Genome wide study of tardive dyskinesia in schizophrenia.
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ABSTRACT:
SUBMITTER: Lim K
PROVIDER: S-EPMC8187404 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
Publications
Genome wide study of tardive dyskinesia in schizophrenia.
Lim Keane K Lam Max M Zai Clement C Tay Jenny J Karlsson Nina N Deshpande Smita N SN Thelma B K BK Ozaki Norio N Inada Toshiya T Sim Kang K Chong Siow-Ann SA Lencz Todd T Liu Jianjun J Lee Jimmy J
Translational psychiatry 20210608 1
Tardive dyskinesia (TD) is a severe condition characterized by repetitive involuntary movement of orofacial regions and extremities. Patients treated with antipsychotics typically present with TD symptomatology. Here, we conducted the largest GWAS of TD to date, by meta-analyzing samples of East-Asian, European, and African American ancestry, followed by analyses of biological pathways and polygenic risk with related phenotypes. We identified a novel locus and three suggestive loci, implicating ...[more]
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Project description:BackgroundTardive dyskinesia (TD) is a common side effect of antipsychotic treatment. This movement disorder consists of orofacial and limb-truncal components. The present study is aimed at investigating the role of serotonin receptors (HTR) in modulating tardive dyskinesia by genotyping patients with schizophrenia.MethodsA set of 29 SNPs of genes of serotonin receptors HTR1A, HTR1B, HTR2A, HTR2C, HTR3A, HTR3B, and HTR6 was studied in a population of 449 Caucasians (226 females and 223 males) with verified clinical diagnosis of schizophrenia (according to ICD-10: F20). Five SNPs were excluded because of low minor allele frequency or for not passing the Hardy-Weinberg equilibrium test. Affinity of antipsychotics to 5-HT2 receptors was defined according to previous publications. Genotyping was carried out with SEQUENOM Mass Array Analyzer 4.ResultsStatistically significant associations of rs1928040 of HTR2A gene in groups of patients with orofacial type of TD and total diagnosis of TD was found for alleles, and a statistical trend for genotypes. Moreover, statistically significant associations were discovered in the female group for rs1801412 of HTR2C for alleles and genotypes. Excluding patients who used HTR2A, respectively, HTR2C antagonists changed little to the associations of HTR2A polymorphisms, but caused a major change of the magnitude of the association of HTR2C variants. Due to the low patient numbers, these sub-analyses did not have significant results.ConclusionWe found significant associations in rs1928040 of HTR2A and for rs1801412 of X-bound HTR2C in female patients. The associations were particularly related to the orofacial type of TD. Excluding patients using relevant antagonists particularly affected rs1801412, but not rs1928040-related associations. This suggest that rs1801412 is directly or indirectly linked to the functioning of HTR2C. Further study of variants of the HTR2C gene in a larger group of male patients who were not using HTR2C antagonists is necessary in order to verify a possible functional role of this receptor.
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Project description:Tardive dyskinesia (TD) is a movement disorder characterized by involuntary oro-facial, limb, and truncal movements. As a genetic basis for inter-individual variation is assumed, there have been a sizeable number of candidate gene studies. All subjects met diagnostic criteria for schizophrenia and were randomized to receive antipsychotic medications as participants in the Clinical Antipsychotic Trials of Intervention Effectiveness project (CATIE). TD was assessed via the Abnormal Involuntary Movement Scale at regular intervals. Probable TD was defined as meeting Schooler-Kane criteria at any scheduled CATIE visit (207/710 subjects, 29.2%). A total of 128 candidate genes were studied in 710 subjects-2,580 SNPs in 118 candidate genes selected from the literature (e.g., dopamine, serotonin, glutamate, and GABA pathways) and composite genotypes for 10 drug-metabolizing enzymes. No single marker or haplotype association reached statistical significance after adjustment for multiple comparisons. Thus, we found no support for either novel or prior associations from the literature.
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Project description:ObjectiveInterleukin-10 (IL-10) is a major immunoregulatory cytokine and its gene plays a fundamental role in anti-inflammatory and immunosuppressive activity. This study aimed to examine the association between the IL10 gene promoter -1082G/A polymorphism (rs1800896) and tardive dyskinesia (TD) in schizophrenia.MethodsTwo hundred and eighty unrelated Korean schizophrenic patients participated in this study (105 TD and 175 non-TD patients). TD was diagnosed using the Research Diagnostic Criteria for TD and Abnormal Involuntary Movement Scale (AIMS). Genotyping was performed by RT-PCR and high-resolution melting curve analysis.ResultsThe distributions of genotypic frequencies did not differ between patients with and without TD (χ2=4.33, p=0.115). However, allelic frequencies of the two groups were different (χ2=4.45, p=0.035); the A allele frequency was higher in TD. The total AIMS scores of the three genotypes were not different (F=1.33, p=0.266). However, the total AIMS scores of the A allele carrier and the A allele non-carrier were significantly different (t=5.79, p<0.001). Logistic regression analaysis showed that IL10 -1082G/A genotype significantly predicts presence of TD (p=0.045) after adjusting for covariates such as age and treatment duration.ConclusionThis finding suggests that the A allele of rs1800896 may be associated with TD development following a low IL-10 function.
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| S-EPMC9733323 | biostudies-literature
Project description:Tardive dyskinesia (TD) is a hyperkinetic movement disorder associated with the prolonged use of antipsychotic drugs. Since prostate apoptosis response 4 (Par-4) is a key ligand of the dopamine D2 receptor, the Par-4 gene (PAWR) is a good candidate gene to study in the context of TD susceptibility. We examined the association between PAWR gene polymorphisms and TD. Three single nucleotide polymorphisms of PAWR were selected for the analysis: rs7979987, rs4842318, and rs17005769. Two hundred and eighty unrelated Korean schizophrenic patients participated in this study (105 TD and 175 non-TD patients). Genotype/allele-wise and haplotype-wise analyses were performed. There were no significant differences in genotype and allele frequencies between the two groups. Haplotype analysis also did not reveal a difference between the two groups. Within the limitations imposed by the size of the clinical sample, these findings suggest that PAWR gene variants do not significantly contribute to an increased risk of TD.
| S-EPMC3372569 | biostudies-literature
Project description:BackgroundTardive dyskinesia is a movement disorder characterised by irregular, stereotyped, and choreiform movements associated with the use of antipsychotic medication. We aim to provide recommendations on the treatment of tardive dyskinesia.MethodsWe performed a systematic review of studies of the treatment of tardive dyskinesia. Studies were rated for methodological quality using the American Academy of Neurology Risk of Bias Classification system. Overall level of evidence classifications and grades of recommendation were made using the Scottish Intercollegiate Guidelines Network framework.ResultsPreventing tardive dyskinesia is of primary importance, and clinicians should follow best practice for prescribing antipsychotic medication, including limiting the prescription for specific indications, using the minimum effective dose, and minimising the duration of therapy. The first-line management of tardive dyskinesia is the withdrawal of antipsychotic medication if clinically feasible. Yet, for many patients with serious mental illness, the discontinuation of antipsychotics is not possible due to disease relapse. Switching from a first-generation to a second-generation antipsychotic with a lower D2 affinity, such as clozapine or quetiapine, may be effective in reducing tardive dyskinesia symptoms. The strongest evidence for a suitable co-intervention to treat tardive dyskinesia comes from tests with the new VMAT inhibitors, deutetrabenazine and valbenazine. These medications have not been approved for use in Canada.ConclusionData on tardive dyskinesia treatment are limited, and the best management strategy remains prevention. More long-term safety and efficacy data are needed for deutetrabenazine and valbenazine, and their routine availability to patients outside of the USA remains in question.
| S-EPMC6591749 | biostudies-literature