Analysis of schizophrenia-associated genetic markers in the HLA region as risk factors for tardive dyskinesia.

OBJECTIVES: The pathology of Tardive Dyskinesia (TD) has yet to be fully understood, but there have been proposed hypotheses for the cause of this condition. Our team previously reported a possible association of TD with the Complement Component C4 gene in the HLA region. In this study, we explored the HLA region further by examining two previously identified schizophrenia-associated HLA-region single-nucleotide polymorphisms (SNPs), namely rs13194504 and rs210133. METHODS: The SNPs rs13194504 and rs210133 were tested for association with the occurrence and severity of TD in a sample of 172 schizophrenia patients who were recruited for four studies from three different clinical sites in Canada and USA. RESULTS: The rs13194504 AA genotype was associated with decreased severity for TD as measured by Abnormal Involuntary Movement Scale (AIMS) scores (p = 0.047) but not for TD occurrence. SNP rs210133 was not significantly associated with either TD occurrence or AIMS scores. CONCLUSION: Our findings suggest that the rs13194504 AA genotype may play a role in TD severity, while SNP rs210133 may not have a major role in the risk or severity of TD.

Associations between Catechol-O-methyltransferase (COMT) polymorphisms and cognitive impairments, psychiatric symptoms and tardive dyskinesia in schizophrenia.

INTRODUCTION: Catechol-O-methyltransferase (COMT) is a crucial enzyme involved in dopamine metabolism and has been implicated in the etiology of tardive dyskinesia (TD). We aimed to investigate the associations between COMT gene polymorphisms and the occurrence and severity of TD in a Chinese population, as well as the impact on the psychiatric symptoms and cognitive impairments observed in TD patients. METHODS: A total of 216 chronic schizophrenia patients, including 59 TD patients and 157 NTD patients, were recruited for this study. Three SNPs of the COMT gene (rs4680, rs165599 and rs4818) were selected and genotyped using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). TD severity, psychopathology and cognitive functioning were assessed using the Abnormal Involuntary Movement Scale (AIMS), the Positive and Negative Syndrome Scale (PANSS) and the Repeated Battery for Assessment of Neuropsychological Status (RBANS), respectively. RESULTS: In TD patients, total AIMs scores were higher in carriers of the rs4680 AA genotype than in carriers of the AG and GG genotypes (p = 0.01, 0.006), carriers of the rs4818 GC and CC genotypes had higher orofacial scores than in GG genotypes (p = 0.032, 0.002). In male TD patients, carriers of the rs165599 GA genotype scored lower in the extremities and trunk scores than AA genotype carriers (p = 0.015). Moreover, in male TD patients, COMT rs4818 was associated with cognition, since the C allele carriers had significantly higher immediate memory (p = 0.043) and verbal function (p = 0.040) scores than the G allele carriers. In addition, rs165599 genotype interacted with TD diagnosis on depressed factor (p = 0.031). CONCLUSION: Within the Chinese population, COMT gene polymorphisms could potentially serve as biomarkers for the symptoms and prognosis of TD patients.

Associations between polymorphisms in the cannabinoid receptor 1 gene, cognitive impairments and tardive dyskinesia in a Chinese population with schizophrenia.

OBJECTIVE: Tardive dyskinesia (TD) is a medically induced movement disorder that occurs as a result of long-term use of antipsychotic medications, commonly seen in patients with schizophrenia (SCZ). The study aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) of the CNR1 gene, TD and cognitive impairments in a Chinese population with SCZ. METHODS: A total of 216 SCZ patients were recruited. The participants were divided into TD and without TD (WTD) groups using the Schooler-Kane International Diagnostic Criteria. The severity of TD was assessed using the Abnormal Involuntary Movement Scale (AIMS). Cognitive function was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) scale. Hardy-Weinberg equilibrium tests, chained disequilibrium analyses and haplotype analyses were performed using SHE-sis software. To explore the main effects of TD diagnosis, genotype and cognitive function, as well as interaction effects, analysis of covariance (ANCOVA) was employed. RESULTS: The prevalence of TD was approximately 27.3%. Significant differences were observed in the rs806368 CT genotype and rs806370 TC genotype within the hypercongenic pattern between the male TD and WTD groups (OR = 2.508, 95% CI: 1.055-5.961, p = 0.037; OR = 2.552, 95% CI: 1.073-6.069, p = 0.034). Among TD patients, those carrying the rs806368 CC genotype exhibited higher limb trunk scores (p < 0.05). Moreover, there was a statistically significant difference in visuospatial/construction between the TD and WTD groups (p = 0.04), and a borderline significant difference in visuospatial/construction when considering the interaction between TD diagnosis and genotype at the rs806368 locus (p = 0.05). CONCLUSION: CNR1 rs806368 and rs806370 polymorphisms may play a role in TD susceptibility. Additionally, CNR1 gene polymorphisms were associated with the severity of involuntary movements and cognitive impairments in TD patients.

Effect of rs1108580 of DBH and rs1006737 of CACNA1C on Cognition and Tardive Dyskinesia in a North Indian Schizophrenia Cohort.

Genetic perturbations in dopamine neurotransmission and calcium signaling pathways are implicated in the etiology of schizophrenia. We aimed to test the association of a functional splice variant each in Dopamine ß-Hydroxylase (DBH; rs1108580) and Calcium voltage-gated channel subunit alpha1 C (CACNA1C; rs1006737) genes in these pathways with schizophrenia (506 cases, 443 controls); Abnormal Involuntary Movement Scale (AIMS) scores in subjects assessed for tardive dyskinesia (76 TD-positive, 95 TD-negative) and Penn Computerized Neurocognitive Battery (PennCNB) scores (334 cases, 234 controls). The effect of smoking status and SNP genotypes on AIMS scores were assessed using ANOVA; health status and SNP genotypes on three performance functions of PennCNB cognitive domains were assessed by ANCOVA with age and sex as covariates. Association with Positive and Negative Syndrome Scale (PANSS) scores in the TD cohort and cognitive scores in healthy controls of the cognition cohort were tested by linear regression. None of the markers were associated with schizophrenia. Smoking status [F(2, 139) = 10.6; p = 5 × 10-5], rs1006737 [F(2, 139) = 7.1; p = 0.001], TD status*smoking [F(2, 139) = 8.0; p = 5.0 × 10-4] and smoking status*rs1006737 [F(4, 139) = 2.7; p = 0.03] had an effect on AIMS score. Furthermore, rs1006737 was associated with orofacial [F(2, 139) = 4.6; p = 0.01] and limb-truncal TD [(F(2, 139) = 3.8; p = 0.02]. Main effect of rs1108580 on working memoryprocessing speed [F(2, 544) = 3.8; p = 0.03] and rs1006737 on spatial abilityefficiency [F(1, 550) = 9.4; p = 0.02] was identified. Health status*rs1006737 interaction had an effect on spatial memoryprocessing speed [F(1, 550) = 6.9; p = 0.01]. Allelic/genotypic association (p = 0.01/0.03) of rs1006737 with disorganized/concrete factor and allelic association of rs1108580 (p = 0.04) with a depressive factor of PANSS was observed in the TD-negative subcohort. Allelic association of rs1006737 with sensorimotor dexterityaccuracy (p = 0.03), attentionefficiency (p = 0.05), and spatial abilityefficiency (p = 0.02); allelic association of rs1108580 with face memoryaccuracy (p = 0.05) and emotionefficiency (p = 0.05); and allelic/genotypic association with emotionaccuracy (p = 0.003/0.009) were observed in healthy controls of the cognition cohort. These association findings may have direct implications for personalized medicine and cognitive remediation.

Genome-wide DNA methylation analysis in schizophrenia with tardive dyskinesia: a preliminary study.

BACKGROUND: Tardive dyskinesia (TD) develops in 20-30% of schizophrenia patients and up to 50% in patients > 50 years old. DNA methylation may play an important role in the development of TD. OBJECTIVE: DNA methylation analyses in schizophrenia with TD. METHODS: We conducted a genome-wide DNA methylation analysis in schizophrenia with TD using methylated DNA immunoprecipitation coupled with next-generation sequencing (MeDIP-Seq) in a Chinese sample including five schizophrenia patients with TD and five without TD (NTD), and five healthy controls. The results were expressed as the log2FC, fold change of normalized tags between two groups within the differentially methylated region (DMR). For validation, the pyrosequencing was used to quantify DNA methylation levels of several methylated genes in an independent sample (n = 30). RESULTS: Through genome-wide MeDIP-Seq analysis, we identified 116 genes that were significantly differentially methylated in promotor regions in comparison of TD group with NTD group including 66 hypermethylated genes (top 4 genes are GABRR1, VANGL2, ZNF534, and ZNF746) and 50 hypomethylated genes (top 4 genes are DERL3, GSTA4, KNCN, and LRRK1). Part of these genes (such as DERL3, DLGAP2, GABRR1, KLRG2, LRRK1, VANGL2, and ZP3) were previously reported to be associated with methylation in schizophrenia. Gene Ontology enrichment and KEGG pathway analyses identified several pathways. So far, we have confirmed the methylation of 3 genes (ARMC6, WDR75, and ZP3) in schizophrenia with TD using pyrosequencing. CONCLUSIONS: This study identified number of methylated genes and pathways for TD and will provide potential biomarkers for TD and serve as a resource for replication in other populations.

Significance of an altered lncRNA landscape in schizophrenia and cognition: clues from a case-control association study.

Genetic etiology of schizophrenia is poorly understood despite large genome-wide association data. Long non-coding RNAs (lncRNAs) with a probable regulatory role are emerging as important players in neuro-psychiatric disorders including schizophrenia. Prioritising important lncRNAs and analyses of their holistic interaction with their target genes may provide insights into disease biology/etiology. Of the 3843 lncRNA SNPs reported in schizophrenia GWASs extracted using lincSNP 2.0, we prioritised n = 247 based on association strength, minor allele frequency and regulatory potential and mapped them to lncRNAs. lncRNAs were then prioritised based on their expression in brain using lncRBase, epigenetic role using 3D SNP and functional relevance to schizophrenia etiology. 18 SNPs were finally tested for association with schizophrenia (n = 930) and its endophenotypes-tardive dyskinesia (n = 176) and cognition (n = 565) using a case-control approach. Associated SNPs were characterised by ChIP seq, eQTL, and transcription factor binding site (TFBS) data using FeatSNP. Of the eight SNPs significantly associated, rs2072806 in lncRNA hsaLB_IO39983 with regulatory effect on BTN3A2 was associated with schizophrenia (p = 0.006); rs2710323 in hsaLB_IO_2331 with role in dysregulation of ITIH1 with tardive dyskinesia (p < 0.05); and four SNPs with significant cognition score reduction (p < 0.05) in cases. Two of these with two additional variants in eQTL were observed among controls (p < 0.05), acting likely as enhancer SNPs and/or altering TFBS of eQTL mapped downstream genes. This study highlights important lncRNAs in schizophrenia and provides a proof of concept of novel interactions of lncRNAs with protein-coding genes to elicit alterations in immune/inflammatory pathways of schizophrenia.

Altered DNA methylation of CYP2E1 gene in schizophrenia patients with tardive dyskinesia.

BACKGROUND: About 20-30% of patients with schizophrenia develop tardive dyskinesia (TD). Oxidative stress is one potential causes of TD. CYP2E1 is considered as an oxidative stress-related gene, however, no study has been reported on the DNA methylation levels of the CYP2E1 in schizophrenia or TD. METHODS: A total of 35 schizophrenia patients with TD, 35 schizophrenia patients without TD (NTD), and 35 health controls (HCs) were collected in Beijing, China. DNA was extracted from peripheral blood samples. The promoter methylation levels of CYP2E1 were detected using pyrosequencing. The generalized linear model (GLM) was used to examine the methylation levels of three CpG sites among three diagnostic groups (TD vs. NTD vs. HC). RESULTS: The average methylation levels were 8.8 ± 10.0, 14.5 ± 11.9 and 15.1 ± 11.3 in TD, NTD and HC groups, respectively. The F-test in GLM revealed overall differences in the average of methylation levels of three CpG sites among three diagnostic groups (p = 0.0227) and in the third CpG site (p = 0.0026). Furthermore, the TD group had lower average methylation levels than HC and NTD groups (p = 0.0115 and 0.0268, respectively). Specifically, TD group showed lower methylation levels in the third CpG site than HC and NTD groups (p = 0.0012 and 0.0072, respectively). Additionally, associations of the methylation levels with clinical features in the TD group were observed using Spearman correlation analysis. CONCLUSION: This study provides the first evidence of DNA methylation levels in the promoter of CYP2E1 gene associated with schizophrenia and TD. The abnormal DNA methylation might serve as a potential mechanism for TD.

Tardive Dyskinesia Development, Superoxide Dismutase Levels, and Relevant Genetic Polymorphisms.

Tardive dyskinesia (TD) is a prevalent movement disorder that significantly impacts patients with schizophrenia (SCZ) due to extended exposure to antipsychotics (AP). Several genetic polymorphisms, including superoxide dismutase (SOD) and DRD3 9ser, have been suggested as explanations why some patients suffer from TD. Methods. A PubMed search was used to search relevant articles using the following keywords: "Tardive Dyskinesia and Superoxide Dismutase". Fifty-eight articles were retrieved. Among them, 16 were included in this review. Results. Overall, 58 studies were retrieved from PubMed. Most studies investigated the association between TD and the SOD-related polymorphisms. In addition, previous studies reported an association between TD occurrence and other genetic polymorphisms. Conclusion. This study found that the risk of TD is associated with altered SOD levels and several genetic polymorphisms, including VAL 66 Met and DRD3 9ser.

Genome wide study of tardive dyskinesia in schizophrenia.

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 immune-related pathways. Through integrating trans-ethnic fine mapping, we identified putative credible causal variants for three of the loci. Post-hoc analysis revealed that SNPs harbored in TNFRSF1B and CALCOCO1 independently conferred three-fold increase in TD risk, beyond clinical risk factors like Age of onset and Duration of illness to schizophrenia. Further work is necessary to replicate loci that are reported in the study and evaluate the polygenic architecture underlying TD.

Schizophrenia-associated gene dysbindin-1 and tardive dyskinesia.

Tardive dyskinesia (TD) is a potentially irreversible movement disorder observed following long-term antipsychotic exposure. Its cause is unknown; however, a genetic component has been supported by studies of affected families. Dysbindin-1, encoded by the dystrobrevin-binding protein 1 DTNBP1 gene, has been associated with schizophrenia and is potentially involved in dopamine neurotransmission through its regulation of dopamine release and dopamine D2 receptor recycling, making it a candidate for investigation in TD. We investigated common variants across the DTNBP1 gene in our schizophrenia/patients with schizoaffective disorder of European ancestry. We found a number of DTNBP1 three-marker haplotypes to be associated with TD occurrence and TD severity (p < 0.05). These preliminary findings, if replicated in larger independent samples, would suggest that drugs targeting dysbindin-1 may be an option in the prevention and treatment of TD.

Genetic association study detected misalignment in previous whole exome sequence: association study of ZNF806 and SART3 in tardive dystonia.

Tardive dystonia is one of the most serious types of extrapyramidal symptoms that antipsychotics can cause. There is no established treatment to relieve this symptom, and its etiology is unclear. Recently, we identified very rare single-nucleotide polymorphisms (SNPs) on ZNF806 and SART3 by exome sequencing in three patients with profoundly severe tardive dystonia. Here, we conducted an association study (case, N = 16 vs. control, N = 96) on the rarest SNP selected from each gene. The results showed that rs2287546 on SART3 was not related to tardive dystonia and that rs4953961 on ZNF806 was a heterozygote in all the subjects, implying the absence of a rare SNP in this locus. We found three other genomic regions with high similarity to the relevant region on ZNF806 by BLAT searches. This strongly suggested a misalignment error in this region in our previous exome sequence. In conclusion, ZNF806 and SART3 are unlikely to be related to tardive dystonia.

A genome-wide association study identifies a gene network associated with paranoid schizophrenia and antipsychotics-induced tardive dyskinesia.

In the present study we conducted a genome-wide association study (GWAS) in a cohort of 505 patients with paranoid schizophrenia (SCZ), of which 95 had tardive dyskinesia (TD), and 503 healthy controls. Using data generated by the PsychENCODE Consortium (PEC) and other bioinformatic databases, we revealed a gene network, implicated in neurodevelopment and brain function, associated with both these disorders. Almost all these genes are in gene or isoform co-expression PEC network modules important for the functioning of the brain; the activity of these networks is also altered in SCZ, bipolar disorder and autism spectrum disorders. The associated PEC network modules are enriched for gene ontology terms relevant to the brain development and function (CNS development, neuron development, axon ensheathment, synapse, synaptic vesicle cycle, and signaling receptor activity) and to the immune system (inflammatory response). Results of the present study suggest that orofacial and limbtruncal types of TD seem to share the molecular network with SCZ. Paranoid SCZ and abnormal involuntary movements that indicate the orofacial type of TD are associated with the same genomic loci on chromosomes 3p22.2, 8q21.13, and 13q14.2. The limbtruncal type of TD is associated with a locus on chromosome 3p13 where the best functional candidate is FOXP1, a high-confidence SCZ gene. The results of this study shed light on common pathogenic mechanisms for SCZ and TD, and indicate that the pathogenesis of the orofacial and limbtruncal types of TD might be driven by interacting genes implicated in neurodevelopment.

Liver enzyme CYP2D6 gene and tardive dyskinesia.

Background: Tardive dyskinesia (TD) is an iatrogenic involuntary movement disorder occurring after extended antipsychotic use with unclear pathogenesis. CYP2D6 is a liver enzyme involved in antipsychotic metabolism and a well-studied gene candidate for TD. Materials & methods: We tested predicted CYP2D6 metabolizer phenotype with TD occurrence and severity in our two samples of European chronic schizophrenia patients (total n = 198, of which 82 had TD). Results: TD occurrence were associated with extreme metabolizer phenotype, controlling for age and sex (p = 0.012). In other words, individuals with either increased and no CYP2D6 activity were at higher risk of having TD. Conclusion: Unlike most previous findings, TD occurrence may be associated with both extremes of CYP2D6 metabolic activity rather than solely for poor metabolizers.

The effect of rs1076560 (DRD2) and rs4680 (COMT) on tardive dyskinesia and cognition in schizophrenia subjects.

OBJECTIVE: The aim of the study is to test the association of a functional variant each in DRD2 and COMT genes with schizophrenia and its endophenotypes. BASIC METHODS: Effect of two functional variants rs1076560 in DRD2 and rs4680 in COMT on (1) schizophrenia (502 cases, 448 controls) diagnosed by Diagnostic and Statistical Manual of Mental Disorders-IV criteria and in subsets with (2) tardive dyskinesia (80 positive, 103 negative), assessed by Abnormal Involuntary Movement Scale (AIMS), positive and negative symptoms assessed by Positive and Negative Syndrome Scale (PANSS) and (3) cognition (299 cases, 245 controls), estimated by Penn Computerized Neurocognitive Battery, were analysed either using analysis of variance (ANOVA) or regression analysis. MAIN RESULTS: No association of two SNPs with schizophrenia, but association of rs4680 (P < 0.05) with tardive dyskinesia was observed. On ANOVA, main effect of smoking [F(2,148) = 16.3; P = 3.9 × 10]; rs4680 [F(2,148) = 3.3; P = 0.04] and interaction effect of tardive dyskinesia-status*Smoking [F(2,148) = 5.4, P = 0.006]; Smoking*rs1076560 [F(3,148) = 3.6; P = 0.01]; Smoking*rs4680 [F(4,148) = 5.3; P = 4.7 × 10] were significant with AIMS tardive dyskinesia score. The main effect of rs1076560 [F(2,148) = 4.5; P = 0.013] and rs4680 [F(2,148) = 4.0; P = 0.02] were significant with limb truncal tardive dyskinesia. Allelic/genotypic (P = 0.004/P = 0.01) association of rs1076560 with negative scale of PANSS in tardive dyskinesia-negative; diminished expression factor of PANSS in tardive dyskinesia-negative subcohort (allelic/genotypic P = 3.3 × 10/6.6 × 10) and tardive dyskinesia cohorts (P = 0.003/0.002); genotypic association (P = 0.05) with disorganised/concrete factor in tardive dyskinesia-positive subcohorts were observed by regression analysis using gPLINKv2.050. Further allelic/genotypic (P = 0.02) association of rs4680 with depressed factor of PANSS in tardive dyskinesia cohort was observed. Allelic/genotypic association of rs1076560 with abstraction and mental flexibilityaccuracy (P = 0.03/0.04), abstraction and mental flexibilityefficiency (P = 0.01/0.02); allelic association with spatial abilityprocessing speed (P = 0.03), emotionefficiency (P = 0.05); and with spatial abilityefficiency (genotypic, P = 0.05) in healthy controls and allelic association of rs4680 with emotionefficiency in cases with schizophrenia (P = 0.04) were notable. PRINCIPAL CONCLUSION: Dopaminergic genes seem to contribute to tardive dyskinesia and cognition warranting replication.

Pyrosequencing analysis of IRS1 methylation levels in schizophrenia with tardive dyskinesia.

Tardive dyskinesia (TD) is a serious side effect of certain antipsychotic medications that are used to treat schizophrenia (SCZ) and other mental illnesses. The methylation status of the insulin receptor substrate 1 (IRS1) gene is reportedly associated with SCZ; however, no study, to the best of the authors' knowledge, has focused on the quantitative DNA methylation levels of the IRS1 gene using pyrosequencing in SCZ with or without TD. The present study aimed to quantify DNA methylation levels of 4 CpG sites in the IRS1 gene using a Chinese sample including SCZ patients with TD and without TD (NTD) and healthy controls (HCs). The general linear model (GLM) was used to detect DNA methylation levels among the 3 proposed groups (TD vs. NTD vs. HC). Mean DNA methylation levels of 4 CpG sites demonstrated normal distribution. Pearson's correlation analysis did not reveal any significant correlations between the DNA methylation levels of the 4 CpG sites and the severity of SCZ. GLM revealed significant differences between the 3 groups for CpG site 1 and the average of the 4 CpG sites (P=0.0001 and P=0.0126, respectively). Furthermore, the TD, NTD and TD + NTD groups demonstrated lower methylation levels in CpG site 1 (P=0.0003, P<0.0001 and P<0.0001, respectively) and the average of 4 CpG sites (P=0.0176, P=0.0063 and P=0.003, respectively) compared with the HC group. The results revealed that both NTD and TD patients had significantly decreased DNA methylation levels compared with healthy controls, which indicated a significant association between the DNA methylation levels of the IRS1 gene with SCZ and TD.

Association of regulatory variants of dopamine ß-hydroxylase with cognition and tardive dyskinesia in schizophrenia subjects.

BACKGROUND: Dopamine-ß-hydroxylase (DBH, EC 1.14.17.1), which converts dopamine to norepinephrine, is a candidate gene in neuropsychiatric diseases. AIM: To assess the effect of regulatory variants in DBH on schizophrenia and its endophenotypes -cognition and tardive dyskinesia. METHODS: We tested association of functional variants 19bp Ins/Del, rs1989787 and rs1611115 in DBH with i) schizophrenia (1236 cases, 1136 controls), ii) tardive dyskinesia (83 positive, 162 negative) and iii) performance functions of cognition (357 cases, 306 controls) estimated by the Penn Computerized Neurocognitive Battery. RESULTS: A modest haplotypic (Ins-C; 19bp Ins/Del - rs1989787 C>T; p=0.04) association was observed with schizophrenia. We observed ~39% reduction in activity of 19bp Del allele on luciferase assay. Analysis of covariance revealed interactions of tardive dyskinesia status and: i) 19bp Ins/Del (genotypic, p=0.04) and ii) rs1989787 and rs1611115 (combined genotypic, p=0.004) on Abnormal Involuntary Movement Scale total score. Association of rs1611115 with positive and negative syndrome scale (PANSS) total score (p=0.05) and allelic/genotypic association with lower positive (p=0.03/0.04), general psychopathology (p=0.01/0.01) PANSS scales in tardive dyskinesia-positive; and allelic/genotypic (p=0.02/0.05) with higher score of depressive factors in tardive dyskinesia-negative subgroups were observed. Analysis of covariance with continuous variable of cognition showed interaction of health status with: i) rs1989787 on accuracy and efficiency (p=0.03) of abstraction and mental flexibility; ii) rs1611115 on accuracy of working memory and emotion (p=0.05); iii) 19bp Ins/Del on processing speed of emotion (p=0.03). Allelic/genotypic association of rs1989787 with spatial ability (p=0.02-0.05) among healthy controls; association of rs1611115 with Global Assessment Scale scores in the past month (p=0.05) among schizophrenia subjects of cognition cohort was also observed. CONCLUSIONS: With modest genotype-phenotype correlations available for DBH variants, personalized treatment regimens based on DBH activity for ameliorating tardive dyskinesia and cognitive symptoms may be plausible.

A preliminary exome sequence in three patients with tardive dystonia.

Tardive dystonia is one of the most serious adverse events that can be caused by antipsychotic treatment, but few studies have examined the etiology of tardive dystonia, and no genetic study using a next-generation sequencing technique has been performed to date. We conducted exome sequencing in three subjects with severe tardive dystonia. We analyzed the results focusing on candidate genes of primary dystonia, for example, TOR1A, GCH1, TH, THAP1, and SGCE. There were no single-nucleotide polymorphisms of these dystonia genes that were commonly shared among our subjects. Instead, the results revealed the presence of rare mutations (minor allele frequency <0.01) on the ZNF806 and SART3 genes in all three patients. This is the first study to analyze whole-exonic regions of the genomes of patients with tardive dystonia. These results were only preliminary, but they suggest that subjects presenting with tardive dystonia induced by antipsychotic treatment can have a genetic predisposition to tardive dystonia.

Putative role of pharmacogenetics to elucidate the mechanism of tardive dyskinesia in schizophrenia.

Identifying biomarkers which can be used as a diagnostic tool is a major objective of pharmacogenetic studies. Most mental and many neurological disorders have a compiled multifaceted nature, which may be the reason why this endeavor has hitherto not been very successful. This is also true for tardive dyskinesia (TD), an involuntary movement complication of long-term treatment with antipsychotic drugs. The observed associations of specific gene variants with the prevalence and severity of a disorder can also be applied to try to elucidate the pathogenesis of the condition. In this paper, this strategy is used by combining pharmacogenetic knowledge with theories on the possible role of a dysfunction of specific cellular elements of neostriatal parts of the (dorsal) extrapyramidal circuits: various glutamatergic terminals, medium spiny neurons, striatal interneurons and ascending monoaminergic fibers. A peculiar finding is that genetic variants which would be expected to increase the neostriatal dopamine concentration are not associated with the prevalence and severity of TD. Moreover, modifying the sensitivity to glutamatergic long-term potentiation (and excitotoxicity) shows a relationship with levodopa-induced dyskinesia, but not with TD. Contrasting this, TD is associated with genetic variants that modify vulnerability to oxidative stress. Reducing the oxidative stress burden of medium spiny neurons may also be the mechanism behind the protective influence of 5-HT2 receptor antagonists. It is probably worthwhile to discriminate between neostriatal matrix and striosomal compartments when studying the mechanism of TD and between orofacial and limb-truncal components in epidemiological studies.

Gnal haploinsufficiency causes genomic instability and increased sensitivity to haloperidol.

GNAL encodes guanine nucleotide-binding protein subunit Gα(olf) which plays a key role in striatal medium spiny neuron (MSN)-dopamine signaling. GNAL loss-of-function mutations are causally-associated with isolated dystonia, a movement disorder characterized by involuntary muscle contractions leading to abnormal postures. Dopamine D2 receptor (D2R) blockers such as haloperidol are mainstays in the treatment of psychosis but may contribute to the development of secondary acute and tardive dystonia. Administration of haloperidol promotes cAMP-dependent signaling in D2R-expressing indirect pathway MSNs. At present, little is known about the cellular relationships among isolated, acute, and tardive dystonia. Herein, we report the effects of acute D2R blockade on motor behavior, DNA repair, cAMP-mediated histone H3 phosphorylation (Ser10), and cell death in Gnal+/- mice and their isogenic Gnal+/+ littermates. In comparison to Gnal+/+ littermates, Gnal+/- mice exhibited increased catalepsy responses, persistent DNA breaks, decreased cAMP-dependent histone H3 phosphorylation (Ser10), and increased cell death in response to haloperidol. In striatum, aged Gnal+/- mice exhibited increased global DNA methylation, increased euchromatin, and dendritic structural abnormalities. Our results provide evidence that Gα(olf) deficiency intensifies the effects of D2R antagonism and suggests that loss-of-function variants in GNAL may increase risk for movement disorders associated with D2R blockers. We hypothesize that the effects of Gα(olf) dysfunction and/or long-term D2R antagonism may lead to epigenetic silencing, transcriptional dysregulation, and, ultimately, cellular senescence and/or apoptosis in human brain.

Genetic study of neuregulin 1 and receptor tyrosine-protein kinase erbB-4 in tardive dyskinesia.

OBJECTIVES: Tardive dyskinesia (TD) is a movement disorder that may develop as a side effect of antipsychotic medication. The aetiology underlying TD is unclear, but a number of mechanisms have been proposed. METHODS: We investigated single-nucleotide polymorphisms (SNPs) in the genes coding for neuregulin-1 and erbB-4 receptor in our sample of 153 European schizophrenia patients for possible association with TD. RESULTS: We found the ERBB4 rs839523 CC genotype to be associated with risk for TD occurrence and increased severity as measured by the Abnormal Involuntary Movement Scale (AIMS) (P = .003). CONCLUSIONS: This study supports a role for the neuregulin signalling pathway in TD, although independent replications are warranted.