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

Abstract

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...

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

“…Studies on 5-HT6 and 5-HTT polymorphisms failed to find any association. 205,251,252 Further studies investigating 5-HT 2C , 5-HT 2A and D 3 genotypes with age and disease phenotypes 249,250 provided significant associations confirming the involvement of dopamine and serotonin systems in susceptibility to TD.…”

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype

“…Another possible explanation is that older patients will generally have been exposed to antipsychotic drugs for a longer period. However, Segman and Lerer (2002b) controlled for years of exposure and found that the age effect on the genetic associations that they observed remained significant. Of the four published studies on the relationship of HTR 2A T102C to TD, in the two that found an association the mean age of the subjects was >50 yr Tan et al, 2001) and in the two which did not find an association the mean age Figure 4.…”

“…Two studies found T102C and A-1438G to be in close linkage disequilibrium (LD), Segman et al (2001) but not Basile et al (2001) observing an association with TD. Segman and Lerer (2002b) found that the association of T102C with TD was demonstrable in older but not younger patients.…”

“…Segman and Lerer (2002b) re-analysed their data for three polymorphisms that were associated with TD in their sample. For two serotonin receptor polymorphisms, HTR 2C -Cys23Ser and HTR 2A -T102C, but not for DRD3, there was a significant effect on AIMS scores only in subjects o47 yr. Segman and Lerer (2002b) suggested that genetically based variations in receptors might become functionally relevant at an older age when receptor reserve is reduced below a critical threshold for reasons related to the ageing process (Versijpt et al, 2003). Another possible explanation is that older patients will generally have been exposed to antipsychotic drugs for a longer period.…”

Clinical implications of pharmacogenomics for tardive dyskinesia

“…Basile et al 58 and Herken et al 59 were unable to replicate these findings and, therefore, the role of the T102C variant in the 5-HT2A gene cannot be unambiguously associated with the occurrence of TD. Segman et al, 60 however, could demonstrate by further analysis that the effect of 5-HT2A in TD is age related: The 5-HT2A variant seems to confer risk for TD in older patients (449 years) but not in younger patients, which may explain the inconsistent findings. Of note, the T102 C and the A-1438G variants were found to be in linkage disequilibrium in the studies of Segman et al 56 and Basile et al; 58 therefore, similar results with both variants were obtained.…”