic studies some clinical or biochemical markers should be used to diminish this variability.…”

mentioning

confidence: 99%

Dopamine D3 receptor (DRD3) gene polymorphism is associated with the intensity of eye movement disturbances in schizophrenic patients and healthy subjects

et al. 2001

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Altered dopamine neurotransmission and eye movement disturbances have been implicated in the pathogenic process of schizophrenia. So far, molecular genetic studies have shown little association between schizophrenia and polymorphism of any dopamine receptor or transporter genes except for some findings concerning D3 receptor (DRD3) gene. Eye movement disturbances occur in a majority of patients with schizophrenia and in a proportion of their first-degree relatives and they have been suggested as a phenotypic marker in genetic studies of this illness. Here we report an association between the Ser9Gly polymorphism of the DRD3 gene and the intensity of eye movement disturbances (fixation and smooth pursuit) observed in 119 schizophrenic patients and in 94 unrelated healthy control subjects. In schizophrenic patients, the mean intensity of both kinds of eye movement disturbances was highest in individuals with the Ser-Ser genotype, significantly lower in Ser-Gly and lowest in the Gly-Gly genotype. The Ser-Ser genotype was more prevalent in patients with a higher intensity of both fixation (58.1 vs 23.9% P Ͻ 0.001) and smooth pursuit disturbances (52.3 vs 25.8%, P Ͻ 0.02) and the Ser-Gly genotype frequency was lower in patients with higher fixation disturbances (37.0 vs 60.9%, P Ͻ 0.02). In control subjects, the genotype frequency Ser-Ser was higher in subjects with any degree of eye movement disturbances compared to subjects without such disturbances both for fixation and smooth pursuit performance (81.0 vs 50.7%, P Ͻ 0.05 and 79.2 vs 50.0%, P Ͻ 0.05, respectively). In control subjects the frequency of Ser-Gly was lower in the first group, for either fixation or smooth pursuit, compared to normal performers (9.5 vs 43.8%, P Ͻ 0.01 and 8.3 vs 45.7, P Ͻ 0.005, respectively). We suggest that the DRD3 Ser9Gly polymorphism may be a contributing factor to the performance of eye movements used as a phenotypic marker of schizophrenia. Molecular Psychiatry (2001) 6, 718-724.The hypothesis of altered dopamine neurotransmission in schizophrenia proposed on the basis of the mechanism of antipsychotic drugs action gained some support from recent neuroimaging data. 1 However, molecular genetic studies performed in recent decades did not show a strong association between schizophrenia and any gene coding either dopamine receptor or transporter except for dopamine receptor D3 (DRD3) gene polymorphism, where the relationship was found with some aspects of this illness. DRD3 is localized in limbic and cortical brain areas and probably affects locomotion as well as emotional and cognitive processes. 2 DRD3 knock-out mice show abnormalities in spontaneous level of locomotor activity. 3 The DRD3 gene was mapped to chromosome 3q13.3 and its polymorphic site in exon 1 with a serine to glycine substitution has been postulated as a useful investigating tool in psychiatric disorder. 4 Association studies of this polymorphism with schizophrenia have been mostly negative, including the most recent work of Joober et al. 5

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“…In order to shed light on these controversial results, recently, Lerer et al 6 performed a combined analysis including data from 780 patients from six research centers, dividing patients into eight groups based on their population origin. Most of the data have been published previously either in peer reviewed journals [43][44][45][46][47] or in abstract form 48,49 (see Table 2 for more details). The authors applied stepwise logistic regression, and confounding effects of group, age and gender were taken into account.…”

Section: The Dopaminergic Systemmentioning

confidence: 99%