Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental diso... more Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, characterized by a persistent pattern of inattention, hyperactivity, and impulsivity. Since the diagnosis of ADHD is defined by operational diagnostic criteria consisting of several clinical symptoms, a number of heterogeneous mechanisms have been considered to be implicated in its pathophysiology. Although no clinically reliable biomarkers are available for the diagnosis of ADHD, several plausible candidate biomarkers have been proposed based on recent advances in biochemistry and molecular biology. This review article summarizes potential peripheral biomarkers associated with ADHD, mainly from recently published case-control studies. These include 1) biochemical markers: neurotransmitters and their receptors, neurotrophic factors, serum electrolytes, and inflammation markers; 2) genetic and epigenetic markers: microRNA, mRNA expression, and peripheral DNA methylation; 3) physiological markers: eye movement and electroencephalography. It also discusses the limitations and future directions of these potential biomarkers for application in clinical practice.
The symptom heterogeneity of schizophrenia is consistent with Wittgenstein’s analogy of a languag... more The symptom heterogeneity of schizophrenia is consistent with Wittgenstein’s analogy of a language game. From the perspective of precision medicine, this study aimed to estimate the symptom presentation and identify the psychonectome in Asian patients, using data obtained from the Research on Asian Psychotropic Prescription Patterns for Antipsychotics. We constructed a network structure of the Brief Psychiatric Rating Scale (BPRS) items in 1438 Asian patients with schizophrenia. Furthermore, all the BPRS items were considered to be an ordered categorical variable ranging in value from 1–7. Motor retardation was situated most centrally within the BPRS network structure, followed by depressive mood and unusual thought content. Contrastingly, hallucinatory behavior was situated least centrally within the network structure. Using a community detection algorithm, the BPRS items were organized into positive, negative, and general symptom clusters. Overall, DSM symptoms were not more centr...
Background: The defined daily dose (DDD) from the Anatomical Therapeutic Chemical Classification ... more Background: The defined daily dose (DDD) from the Anatomical Therapeutic Chemical Classification System can be utilised as a reference for international drug utilization research, according to the World Health Organization. Alternatively, chlorpromazine equivalent (CPZeq) is a traditional method that has been used to indicate the dose of antipsychotics for decades. The aim of this study was to investigate and compare the DDD and CPZeq methods in order to calculate the total antipsychotic dose of inpatients with schizophrenia. Methods and Findings: Six countries (China, Hong Kong, Japan, Korea, Singapore, and Taiwan) participated in antipsychotic prescription pattern surveys conducted four times during 2001, 2004, 2009, and 2016. The antipsychotic loading (APL) values of each prescription, calculated using the DDD and CPZeq methods, and their correlations were compared. A total of 6986 prescriptions from inpatients with schizophrenia were analysed. Spearman’s correlation coefficients...
Schizophrenia (SCZ) is known to be a heritable disorder; however, its multifactorial nature has s... more Schizophrenia (SCZ) is known to be a heritable disorder; however, its multifactorial nature has significantly hampered attempts to establish its pathogenesis. Therefore, in this study, we performed genome-wide copy-number variation (CNV) analysis of 2940 patients with SCZ and 2402 control subjects and identified a statistically significant association between SCZ and exonic CNVs in the ARHGAP10 gene. ARHGAP10 encodes a member of the RhoGAP superfamily of proteins that is involved in small GTPase signaling. This signaling pathway is one of the SCZ-associated pathways and may contribute to neural development and function. However, the ARHGAP10 gene is often confused with ARHGAP21, thus, the significance of ARHGAP10 in the molecular pathology of SCZ, including the expression profile of the ARHGAP10 protein, remains poorly understood. To address this issue, we focused on one patient identified to have both an exonic deletion and a missense variant (p.S490P) in ARHGAP10. The missense var...
Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays a... more 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 ...
Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental im... more 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 miss...
Background Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD... more Background Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in NRXN1, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ. Methods To discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced NRXN1 coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detecte...
Tardive dyskinesia (TD) is a severe condition characterized by repetitive involuntary movement of... more 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. Multivariate analyses of polygenic risk for TD supports the genetic susceptibility of TD, with relatively lower allele frequencies variants being associated with TD, beyond that of antipsychotic medication. Together, these findings provide new insights into the genetic architecture and biology of TD.
Background: We aimed to determine the similarities and differences in the roles of genic and regu... more 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 the largest known 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 (NDD-CNVs) 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 NDD-CNVs. We identified three 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 NDD-CNVs, 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. PCDH15 20% from cells PCDH15 Rare
Early detection of perinatal depression is an urgent issue. Our study aimed to examine the constr... more Early detection of perinatal depression is an urgent issue. Our study aimed to examine the construct validity and factor structure of the Japanese version of the Edinburgh Postnatal Depression Scale (EPDS) from a prospective cohort study from pregnancy to postpartum. A total of 1075 women completed all items of the EPDS at four time points: early pregnancy, late pregnancy, 5 days postpartum and 1 month postpartum. The participants were randomly divided into two sample sets. The first sample set (n = 304) was used for exploratory factor analysis, and the second sample set (n = 771) was used for confirmatory factor analysis. As a result, the Cronbach’s alpha coefficients of the EPDS items were 0.762, 0.740, 0.765 and 0.772 at the four time points. From the confirmatory factor analysis of the EPDS in a sample set of Japanese women from pregnancy to postpartum, the following three factors were detected: depression (items 7, 9), anxiety (items 4, 5) and anhedonia (items 1, 2). In conclus...
Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental diso... more Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, characterized by a persistent pattern of inattention, hyperactivity, and impulsivity. Since the diagnosis of ADHD is defined by operational diagnostic criteria consisting of several clinical symptoms, a number of heterogeneous mechanisms have been considered to be implicated in its pathophysiology. Although no clinically reliable biomarkers are available for the diagnosis of ADHD, several plausible candidate biomarkers have been proposed based on recent advances in biochemistry and molecular biology. This review article summarizes potential peripheral biomarkers associated with ADHD, mainly from recently published case-control studies. These include 1) biochemical markers: neurotransmitters and their receptors, neurotrophic factors, serum electrolytes, and inflammation markers; 2) genetic and epigenetic markers: microRNA, mRNA expression, and peripheral DNA methylation; 3) physiological markers: eye movement and electroencephalography. It also discusses the limitations and future directions of these potential biomarkers for application in clinical practice.
The symptom heterogeneity of schizophrenia is consistent with Wittgenstein’s analogy of a languag... more The symptom heterogeneity of schizophrenia is consistent with Wittgenstein’s analogy of a language game. From the perspective of precision medicine, this study aimed to estimate the symptom presentation and identify the psychonectome in Asian patients, using data obtained from the Research on Asian Psychotropic Prescription Patterns for Antipsychotics. We constructed a network structure of the Brief Psychiatric Rating Scale (BPRS) items in 1438 Asian patients with schizophrenia. Furthermore, all the BPRS items were considered to be an ordered categorical variable ranging in value from 1–7. Motor retardation was situated most centrally within the BPRS network structure, followed by depressive mood and unusual thought content. Contrastingly, hallucinatory behavior was situated least centrally within the network structure. Using a community detection algorithm, the BPRS items were organized into positive, negative, and general symptom clusters. Overall, DSM symptoms were not more centr...
Background: The defined daily dose (DDD) from the Anatomical Therapeutic Chemical Classification ... more Background: The defined daily dose (DDD) from the Anatomical Therapeutic Chemical Classification System can be utilised as a reference for international drug utilization research, according to the World Health Organization. Alternatively, chlorpromazine equivalent (CPZeq) is a traditional method that has been used to indicate the dose of antipsychotics for decades. The aim of this study was to investigate and compare the DDD and CPZeq methods in order to calculate the total antipsychotic dose of inpatients with schizophrenia. Methods and Findings: Six countries (China, Hong Kong, Japan, Korea, Singapore, and Taiwan) participated in antipsychotic prescription pattern surveys conducted four times during 2001, 2004, 2009, and 2016. The antipsychotic loading (APL) values of each prescription, calculated using the DDD and CPZeq methods, and their correlations were compared. A total of 6986 prescriptions from inpatients with schizophrenia were analysed. Spearman’s correlation coefficients...
Schizophrenia (SCZ) is known to be a heritable disorder; however, its multifactorial nature has s... more Schizophrenia (SCZ) is known to be a heritable disorder; however, its multifactorial nature has significantly hampered attempts to establish its pathogenesis. Therefore, in this study, we performed genome-wide copy-number variation (CNV) analysis of 2940 patients with SCZ and 2402 control subjects and identified a statistically significant association between SCZ and exonic CNVs in the ARHGAP10 gene. ARHGAP10 encodes a member of the RhoGAP superfamily of proteins that is involved in small GTPase signaling. This signaling pathway is one of the SCZ-associated pathways and may contribute to neural development and function. However, the ARHGAP10 gene is often confused with ARHGAP21, thus, the significance of ARHGAP10 in the molecular pathology of SCZ, including the expression profile of the ARHGAP10 protein, remains poorly understood. To address this issue, we focused on one patient identified to have both an exonic deletion and a missense variant (p.S490P) in ARHGAP10. The missense var...
Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays a... more 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 ...
Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental im... more 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 miss...
Background Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD... more Background Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in NRXN1, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ. Methods To discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced NRXN1 coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detecte...
Tardive dyskinesia (TD) is a severe condition characterized by repetitive involuntary movement of... more 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. Multivariate analyses of polygenic risk for TD supports the genetic susceptibility of TD, with relatively lower allele frequencies variants being associated with TD, beyond that of antipsychotic medication. Together, these findings provide new insights into the genetic architecture and biology of TD.
Background: We aimed to determine the similarities and differences in the roles of genic and regu... more 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 the largest known 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 (NDD-CNVs) 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 NDD-CNVs. We identified three 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 NDD-CNVs, 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. PCDH15 20% from cells PCDH15 Rare
Early detection of perinatal depression is an urgent issue. Our study aimed to examine the constr... more Early detection of perinatal depression is an urgent issue. Our study aimed to examine the construct validity and factor structure of the Japanese version of the Edinburgh Postnatal Depression Scale (EPDS) from a prospective cohort study from pregnancy to postpartum. A total of 1075 women completed all items of the EPDS at four time points: early pregnancy, late pregnancy, 5 days postpartum and 1 month postpartum. The participants were randomly divided into two sample sets. The first sample set (n = 304) was used for exploratory factor analysis, and the second sample set (n = 771) was used for confirmatory factor analysis. As a result, the Cronbach’s alpha coefficients of the EPDS items were 0.762, 0.740, 0.765 and 0.772 at the four time points. From the confirmatory factor analysis of the EPDS in a sample set of Japanese women from pregnancy to postpartum, the following three factors were detected: depression (items 7, 9), anxiety (items 4, 5) and anhedonia (items 1, 2). In conclus...
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