RESUMO
Autism spectrum disorder (ASD) is a complex group of clinically heterogeneous neurodevelopmental disorders with unclear etiology and pathogenesis. Genetic studies have identified numerous candidate genetic variants, including de novo mutated ASD-associated genes; however, the function of these de novo mutated genes remains unclear despite extensive bioinformatics resources. Accordingly, it is not easy to assign priorities to numerous candidate ASD-associated genes for further biological analysis. Here we developed a convenient system for identifying an experimental evidence-based annotation of candidate ASD-associated genes. We performed trio-based whole-exome sequencing in 30 sporadic cases of ASD and identified 37 genes with de novo single-nucleotide variations (SNVs). Among them, 5 of those 37 genes, POGZ, PLEKHA4, PCNX, PRKD2 and HERC1, have been previously reported as genes with de novo SNVs in ASD; and consultation with in silico databases showed that only HERC1 might be involved in neural function. To examine whether the identified gene products are involved in neural functions, we performed small hairpin RNA-based assays using neuroblastoma cell lines to assess neurite development. Knockdown of 8 out of the 14 examined genes significantly decreased neurite development (P<0.05, one-way analysis of variance), which was significantly higher than the number expected from gene ontology databases (P=0.010, Fisher's exact test). Our screening system may be valuable for identifying the neural functions of candidate ASD-associated genes for further analysis and a substantial portion of these genes with de novo SNVs might have roles in neuronal systems, although further detailed analysis might eliminate false positive genes from identified candidate ASD genes.
Assuntos
Transtorno do Espectro Autista/genética , Exoma , Neuritos , Análise de Sequência , Adulto , Animais , Linhagem Celular , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Adulto JovemRESUMO
AIM: Patients with schizophrenia in remission have shown significantly higher levels of neurocognitive function than patients not in remission. However, previous studies have mainly examined the association between neurocognitive function and the remission status of schizophrenia without considering the time component of the definition for remission using cross-sectional methods. The purpose of this study was to investigate the relations between remission status with considering time components and three cognitive functions of intellectual ability, memory and attention, which were examined before fulfilling the remission criteria, using longitudinal methods. METHODS: We assessed the remission status using the Positive and Negative Syndrome Scale (PANSS) on the same patients twice: at recruitment and at 6 months after the first PANSS assessment. Cognitive tests were performed within 3 months after recruitment. At recruitment, 337 patients were enrolled. Of the patients, 63 patients were followed up and completedthe first and second PANSS assessments and three cognitive tests at the end of study. RESULTS: Of the patients, 33 patients fulfilled the remission criteria, while 30 patients did not fulfill the criteria. Patients in remission showed significantly higher levels of 2-digit (P = 0.020) and 3-digit (P = 0.015) Continuous Performance Test scores, attention/concentration in the Wechsler Memory Scale-Revised (P = 0.034) and processing speeds in the Wechsler Adult Intelligence Scale-III (P = 0.047) than patients not in remission. Additionally, these cognitive scores were positively correlated with each other (P < 0.05). CONCLUSION: Our findings suggest that patients who achieve remission may demonstrate a pre-existing higher level of attention than patients who do not achieve remission.
Assuntos
Atenção , Inteligência , Memória , Psicologia do Esquizofrênico , Adulto , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Adulto JovemRESUMO
AIMS: Progressive cognitive decline has been an important issue in the treatment and care of patients with schizophrenia. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the biosynthesis of catecholamine, including dopamine and noradrenaline. In this report, we examined a possible association of a genetic variant in the TH promoter region. METHODS: Association of a genetic variant in the TH promoter region, C-824T (rs10770141), with intellectual ability in 132 patients with schizophrenia and 282 healthy subjects was examined. The transcriptional activity of the plasmids harboring the TH promoter region with either C or T nucleotide at -824 was assayed using a luciferase gene as a reporter. RESULTS: We found significant effects of the genotype on the full-scale IQ, verbal IQ, and performance IQ, in patients with schizophrenia. IQ was lower in individuals with the C/C genotype than those with T carriers. The plasmid with the T allele at -824 showed higher transcriptional activity than that with the C allele in a transient transfection experiment using a luciferase gene as a reporter, implying that the T carriers may have higher TH activities and retain higher levels of catecholamines in the brain. CONCLUSIONS: The present data suggest that the biosynthesis of catecholamine by the action of TH should be deeply involved in decreased intellectual ability in patients with schizophrenia. This is the first report, as far as we know, showing a correlation between TH expression and IQ in humans.
Assuntos
Testes de Inteligência , Inteligência/genética , Esquizofrenia/genética , Psicologia do Esquizofrênico , Tirosina 3-Mono-Oxigenase/genética , Adulto , Alelos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Polimorfismo de Nucleotídeo Único/genética , Transcrição GênicaRESUMO
AIM: Patients with schizophrenia have been reported to perform worse than non-schizophrenic populations on neuropsychological tests, which may be affected by cultural factors. The aim of this study was to examine the performance of a sizable number of patients with schizophrenia on the Japanese version of the Wechsler Adult Intelligence Scale-III (WAIS-III) compared with healthy controls. METHODS: Performance on the WAIS-III was evaluated in 157 Japanese patients with schizophrenia and in 264 healthy control subjects. RESULTS: All IQ scores and four indices from the WAIS-III were impaired for patients with schizophrenia compared with healthy controls. Processing Speed was markedly disturbed, approximately 2 SD below that of the healthy control group. Among the 13 subtests, Comprehension (z = -1.70, d = 1.55), Digit Symbol Coding (z = -1.84, d = 1.88), and Symbol Search (z = -1.85, d = 1.77) were profoundly impaired relative to the healthy controls. CONCLUSION: These results indicate that the pattern and degree of impairment, as evaluated by the WAIS-III, in Japanese patients are similar to those previously reported in English-speaking patients and that the deficits of some neuropsychological domains relevant to functional outcomes are universally characteristic of schizophrenia.
Assuntos
Transtornos Cognitivos/psicologia , Compreensão , Inteligência , Psicologia do Esquizofrênico , Adulto , Povo Asiático , Cultura , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Psicometria , Escalas de Wechsler , Adulto JovemRESUMO
Genome-wide association studies have reported an association between schizophrenia and rs12807809 of the neurogranin (NRGN) gene. We have recently found that an rs12807809-rs12278912 haplotype of the gene is associated with schizophrenia in a Japanese population and that the NRGN expression of the high-risk TG haplotype is lower than that of the protective TA haplotype in immortalized lymphoblasts. In this study, we investigated the influences of neurogranin genotypes (rs12807809 and rs12278912), haplotypes and diplotypes and genetic variant-diagnosis interactions on intellectual ability in 414 Japanese patients with schizophrenia and healthy subjects. We detected possible effects of the genome-wide screen-supported rs12807809, haplotypes, diplotypes and their genetic variant-diagnosis interactions on intellectual abilities at the threshold level of P<0.05. After applying Bonferroni correction for 13 genotype measures and setting P-values for significance (P<0.0039; 0.05/13), three effects remained significant: the rs12807809-rs12278912 diplotype-diagnosis interactions on performance intelligence quotient (CG/CG: P=3.9 × 10(-13); TA/TA: P=1.1 × 10(-7)) and TA/TA diplotype on performance intelligence quotient in patients with schizophrenia (P=8.2 × 10(-8)) remained significant. The intellectual abilities of the high-risk TG/TG diplotype of the neurogranin gene were lower compared to those with the non-risk TA/TA diplotype. Our findings suggest that the genetic risk variant in the neurogranin gene may be related to reduced intellectual ability.
Assuntos
Estudo de Associação Genômica Ampla/métodos , Inteligência/genética , Neurogranina/genética , Esquizofrenia/genética , Adulto , Alelos , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Neurogranina/metabolismo , Polimorfismo de Nucleotídeo Único , Análise de Regressão , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Genome-wide significant associations of schizophrenia with eight SNPs in the CNNM2, MIR137, PCGEM1, TRIM26, CSMD1, MMP16, NT5C2 and CCDC68 genes have been identified in a recent mega-analysis of genome-wide association studies. To date, the role of these SNPs on gray matter (GM) volumes remains unclear. METHODS: After performing quality control for minor-allele frequency > 5% using a JPT HapMap sample and our sample, a genotyping call rate > 95% and Hardy-Weinberg equilibrium testing (p > 0.01), five of eight SNPs were eligible for analysis. We used a comprehensive voxel-based morphometry (VBM) technique to investigate the effects of these five SNPs on GM volumes between major-allele homozygotes and minor-allele carriers in Japanese patients with schizophrenia (n = 173) and healthy subjects (n = 449). RESULTS: The rs7914558 risk variant at CNNM2 was associated with voxel-based GM volumes in the bilateral inferior frontal gyri (right T = 4.96, p = 0.0088, left T = 4.66, p = 0.031). These peak voxels, which were affected by the variant, existed in the orbital region of the inferior frontal gyri. Individuals with the risk G/G genotype of rs7914558 had smaller GM volumes in the bilateral inferior frontal gyri than carriers of the non-risk A-allele. Although several effects of the genotype and the genotype-diagnosis interaction of other SNPs on GM volumes were observed in the exploratory VBM analyses, these effects did not remain after the FWE-correction for multiple tests (p > 0.05). CONCLUSIONS: Our findings suggest that the genetic variant in the CNNM2 gene could be implicated in the pathogenesis of schizophrenia through the GM volumetric vulnerability of the orbital regions in the inferior frontal gyri.
Assuntos
Ciclinas/genética , Lobo Frontal/fisiologia , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Adulto , Povo Asiático/genética , Povo Asiático/estatística & dados numéricos , Proteínas de Transporte de Cátions , Feminino , Frequência do Gene , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto JovemRESUMO
A biomarker is defined as a biological indicator of normal or pathological processes, and a pharmacological response to a therapeutic intervention, whose characteristics can be measured and evaluated objectively. In medicine and health, biomarkers can be paraphrased as diagnostic methods objectively conducive to treatment. Here, we discuss biomarkers of schizophrenia as a representative mental illness, whose research has advanced compared with that of other disorders. Schizophrenia is a syndrome with a typical course and symptoms. Its pathophysiology and pathogenesis have not been elucidated (medically however, its underlying biological mechanisms are assumed to be present. That is, in biomarker discovery, when the pathogenesis and cause are elucidated, the patient group would not consiste of schizophrenia but, it is a new disease of "x x disease." For example, neurosyphilis is exogenous psychosis, by finding a biomarker of syphilis spirochete, a new disease concept of neurosyphilis could be distinguished from the schizophrenia). In this way, it can be said that biomarker research is essential for the development of new diagnostic and treatment methods for mental illness. There are several biomarker research methods such as genetic analysis, biological sample analysis, cognitive analysis, neurophysiology, neuroimaging, animal models, and post-mortem brain analysis. Further, studies have been made, however, biomarkers that can explain all of schizophrenia has not been found yet. As schizophrenia is assumed to be a heterogenous syndrome, it is believed that the etiology varies. Thus, there is a possibility that targeting schizophrenia as a whole will make it difficulty to find biomarkers for patients with schizophrenia. It is considered that appropriate subgroup analysis is needed. In order to overcome it, amount-of-resources strategy to find patients by using large of samples has been made mainly in Europe and the United States. In Japan, we have used sub-group analysis strategy to elaborate this issue such as the use of an intermediate phenotype. It is not possible to research a similar strategy, because of the limited funds and manpower in Japan compared to U. S. and Europe. As nationwide research organizations in Japan, such as IGC (Imaging genetics consortium), combination analysis of genetics and neuroimaging and COCORO (Cognitive genetics collaborative research organization), combination analysis of genetics and cognitive function, have been established, the development of biomarkers for mental illnesses is expected in the near future.
Assuntos
Biomarcadores/análise , Transtornos Mentais/diagnóstico , Humanos , Esquizofrenia/diagnósticoRESUMO
Genome-wide association and follow-up studies have reported an association between schizophrenia and rs12807809 of the NRGN gene on chromosome 11q24.2. We investigated the association of five linkage disequilibrium-tagging SNPs and haplotypes that cover the NRGN gene with schizophrenia in a Japanese sample of 2,019 schizophrenia patients and 2,574 controls to determine whether rs12807809 is the most strongly associated variant for schizophrenia in the vicinity of the NRGN gene. We found that the rs12807809-rs12278912 haplotype of the NRGN gene was associated with schizophrenia (global P = 0.0042). The frequencies of the TG and TA haplotypes of rs12807809-rs12278912 in patients were higher (OR = 1.14, P = 0.0019) and lower (OR = 0.85, P = 0.0053), respectively, than in the controls. We did not detect any evidence of association of schizophrenia with any SNPs; however, two nominal associations of rs12278912 (OR = 1.10, P = 0.057) and rs2075713 (OR = 1.10, P = 0.057) were observed. Furthermore, we detected an association between the rs12807809-rs12278912 haplotype and NRGN expression in immortalized lymphoblasts derived from 45 HapMap JPT subjects (z = 2.69, P = 0.007) and confirmed the association in immortalized lymphoblasts derived from 42 patients with schizophrenia and 44 healthy controls (z = 3.09, P = 0.002). The expression of the high-risk TG haplotype was significantly lower than the protective TA haplotype. The expression was lower in patients with schizophrenia than in controls; however, this difference was not statistically significant. This study provides further evidence of the association of the NRGN gene with schizophrenia, and our results suggest that there is a link between the TG haplotype of rs12807809-rs12278912, decreased expression of NRGN and risk of developing schizophrenia.
Assuntos
Regulação da Expressão Gênica , Predisposição Genética para Doença , Variação Genética , Neurogranina/genética , Esquizofrenia/genética , Adulto , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Genoma Humano/genética , Haplótipos/genética , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
The dysbindin-1 and neuregulin-1 (NRG-1) genes are related to schizophrenia. Expression studies in postmortem brains have revealed lower expression of dysbindin-1 and higher expression of NRG-1 in brain tissue from subjects with schizophrenia. In addition to the difficulty of sampling, the use of postmortem brain tissues is not ideal because these tissues are heterogeneous with respect to biochemical parameters, lifetime history of medications and physiological status at the time of death. In contrast, medication and environmental influences that could mask the genetic basis of differences in RNA expression are removed in immortalized lymphocytes by culturing. Only a few microarray analysis studies using immortalized lymphocytes in schizophrenia have been reported, and whether immortalized lymphocytes are an appropriate alternative to neuronal tissue remains controversial. In this study, we measured the mRNA expression levels of dysbindin-1, NRG-1 and two other genes (NPY1R and GNAO1) in immortalized lymphocytes from 45 patients with schizophrenia and 45 controls using real-time quantitative reverse transcriptase-PCR. No difference was observed between patients and controls with respect to the expression of dysbindin-1, NRG-1, NPY1R or GNAO1 gene. Our findings suggest that the gene expression profile of immortalized lymphocyte from schizophrenic patients is different from that in postmortem brain tissue at least with respect to the dysbindin-1 and NRG-1 genes.
Assuntos
Proteínas de Transporte/genética , Linfócitos/metabolismo , Neuregulina-1/genética , Esquizofrenia/genética , Adulto , Proteínas de Transporte/metabolismo , Disbindina , Proteínas Associadas à Distrofina , Feminino , Humanos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Neuregulina-1/metabolismo , RNA Mensageiro/metabolismo , Esquizofrenia/metabolismoRESUMO
Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. However, the precise mechanisms underlying the trafficking of neurotrophin receptors to synapses remain elusive. Here, we demonstrate that a brain-enriched sorting nexin, ARHGAP33, is a new type of regulator for the intracellular trafficking of TrkB, a high-affinity receptor for brain-derived neurotrophic factor. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. Mechanistically, ARHGAP33 interacts with SORT1 to cooperatively regulate TrkB trafficking. Human ARHGAP33 is associated with brain phenotypes and reduced SORT1 expression is found in patients with schizophrenia. We propose that ARHGAP33/SORT1-mediated TrkB trafficking is essential for synapse development and that the dysfunction of this mechanism may be a new molecular pathology of neuropsychiatric disorders.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Comportamento Animal , Espinhas Dendríticas/genética , Proteínas Ativadoras de GTPase/genética , Neurônios/metabolismo , Transporte Proteico/genética , RNA Mensageiro/metabolismo , Receptor trkB/metabolismo , Esquizofrenia/genética , Nexinas de Classificação/genética , Sinapses/genética , Adulto , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Casos e Controles , Células Cultivadas , Espinhas Dendríticas/metabolismo , Feminino , Proteínas Ativadoras de GTPase/metabolismo , Células HEK293 , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Immunoblotting , Imuno-Histoquímica , Hibridização In Situ , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Técnicas de Patch-Clamp , Fenótipo , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Nexinas de Classificação/metabolismo , Sinapses/metabolismoRESUMO
Cognitive impairments are a core feature in patients with schizophrenia. These deficits could serve as effective tools for understanding the genetic architecture of schizophrenia. This study investigated whether genetic variants associated with cognitive impairments aggregate in functional gene networks related to the pathogenesis of schizophrenia. Here, genome-wide association studies (GWAS) of a range of cognitive phenotypes relevant to schizophrenia were performed in 411 healthy subjects. We attempted to replicate the GWAS data using 257 patients with schizophrenia and performed a meta-analysis of the GWAS findings and the replicated results. Because gene networks, rather than a single gene or genetic variant, may be strongly associated with the susceptibility to schizophrenia and cognitive impairments, gene-network analysis for genes in close proximity to the replicated variants was performed. We observed nominal associations between 3054 variants and cognitive phenotypes at a threshold of P < 1.0 × 10(-) (4). Of the 3054 variants, the associations of 191 variants were replicated in the replication samples (P < .05). However, no variants achieved genome-wide significance in a meta-analysis (P > 5.0 × 10(-) (8)). Additionally, 115 of 191 replicated single nucleotide polymorphisms (SNPs) have genes located within 10 kb of the SNPs (60.2%). These variants were moderately associated with cognitive phenotypes that ranged from P = 2.50 × 10(-) (5) to P = 9.40 × 10(-) (8). The genes located within 10 kb from the replicated SNPs were significantly grouped in terms of glutamate receptor activity (false discovery rate (FDR) q = 4.49 × 10(-) (17)) and the immune system related to major histocompatibility complex class I (FDR q = 8.76 × 10(-) (11)) networks. Our findings demonstrate that genetic variants related to cognitive trait impairment in schizophrenia are involved in the N-methyl-d-aspartate glutamate network.
Assuntos
Transtornos Cognitivos/genética , Redes Reguladoras de Genes/genética , Estudo de Associação Genômica Ampla , Receptores de Glutamato/metabolismo , Esquizofrenia/genética , Adulto , Transtornos Cognitivos/classificação , Transtornos Cognitivos/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Esquizofrenia/classificação , Esquizofrenia/complicações , Adulto JovemRESUMO
Hypofunction of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors may be involved in the pathophysiology of schizophrenia. Many studies have investigated peripheral NMDA receptor-related glutamatergic amino acid levels because of their potential as biological markers. Peripheral d-serine levels and the ratio of d-serine to total serine have been reported to be significantly lower in patients with schizophrenia than in controls. Peripheral d-serine levels and the d-/l-serine ratio have also been reported to significantly increase in patients with schizophrenia as their clinical symptoms improve from the time of admission to the time of discharge. In this study, we examined whether peripheral NMDA receptor-related glutamatergic amino acids levels were altered in patients with treatment-resistant schizophrenia compared to controls and whether these peripheral amino acids levels were altered by clozapine treatment. Twenty-two patients with treatment-resistant schizophrenia and 22 age- and gender-matched healthy controls were enrolled. The plasma levels of d-serine, l-serine, glycine, glutamate, and glutamine were measured before and after clozapine treatment. We found that the plasma levels of d-serine and the d-/l-serine ratio were significantly lower in the patients before clozapine treatment than in the controls. The d-/l-serine ratio was significantly increased by clozapine treatment in patients, and no significant difference was observed in the plasma levels of d-serine and the d-/l-serine ratio between the patients after clozapine treatment and the controls. We also found that plasma glycine levels and the glycine/l-serine ratio were significantly increased following clozapine treatment in the patients, and the glycine/l-serine ratio was significantly higher in the patients after clozapine treatment than in the controls. There was no significant difference in the plasma levels of glutamate and glutamine both between the controls and patients and between before and after clozapine treatment. This study firstly demonstrated changes of d-/l-serine and glycine/l-serine ratio between before and after clozapine treatment, suggesting that the plasma d-/l-serine ratio and glycine/l-serine ratio could be markers of therapeutic efficacy or clinical state in treatment-resistant schizophrenia.
Assuntos
Antipsicóticos/uso terapêutico , Clozapina/uso terapêutico , Glicina/sangue , Esquizofrenia/tratamento farmacológico , Serina/sangue , Adulto , Estudos de Casos e Controles , Feminino , Ácido Glutâmico/sangue , Glutamina/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/sangue , Serina/química , Estereoisomerismo , Falha de TratamentoRESUMO
AIM: To investigate executive function in Japanese adolescents and adults with autism spectrum disorders (ASD) compared to Japanese controls. METHODS: Thirty-three individuals with ASD and 33 controls participated. The ASD and control groups' demographic variables were matched for gender (male/female: 20/13 vs 20/13), age (26.1 ± 11.5 vs 26.8 ± 9.6), years of education (13.2 ± 2.9 vs 14.2 ± 1.9), full-scale intelligence quotient (IQ) (103.0 ± 16.7 vs 103.7 ± 14.7), performance IQ (96.2 ± 16.1 vs 97.8 ± 15.0), and verbal IQ (107.9 ± 16.3 vs 107.7 ± 14.4). Participants performed the Wisconsin Card Sorting Test (WCST), which assesses the executive processes involved in problem solving and cognitive flexibility, and the Continuous Performance Test (CPT), which assesses attention and impulsivity. Symptoms were assessed by the Autism-Spectrum Quotient Japanese version (AQ-J). First, we compared the scores of the WCST between the groups using a Mann-Whitney U-test and conducted an analysis of covariance for the variables with the scores of category archives and CPT scores as covariates. Second, we analyzed the correlation between the scores of the WCST and the AQ-J in the ASD group using Pearson's r. RESULTS: The total errors (TE) and the percentages of perseverative errors of the Milner type (%PEM) and Nelson type (%PEN) among the TE in the ASD group were significantly worse compared with the control group (ASD vs Control, respectively: TE: 16.0 ± 6.2 vs 12.6 ± 3.5, P = 0.012; %PEM: 11.7 ± 10.7 vs 6.6 ± 8.9, P = 0.037; %PEN: 20.1 ± 14.5 vs 8.7 ± 10.4, P = 0.0011). In contrast, no significant difference was observed between the two groups in the scores of categories achieved on the WCST or the CPT. An analysis of covariance revealed significant differences between the groups in the %PEN scores (P = 0.0062) but not in the TE or the %PEM scores. These results suggest that Japanese adolescents and adults with ASD have cognitive inflexibility. Furthermore, our results suggest that Japanese adolescents and adults with ASD may have difficulties using negative feedback because perseverative errors of the Nelson type indicate persistence in choosing the incorrect reaction. By contrast, there was no significant correlation between the WCST and AQ-J scores. CONCLUSION: We confirmed the presence of cognitive inflexibility in Japanese adolescents and adults with ASD. Our results also indicated that subjects with ASD may not use negative feedback effectively.
RESUMO
Many gene expression studies have examined postmortem brain tissues of patients with schizophrenia. However, only a few expression studies of the genes identified in genome-wide association study (GWAS) have been published to date. We measured the expression levels of the genes identified in GWAS (ZNF804A, OPCML, RPGRIP1L, NRGN, and TCF4) of the postmortem brain tissues of patients with schizophrenia and controls from two separate sample sets (i.e., the Australian Tissue Resource Center and Stanley Medical Research Institute). We also determined whether the single-nucleotide polymorphisms (SNPs) identified in the GWAS were related to the gene expression changes in the prefrontal cortex. No difference was observed between the patients with schizophrenia and controls from the Australian Tissue Resource Center samples in the mRNA levels of ZNF804A, OPCML, RPGRIP1L, NRGN, or TCF4. The lack of mRNA change for these five transcripts was also found in the brain samples from the Stanley Medical Research Institute. In addition, no relationship between the schizophrenia-associated SNPs identified in the GWAS and the corresponding gene expression was observed in either sample set. Our results suggest that major changes in the transcript levels of the five candidate genes identified in the GWAS may not occur in adult patients with schizophrenia. The lack of linkage between the risk gene polymorphisms and the expression levels of their major transcripts suggests that the control of pan mRNA levels may not be a prominent mechanism by which the genes identified in the GWAS contribute to the pathophysiology of schizophrenia. Further studies are needed to examine how the genes identified in the GWAS contribute to the pathophysiology of schizophrenia.
Assuntos
Encéfalo/metabolismo , Esquizofrenia/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Estudos de Casos e Controles , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Pessoa de Meia-Idade , Neurogranina/genética , Neurogranina/metabolismo , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/metabolismo , Esquizofrenia/metabolismo , Fator de Transcrição 4 , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Guanosine triphosphate cyclohydrolase 1 (GCH1) is the rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin, a cofactor for aromatic amino acid hydroxylases and nitric oxide synthases. As monoamine neurotransmitters are synthesized by the reactions catalyzed by tyrosine hydroxylase and tryptophan hydroxylase, alterations in the content of tetrahydrobiopterin affect the monoamine levels in the brain. Here, we examined the possible association of a functional single-nucleotide polymorphism (SNP) of the GCH1 gene, rs841 (C+243T), with attentional function as assessed by the Continuous Performance Test-Identical Pairs version (CPT-IP) in healthy individuals. We found that homozygous T/T genotype carriers of rs841 scored lower performance on the CPT-IP test. Our data suggest that alterations in GCH1 activity affect attentional function, especially sustained attention and vigilance.
Assuntos
Atenção , Cognição , GTP Cicloidrolase/genética , Adulto , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
BACKGROUND: The dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) is a promising schizophrenia susceptibility gene, known to localize almost exclusively to neurons in the brain, and participates in the regulation of neurotransmitter release, membrane-surface receptor expression, and synaptic plasticity. Sandy mice, with spontaneous Dtnbp1 deletion, display behavioral abnormalities relevant to symptoms of schizophrenia. However, it remains unknown if dysbindin-1 gain-of-function is beneficial or detrimental. RESULTS: To answer this question and gain further insight into the pathophysiology and therapeutic potential of dysbindin-1, we developed transgenic mice expressing human DTNBP1 (Dys1A-Tg) and analyzed their behavioral phenotypes. Dys1A-Tg mice were born viable in the expected Mendelian ratios, apparently normal and fertile. Primary screening of behavior and function showed a marginal change in limb grasping in Dys1A-Tg mice. In addition, Dys1A-Tg mice exhibited increased hyperlocomotion after methamphetamine injection. Transcriptomic analysis identified several up- and down-regulated genes, including the immediate-early genes Arc and Egr2, in the prefrontal cortex of Dys1A-Tg mice. CONCLUSIONS: The present findings in Dys1A-Tg mice support the role of dysbindin-1 in psychiatric disorders. The fact that either overexpression (Dys1A-Tg) or underexpression (Sandy) of dysbindin-1 leads to behavioral alterations in mice highlights the functional importance of dysbindin-1 in vivo.
Assuntos
Comportamento Animal , Proteínas Associadas à Distrofina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Disbindina , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Metanfetamina/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenciclidina/farmacologiaRESUMO
Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. Peripheral BDNF levels in patients with schizophrenia have been widely reported in the literature. However, it is still controversial whether peripheral levels of BDNF are altered in patients with schizophrenia. The peripheral BDNF levels previously reported in patients with schizophrenia were total BDNF (proBDNF and mature BDNF) as it was unable to specifically measure mature BDNF due to limited BDNF antibody specificity. In this study, we examined whether peripheral levels of mature BDNF were altered in patients with treatment-resistant schizophrenia. Matrix metalloproteinase-9 (MMP-9) levels were also measured, as MMP-9 plays a role in the conversion of proBDNF to mature BDNF. Twenty-two patients with treatment-resistant schizophrenia treated with clozapine and 22 age- and sex-matched healthy controls were enrolled. The plasma levels of mature BDNF and MMP-9 were measured using ELISA kits. No significant difference was observed for mature BDNF however, MMP-9 was significantly increased in patients with schizophrenia. The significant correlation was observed between mature BDNF and MMP-9 plasma levels. Neither mature BDNF nor MMP-9 plasma levels were associated clinical variables. Our results do not support the view that peripheral BDNF levels are associated with schizophrenia. MMP-9 may play a role in the pathophysiology of schizophrenia and serve as a biomarker for schizophrenia.
Assuntos
Antipsicóticos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/sangue , Clozapina/uso terapêutico , Metaloproteinase 9 da Matriz/sangue , Precursores de Proteínas/sangue , Esquizofrenia/tratamento farmacológico , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/sangue , Falha de TratamentoRESUMO
ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. However, the biological functions of ZNF804A are not entirely understood. To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). Furthermore, we confirmed that the expression of ANKRD1, PIK3AP1, INHBE and DDIT3 at the protein level was significantly increased by ZNF804A-overexpression. This is the first report to identify genes whose protein expressions are regulated by ZNF804A. ANKRD1, PIK3AP1, INHBE and DDIT3 are related to transforming growth factor-ß (TGF-ß) signaling, which plays a crucial role in cell growth and differentiation. On the other hand, recent studies have reported that TGF-ß signaling is associated with schizophrenia. These results provide basis for a more progressive investigation of ZNF804A contributions to the susceptibility or pathophysiology of schizophrenia.
Assuntos
Regulação da Expressão Gênica/genética , Fatores de Transcrição Kruppel-Like/genética , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular Transformada , Perfilação da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/metabolismo , Estatísticas não Paramétricas , Transfecção , Fator de Crescimento Transformador beta/genéticaRESUMO
BACKGROUND: Hypofunction of the glutamate N-Methyl-d-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. p250GAP is a brain-enriched NMDA receptor-interacting RhoGAP. p250GAP is involved in spine morphology, and spine morphology has been shown to be altered in the post-mortem brains of patients with schizophrenia. Schizotypal personality disorder has a strong familial relationship with schizophrenia. Several susceptibility genes for schizophrenia have been related to schizotypal traits. METHODS: We first investigated the association of eight linkage disequilibrium-tagging single-nucleotide polymorphisms (SNPs) that cover the p250GAP gene with schizophrenia in a Japanese sample of 431 schizophrenia patients and 572 controls. We then investigated the impact of the risk genetic variant in the p250GAP gene on schizotypal personality traits in 180 healthy subjects using the Schizotypal Personality Questionnaire. RESULTS: We found a significant difference in genotype frequency between the patients and the controls in rs2298599 (χ(2) = 17.6, p = 0.00015). The minor A/A genotype frequency of rs2298599 was higher in the patients (18%) than in the controls (9%) (χ(2) = 15.5, p = 0.000083). Moreover, we found that subjects with the rs2298599 risk A/A genotype, compared with G allele carriers, had higher scores of schizotypal traits (F(1,178) = 4.08, p = 0.045), particularly the interpersonal factor (F(1,178) = 5.85, p = 0.017). DISCUSSION: These results suggest that a genetic variation in the p250GAP gene might increase susceptibility not only for schizophrenia but also for schizotypal personality traits. We concluded that the p250GAP gene might be a new candidate gene for susceptibility to schizophrenia.