RESUMO
Psychiatric disorders are highly inheritable, and most psychiatric disorders exhibit genetic overlap. Recent studies associated the 3q29 recurrent deletion with schizophrenia (SCZ) and autism spectrum disorder (ASD). In this study, we investigated the association of genes in the 3q29 region with SCZ and ASD. TM4SF19 and PAK2 were chosen as candidate genes for this study based on evidence from previous research. We sequenced TM4SF19 and PAK2 in 437 SCZ cases, 187 ASD cases and 524 controls in the Japanese population. Through targeted sequencing, we identified 6 missense variants among the cases (ASD & SCZ), 3 missense variants among controls, and 1 variant common to both cases and controls; however, no loss-of-function variants were identified. Fisher's exact test showed a significant association of variants in TM4SF19 among cases (p=0.0160). These results suggest TM4SF19 variants affect the etiology of SCZ and ASD in the Japanese population. Further research examining 3q29 region genes and their association with SCZ and ASD is thus needed.
Assuntos
Povo Asiático , Transtorno do Espectro Autista , Predisposição Genética para Doença , Esquizofrenia , Humanos , Transtorno do Espectro Autista/genética , Esquizofrenia/genética , Feminino , Masculino , Japão , Povo Asiático/genética , Predisposição Genética para Doença/genética , Quinases Ativadas por p21/genética , Cromossomos Humanos Par 3/genética , Adulto , Mutação de Sentido Incorreto/genética , Estudos de Casos e Controles , Estudos de Associação Genética , População do Leste AsiáticoRESUMO
Recent genetic studies have found common genomic risk variants among psychiatric disorders, strongly suggesting the overlaps in their molecular and cellular mechanism. Our research group identified the variant in ASTN2 as one of the candidate risk factors across these psychiatric disorders by whole-genome copy number variation analysis. However, the alterations in the human neuronal cells resulting from ASTN2 variants identified in patients remain unknown. To address this, we used patient-derived and genome-edited iPS cells with ASTN2 deletion; cells were further differentiated into neuronal cells. A comprehensive gene expression analysis using genome-edited iPS cells with variants on both alleles revealed that the expression level of ZNF558, a gene specifically expressed in human forebrain neural progenitor cells, was greatly reduced in ASTN2-deleted neuronal cells. Furthermore, the expression of the mitophagy-related gene SPATA18, which is repressed by ZNF558, and mitophagy activity were increased in ASTN2-deleted neuronal cells. These phenotypes were also detected in neuronal cells differentiated from patient-derived iPS cells with heterozygous ASTN2 deletion. Our results suggest that ASTN2 deletion is related to the common pathogenic mechanism of psychiatric disorders by regulating mitophagy via ZNF558.
Assuntos
Glicoproteínas , Células-Tronco Pluripotentes Induzidas , Transtornos Mentais , Proteínas do Tecido Nervoso , Neurônios , Humanos , Diferenciação Celular/genética , Variações do Número de Cópias de DNA , Deleção de Genes , Células-Tronco Pluripotentes Induzidas/metabolismo , Transtornos Mentais/genética , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Fatores de Transcrição/genética , Glicoproteínas/genética , Proteínas do Tecido Nervoso/genéticaRESUMO
Whole genome analysis has identified rare copy number variations (CNV) that are strongly involved in the pathogenesis of psychiatric disorders, and 3q29 deletion has been found to have the largest effect size. The 3q29 deletion mice model (3q29-del mice) has been established as a good pathological model for schizophrenia based on phenotypic analysis; however, circadian rhythm and sleep, which are also closely related to neuropsychiatric disorders, have not been investigated. In this study, our aims were to reevaluate the pathogenesis of 3q29-del by recreating model mice and analyzing their behavior and to identify novel new insights into the temporal activity and temperature fluctuations of the mouse model using a recently developed small implantable accelerometer chip, Nano-tag. We generated 3q29-del mice using genome editing technology and reevaluated common behavioral phenotypes. We next implanted Nano-tag in the abdominal cavity of mice for continuous measurements of long-time activity and body temperature. Our model mice exhibited weight loss similar to that of other mice reported previously. A general behavioral battery test in the model mice revealed phenotypes similar to those observed in mouse models of schizophrenia, including increased rearing frequency. Intraperitoneal implantation of Nano-tag, a miniature acceleration sensor, resulted in hypersensitive and rapid increases in the activity and body temperature of 3q29-del mice upon switching to lights-off condition. Similar to the 3q29-del mice reported previously, these mice are a promising model animals for schizophrenia. Successive quantitative analysis may provide results that could help in treating sleep disorders closely associated with neuropsychiatric disorders.
Assuntos
Deficiências do Desenvolvimento , Deficiência Intelectual , Humanos , Criança , Camundongos , Animais , Deficiências do Desenvolvimento/genética , Deleção Cromossômica , Variações do Número de Cópias de DNA , Temperatura Corporal , Deficiência Intelectual/genética , Modelos Animais de Doenças , FenótipoRESUMO
AIM: The present study aimed to examine the association between copy number variations (CNVs) in parkin (PRKN) and schizophrenia (SCZ) and autism spectrum disorder (ASD) in a large case-control sample. METHOD: Array comparative genomic hybridization was performed on 3111 cases with SCZ, 1236 cases with ASD, and 2713 controls. We systematically prioritized likely pathogenic CNVs (LP-CNVs) in PRKN and examined their association with SCZ and ASD. RESULTS: In total, 3014 SCZ cases (96.9%), 1205 ASD cases (97.5%), and 2671 controls (98.5%) passed quality control. We found that monoallelic carriers of LP-CNVs in PRKN were common (70/6890, 1.02%) and were not at higher risk of SCZ (p = 0.29) or ASD (p = 0.72). We observed that the distribution pattern of LP-CNVs in the Japanese population was consistent with those in other populations. We also identified a patient diagnosed with SCZ and early-onset Parkinson's disease carrying biallelic pathogenic CNVs in PRKN. The absence of Parkinson's symptoms in 10 other monoallelic carriers of the same pathogenic CNV further reflects the lack of effect of monoallelic pathogenic variants in PRKN in the absence of a second hit. CONCLUSION: The present findings suggest that monoallelic CNVs in PRKN do not confer a significant risk for SCZ or ASD. However, further studies to investigate the association between biallelic CNVs in PRKN and SCZ and ASD are warranted.
Assuntos
Transtorno do Espectro Autista , Esquizofrenia , Humanos , Transtorno do Espectro Autista/genética , Estudos de Casos e Controles , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Ubiquitina-Proteína Ligases/genéticaRESUMO
A number of genomic mutations that are thought to be strongly involved in the development of schizophrenia (SCZ) and autism spectrum disorder (ASD) have been identified. Abnormalities involving oligodendrocytes have been reported in SCZ, and as a related gene, oligodendrocyte lineage transcription factor 2 (OLIG2) has been reported to be strongly associated with SCZ. In this study, based on the common disease-rare variant hypothesis, target sequencing of candidate genes was performed to identify rare mutations with a high effect size and the possibility that the identified mutations may increase the risks of SCZ and ASD in the Japanese population. In this study, the exon region of OLIG2 was targeted; 370 patients with SCZ and 192 with ASD were subjected to next-generation sequencing. As a result, one rare missense mutation (A33T) was detected. We used the Sanger method to validate this missense mutation with a low frequency (<1%), and then carried out a genetic association analysis involving 3299 unrelated individuals (1447 with SCZ, 380 with ASD, and 1472 healthy controls) to clarify whether A33T was associated with SCZ or ASD. A33T was not found in either case group, and in only one control. We did not find evidence that p.A33T is involved in the onset of ASD or SCZ; however, associations with this variant need to be evaluated in larger samples to confirm our results.
Assuntos
Transtorno do Espectro Autista , Fator de Transcrição 2 de Oligodendrócitos , Esquizofrenia , Transtorno do Espectro Autista/genética , Humanos , Mutação , Mutação de Sentido Incorreto/genética , Fator de Transcrição 2 de Oligodendrócitos/genética , Esquizofrenia/genéticaRESUMO
BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.
Assuntos
Transtorno do Espectro Autista , Transtorno Bipolar , Esquizofrenia , Transtorno do Espectro Autista/genética , Transtorno Bipolar/genética , Cromatina , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Esquizofrenia/genéticaRESUMO
Chromatin remodelling is an important process in neural development and is related to autism spectrum disorder (ASD) and schizophrenia (SCZ) aetiology. To further elucidate the involvement of chromatin remodelling genes in the genetic aetiology of ASD and SCZ in the Japanese population, we performed a case-control study. Targeted sequencing was conducted on coding regions of four BAF chromatin remodelling complex genes: SMARCA2, SMARCA4, SMARCC2, and ARID1B in 185 ASD, 432 SCZ patients, and 517 controls. 27 rare non-synonymous variants were identified in ASD and SCZ patients, including 25 missense, one in-frame deletion in SMRACA4, and one frame-shift variant in SMARCC2. Association analysis was conducted to investigate the burden of rare variants in BAF genes in ASD and SCZ patients. Significant enrichment of rare missense variants in BAF genes, but not synonymous variants, was found in ASD compared to controls. Rare pathogenic variants indicated by in silico tools were significantly enriched in ASD, but not statistically significant in SCZ. Pathogenic-predicted variants were located in disordered binding regions and may confer risk for ASD and SCZ by disrupting protein-protein interactions. Our study supports the involvement of rare missense variants of BAF genes in ASD and SCZ susceptibility.
Assuntos
Transtorno do Espectro Autista , Montagem e Desmontagem da Cromatina , Transtorno do Espectro Autista/genética , Estudos de Casos e Controles , Montagem e Desmontagem da Cromatina/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Humanos , Japão , Mutação de Sentido Incorreto , Proteínas Nucleares/genética , Esquizofrenia , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Most sequencing studies of schizophrenia (SCZ) have focused on de novo genetic variants due to interpretability. However, investigating shared rare variants among patients in the same multiplex family is also important. Relatively large-scale analyses of SCZ multiplex families have been done in Caucasian populations, but whether detected variants are also pathogenic in the Japanese population is unclear because of ethnic differences in rare variants. MATERIALS AND METHODS: We performed whole-exome sequencing (WES) of 14 Japanese SCZ multiplex families. After quality control and filtering, we identified rare variants shared among affected persons within the same family. A gene ontology (GO) analysis was performed to identify gene categories possibly affected by these candidate variants. RESULTS: We found 530 variants in 486 genes as potential candidate variants from the 14 SCZ multiplex families examined. The GO analysis demonstrated significant enrichment in calcium channel activity. CONCLUSION: This study provides supporting evidence that calcium ion channel activity is involved in SCZ. WES of multiplex families is a potential means of identifying disease-associated rare variants for SCZ.
Assuntos
Esquizofrenia , Canais de Cálcio/genética , Exoma/genética , Predisposição Genética para Doença , Humanos , Japão , Esquizofrenia/genética , Sequenciamento do ExomaRESUMO
Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays an essential role in correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal, and postmortem studies. Recently, increasing attention has been given to rare single-nucleotide variants (SNVs) found by deep sequencing of candidate genes. In this study, we performed exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency <1%. We detected two rare missense mutations (G382C, V129I) and then performed a genetic association study in a sample comprising 1763 SCZ, 380 ASD, and 2190 healthy control subjects. Although no statistically significant association with the detected mutations was observed for either SCZ or ASD, G382C was found only in the case group, and in silico analyses and in vitro functional assays suggested that G382C alters the function of the DAB1 protein. The rare variants of DAB1 found in the present study should be studied further to elucidate their potential functional relevance to the pathophysiology of SCZ and ASD.
RESUMO
Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (KDM4C) have been suggested to confer a risk for such disorders. However, rare genetic variants in KDM4C have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in KDM4C and SCZ (p = 0.003) and ASD (p = 0.04). We also observed a significant association between deletions in KDM4C and SCZ (corrected p = 0.04). Next, to explore the contribution of single nucleotide variants in KDM4C, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with KDM4C deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between KDM4C CNVs and these two disorders and for their potential functional effect on histone methylation patterns.
Assuntos
Transtorno do Espectro Autista , Esquizofrenia , Transtorno do Espectro Autista/genética , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Histona Desmetilases/genética , Histonas , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Esquizofrenia/genéticaRESUMO
PURPOSE: We assessed lateralization of interictal epileptiform discharges (IEDs) in children with intractable epilepsy secondary to tuberous sclerosis complexes (TSCs) during rapid eye movement sleep (R), compared with non-rapid eye movement sleep (NR) and wakefulness (W), to determine epileptogenicity of R-IEDs. METHODS: We retrospectively studied 23 children with TSC, who underwent prolonged scalp video-electroencephalography (EEG) and magnetic resonance imaging (MRI). We determined the lateralization of ictal EEG, clinical semiology, and the largest tuber on MRI. We analyzed a minimum of 100 IEDs during R, NR, and W to classify right/left/generalized spikes to compare the lateralization with ictal EEG, clinical semiology, and MRI. KEY FINDINGS: R-IEDs were lateralized in 22 patients (96%), W-IEDs in 19 (83%), and NR-IEDs in 16 (70%). Ictal EEGs were lateralized in 15 patients (65%) and clinical semiology in 5 (22%). Ictal EEG lateralization was concordant to R-IEDs in 14 patients (93%), W-IEDs in 11 (73%), and NR-IEDs in 10 (67%). The lateralization of clinical semiology was concordant with R-IEDs in 4 (80%), W-IEDs in 3 (60%), and NR-IEDs in 2 (40%). MRI lateralization of the largest tuber was concordant with R-IEDs in 16 (70%), W-IEDs in 12 (52%), and NR-IEDs in 11 (48%). Thirteen patients (57%) underwent resective surgery, the hemisphere of which was concordant with R-IEDs in 13 (100%), W-IEDs in 8 (62%), and NR-IEDs in 8 (62%). Nine (69%) of them achieved good seizure control after surgery. SIGNIFICANCE: R provoked the most lateralized IEDs compared to NR and W in children with TSC. Lateralization of R-IEDs corresponded with the hemisphere of ictal EEG and largest tuber, and can be used to identify surgical candidacy in TSC children with intractable epilepsy.