Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

Although several studies have found significant relationships between autistic traits and depression/anxiety, the relationships between autistic traits and postpartum depression/anxiety remain unclear. Moreover, few studies have examined the relationships between autistic traits and mother–infant bonding while considering depression or anxiety.

Methods

This study used a cross-sectional data analysis design. Participants were 2692 women who completed the Autism-Spectrum Quotient (AQ), Hospital Anxiety and Depression Scale (HADS), and Mother-to-Infant Bonding Scale (MIBS) at 1 month postpartum. We performed path analysis that included parity, the five AQ subscales (social skills, attention switching, attention to detail, communication, and imagination), both HADS subscales (anxiety and depression), and the two MIBS subscales (lack of affection and anger and rejection).

Results

Our path analysis revealed that higher scores for social skills, attention switching, communication, and imagination were associated with higher scores for depression. Higher scores for social skills, attention switching, attention to detail, and communication were associated with higher scores for anxiety. Moreover, difficulties in social skills and imagination were associated with failure of maternal–infant bonding. However, more attention to detail was associated with better maternal–infant bonding.

Conclusions

This study suggests that maternal autistic traits are related to anxiety and depression to a certain degree, but only slightly related to maternal–infant bonding at 1 month postpartum. To improve autistic women’s quality of life and that of their newborns, perinatal mental health issues such as anxiety, depression, and maternal–fetal bonding difficulties should be appropriately addressed.

DOI： 10.1186/s12888-023-04970-y

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Other Link： https://link.springer.com/article/10.1186/s12888-023-04970-y/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)  

The pathophysiology underlying major depressive disorder (MDD) and schizophrenia is related to endocrine system functions and includes changes in the blood levels of cortisol and insulin-like growth factor 1 (IGF-1). However, these hormones have not been investigated simultaneously in patients with MDD and schizophrenia. We investigated the differences in serum cortisol and IGF-1 levels among patients with MDD and schizophrenia and controls. We included 129 patients with MDD, 71 patients with schizophrenia, and 71 healthy volunteers. Blood tests were performed between 6:00 am and 11:00 am after fasting. Serum cortisol levels were significantly higher in patients with schizophrenia than in patients with MDD and controls. Serum cortisol levels were significantly higher in patients with MDD than in controls. Serum IGF-1 levels were higher in both patient groups than in controls, whereas there was no significant difference between patients with MDD and schizophrenia. Both cortisol and IGF-1 levels were positively correlated with the Hamilton Rating Scale for Depression score in patients with MDD, whereas cortisol level was positively correlated and IGF-1 level was negatively correlated with the Brief Psychiatric Rating Scale score in patients with schizophrenia. The differences in the level of these hormones suggest pathophysiological differences between these disorders.

DOI： 10.1038/s41598-023-28449-8

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Language：English   Publishing type：Research paper (scientific journal)  

The parental bonding instrument (PBI) is often used to examine the perceptions of children and adolescents regarding parenting practices. Previous studies have investigated the factor structure of the PBI. However, although it is important to examine the relationships between the perceived parenting practices and perinatal mental health, few studies have included perinatal women. We aimed to accurately clarify which PBI factor structure was useful in assessing perinatal women (n = 4633). Furthermore, we evaluated the measurement invariance between primipara and multipara groups, and between the paternal and maternal PBI forms. Our exploratory and confirmatory factor analyses revealed that a three-factor PBI structure was most plausible for perinatal women. Moreover, we found complete invariance (residual invariance) of the PBI ratings across primipara and multipara women for the paternal and maternal forms. In contrast, we found weak invariance (metric invariance) of the PBI ratings across the paternal and maternal forms. Our participants tended to rate fathers as less caring and less overprotective than mothers. This three-factor structure shows measurement invariance in perinatal women and can be used to accurately determine how the perceived parenting style before adolescence influences women's mental health in the perinatal period.

DOI： 10.1038/s41598-022-22017-2

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Language：English  

DOI： 10.1111/pcn.13494

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/pcn5.28

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/pcn5.28

Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/pcn5.24

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/pcn5.24

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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.

DOI： 10.1016/j.biopsych.2022.04.003

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SETD1A has been identified as a substantial risk gene for schizophrenia. To further investigate the role of SETD1A in the genetic etiology of schizophrenia in the Japanese population, we performed resequencing and association analyses. First, we resequenced the SETD1A coding regions of 974 patients with schizophrenia. Then, we genotyped variants, prioritized via resequencing, in 2,027 patients with schizophrenia and 2,664 controls. Next, we examined the association between SETD1A and schizophrenia in 3,001 patients with schizophrenia and 2,664 controls. Finally, we performed a retrospective chart review of patients with prioritized SETD1A variants. We identified two novel missense variants (p.Ser575Pro and p.Glu857Gln) via resequencing. We did not detect these variants in 4,691 individuals via genotyping. These variants were not significantly associated with schizophrenia in the association analysis. Additionally, we found that a schizophrenia patient with the p.Glu857Gln variant had developmental delays. In conclusion, novel SETD1A missense variants were exclusively identified in Japanese patients with schizophrenia. However, our study does not provide evidence for the contribution of these variants to the genetic etiology of schizophrenia in the Japanese population.

DOI： 10.1016/j.psychres.2022.114481

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BACKGROUND: Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that promotes neurogenesis and neuroprotection. MIF is predominantly expressed in astrocytes in the brain. The serum MIF level and microsatellites/single nucleotide polymorphisms (SNPs) in the MIF gene promoter region are known to be associated with schizophrenia (SCZ). Interestingly, previous studies reported that hypoxia, an environmental risk factor for SCZ, induced MIF expression through binding of the hypoxia inducible factor (HIF)-1 to the hypoxia response element (HRE) in the MIF promoter. METHODS: We investigated the involvement of MIF in SCZ while focusing on the HIF pathway. First, we conducted an association study of the SNP rs17004038 (C>A) in the HRE of the MIF promoter between 1758 patients with SCZ and 1507 controls. Next, we investigated the effect of hypoxia on MIF expression in primary cultured astrocytes derived from neonatal mice forebrain. RESULTS: SNP rs17004038 was significantly associated with SCZ (p = 0.0424, odds ratio = 1.445), indicating that this SNP in the HRE of the MIF promoter was a genetic risk factor for SCZ. Hypoxia induced MIF mRNA expression and MIF protein production and increased HIF-1 binding to the MIF promoter, while the activity of the MIF promoter was suppressed by mutations in the HRE and by deletion of the HRE in astrocytes. CONCLUSION: These results suggest that SNP rs17004038 in the HRE of the MIF promoter was significantly associated with SCZ and may be involved in the pathophysiology of SCZ via suppression of hypoxia and HIF pathway-induced MIF expression.

DOI： 10.1371/journal.pone.0265738

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PURPOSE: There is little evidence regarding the effects of dental status on body mass index (BMI) in inpatients with schizophrenia. Thus, we performed a cross-sectional study to explore the associations between the number of remaining teeth and BMI in Japanese inpatients with schizophrenia. PATIENTS AND METHODS: We performed multiple regression analysis to assess the effects of potential predictors (age, sex, number of remaining teeth, number of antipsychotics prescribed, chlorpromazine equivalent dose, and antipsychotic type) on BMI in 212 inpatients with schizophrenia. We then compared the number of remaining teeth between inpatients with schizophrenia and the Japanese general population (3283 individuals) from the Japan Dental Diseases Survey 2016, using an analysis of covariance with age and sex as covariates. RESULTS: Multiple regression analysis showed that the number of remaining teeth and the number of antipsychotics prescribed were significantly correlated with BMI (standardized regression coefficient = 0.201 and 0.235, respectively). In the analysis of covariance, inpatients with schizophrenia had significantly fewer remaining teeth compared with the Japanese general population (mean 14.8 [standard deviation: 10.9] vs mean 23.0 [standard deviation: 8.1]). CONCLUSION: These results suggested that tooth loss and antipsychotic polypharmacy affect BMI in inpatients with schizophrenia, and that inpatients with schizophrenia lose more teeth compared with the general population.

DOI： 10.2147/NDT.S387724

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AIM: This study was aimed towards detecting how perceived parenting practices before adolescence affect maternal-infant bonding in the perinatal period, considering factors such as depression, anxiety, and parity. METHODS: We used the Parental Bonding Instrument (PBI) to examine perceived parenting practices. Participants included 1301 pregnant women who completed the Hospital Anxiety and Depression Scale (HADS) and Mother-to-Infant Bonding Scale (MIBS) at three time points: early pregnancy (approximately 12-15 weeks), late pregnancy (approximately 30-34 weeks) and postpartum (4 weeks after childbirth). We performed a path analysis with factors including parity, PBI subscales (paternal care, paternal overprotection, maternal care and maternal overprotection), HADS and MIBS. RESULTS: Perceived paternal or maternal low care parenting predicted higher HADS and MIBS scores in early pregnancy. Moreover, perceived maternal low care parenting predicted higher HADS scores at postpartum and higher MIBS scores in late pregnancy. Perceived paternal or maternal overprotective parenting predicted higher HADS scores in the pregnancy period. Furthermore, perceived maternal overprotective parenting predicted higher MIBS scores in late pregnancy. Being primipara predicted higher HADS scores at postpartum and higher MIBS scores in early pregnancy and at postpartum. Being multipara predicted higher MIBS scores in late pregnancy. CONCLUSION: This study suggests that perceived negative parenting before adolescence has indirect effects (via anxiety and depression) and direct effects on maternal-infant bonding in the perinatal period.

DOI： 10.1111/pcn.13289

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It is important to clarify how the breastfeeding method affects women's mental health, and how women's mental health affects the breastfeeding method in the early postpartum period when major depression and other psychiatric problems are most likely to occur. This study aimed to examine this bidirectional relationship in the early postpartum period. Participants were 2020 postpartum women who completed the Hospital Anxiety and Depression Scale (HADS) and Mother-to-Infant Bonding Scale (MIBS). We obtained data for participants' breastfeeding method for four weeks after childbirth. We performed a path analysis with factors including breastfeeding method (exclusive breastfeeding or non-exclusive breastfeeding), parity (primipara or multipara), the two HADS subscales (anxiety and depression), and the two MIBS subscales (lack of affection and anger and rejection). The path analysis showed that breastfeeding method did not significantly affect depression, anxiety, and maternal-infant bonding in the early postpartum period. Women with higher anxiety tended to use both formula-feeding and breastfeeding. Our study suggests that exclusive breastfeeding is not associated with maternal-fetal bonding in early postpartum, considering depression, anxiety, and parity.

DOI： 10.3390/nu13041184

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Background: Growth-associated protein 43 (GAP43), a synaptic protein involved in axonal growth and synaptic plasticity, is implicated in the pathophysiology of autism spectrum disorder (ASD) and schizophrenia. To examine the role of rare GAP43 variants in the genetic etiology of ASD and schizophrenia in a Japanese population, we performed resequencing and association analysis.Methods: First, we resequenced the GAP43 coding region in 295 ASD patients, 323 schizophrenia patients and 304 controls. Second, we genotyped rs561268447 in 273 ASD patients, 1,150 schizophrenia patients and 1,022 controls. Third, we performed an association analysis of rs561268447 in 568 ASD patients, 1,473 schizophrenia patients and 10,127 controls.Results: We identified a rare putatively damaging missense variant (rs561268447) in an ASD patient via resequencing. However, we did not detect the variant in 2,445 individuals via genotyping. The variant was not significantly associated with ASD or schizophrenia in the association analysis.Conclusion: This study does not provide evidence for the contribution of rare GAP43 variants to ASD or schizophrenia susceptibility in the Japanese population.

DOI： 10.1016/j.rasd.2021.101729

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞ポイント ◆COVID-19パンデミック下で医療従事者の約25%が不安や抑うつを有している.◆専門職による心理的介入だけでなく基本的なセルフケアの確保など現場の医療従事者が求める支援の実施が重要である.◆医療従事者は偏見や差別にさらされており,これらの克服など行政的な取り組みも必要である.

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Purpose: The Hospital Anxiety and Depression Scale (HADS) is a self-report questionnaire widely used to assess anxiety and depression. To the best of our knowledge, only four studies have examined the factor structure of the HADS for assessing pregnant women, with conflicting results. This study aimed to assess the factor structure and measurement invariance of the HADS for use with pregnant Japanese women. Participants and Methods: A total of 936 pregnant Japanese women completed the HADS questionnaire at three time points: the first and third trimester of pregnancy, and postpartum. We examined the factor structure of the HADS in Group 1 (n = 466) using exploratory factor analysis (EFA). We then compared the models identified in Group 1 with those from previous studies using confirmatory factor analysis (CFA) in Group 2 (n = 470). We performed multiple-group CFA for Group 2 to test the measurement invariance of the best-fit model across the three time points. Results: The EFA for the Group 1 data at the three time points revealed a two-factor model. In the CFA, the two-factor model from Group 1 showed the best fit with the data at the three time points. In the multiple-group CFA for Group 2, we confirmed the configural and metric invariance of the two-factor model across the three time points. Conclusion: Our findings provide evidence for a two-factor structure and weak measurement invariance of the HADS in pregnant Japanese women during the peripartum period.

DOI： 10.2147/NDT.S294918

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Purpose: Identification of pregnant women with bonding difficulties is important to provide early intervention. However, few studies have examined the utility of self-report questionnaires that assess mother-infant bonding as screening tools for bonding difficulties. This longitudinal study aimed to identify pregnant women with bonding difficulties using the Japanese version of the Mother-to-Infant Bonding Scale (MIBS-J) and to estimate its optimal cutoff points in the peripartum period. Patients and Methods: A total of 1301 pregnant women completed the MIBS-J and Hospital Anxiety and Depression Scale (HADS) at three time points: first trimester (T1; approximately 12-15 weeks gestation), third trimester (T2; approximately 30-34 weeks gestation), and postpartum (T3; approximately 4 weeks postpartum). A two-step cluster analysis was conducted to classify pregnant women based on their MIBS-J subscale scores at the three time points. Based on the cluster analysis results, receiver operating characteristic curve analysis was performed to estimate the optimal cutoff scores for the MIBS-J total score at each time point. Results: The two-step cluster analysis produced two clusters: Cluster 1 (n = 824) and Cluster 2 (n = 477). Both the MIBS-J and HADS scores were significantly higher in Cluster 2 than in Cluster 1 at all time points. The MIBS-J tentative cutoff points were 3/4, 3/4, and 2/3 at T1, T2, and T3, respectively. Conclusion: We identified two distinct groups across the perinatal period: pregnant women with bonding difficulties and pregnant women with normal bonding. Our findings suggest the usefulness of the MIBS-J as a screening tool to identify bonding difficulties during pregnancy.

DOI： 10.2147/NDT.S336819

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Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Clinical Neuropsychopharmacology  

DOI： 10.5234/cnpt.11.23

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Whole-exome sequencing (WES) studies have shown that de-novo variants contribute to the genetic etiology of schizophrenia. WES studies of families with a monozygotic twin pair concordant or discordant for a disease may be fruitful for identifying de-novo pathogenic variants. Here, we performed WES in six individuals from one family (affected monozygotic twins, their unaffected parents, and two siblings) and identified three de-novo missense variants (CPT2 Ala283Thr, CPSF3 Val584Ile, and RNF148 Val210Ile) in the monozygotic twin pair concordant for schizophrenia. These three missense variants were not found in 1760 patients with schizophrenia or schizoaffective disorder or 1508 healthy controls. Our data do not support the role of the three missense variants in conferring risk for schizophrenia.

DOI： 10.1097/YPG.0000000000000250

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Purpose: Postpartum depression is a well-known risk factor, and postpartum anxiety and parity are potential risk factors, for mother-infant bonding disorder. However, few studies have focused on the relationships among these factors and mother-infant bonding. This cross-sectional study explored the associations between depression, anxiety and parity, and mother-infant bonding. Materials and Methods: Japanese mothers, both primiparas and multiparas, completed the Mother-to-Infant Bonding Scale (MIBS) and the Hospital Anxiety and Depression Scale (HADS) one month after childbirth. We performed a stepwise multiple regression analysis with the forward selection method to assess the effects of HADS anxiety and depression scores and parity as independent variables on mother-infant bonding as the dependent variable. Results: A total of 2379 Japanese mothers (1116 primiparas and 1263 multiparas) took part in the study. MIBS score (2.89 ± 2.68 vs 1.60 ± 2.11; p < 0.0001) was significantly higher in primiparas than in multiparas. HADS anxiety (6.55 ± 4.06 vs 4.63 ± 3.41; p < 0.0001) and depression (6.56 ± 3.43 vs 5.98 ± 3.20; p < 0.0001) scores were also significantly higher in primiparas than in multiparas. A stepwise multiple regression analysis with the forward selection method revealed that HADS depression and anxiety scores and parity were significantly associated with MIBS score (p = 0.003, 0.015 and 0.023). Conclusion: Depression, anxiety and primiparity were negatively associated with mother-infant bonding one month after childbirth.

DOI： 10.2147/NDT.S287036

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Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations.

DOI： 10.1093/schbul/sby140

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Purpose: Whole-exome sequencing (WES) of multiplex families is a promising strategy for identifying causative variations for common diseases. To identify rare recessive risk variations for schizophrenia, we performed a WES study in a consanguineous family with affected siblings. We then performed follow-up sequencing of SPATA7 in schizophrenia-affected families. In addition, we performed a case-control study to investigate association between SPATA7 variations and schizophrenia. Patients and methods: WES was performed on two affected siblings and their unaffected parents, who were second cousins, of a multiplex schizophrenia family. Subsequently, we sequenced the coding region of SPATA7, a potential risk gene identified by the WES analysis, in 142 affected offspring from 137 families for whom parental DNA samples were available. We further tested rare recessive SPATA7 variations, identified by WES and sequencing, for associations with schizophrenia in 2,756 patients and 2,646 controls. Results: Our WES analysis identified rare compound heterozygous missense SPATA7 variations, p.Asp134Gly and p.Ile332Thr, in both affected siblings. Sequencing SPATA7 coding regions from 137 families identified no rare recessive variations in affected offspring. In the case-control study, we did not detect the rare compound heterozygous SPATA7 missense variations in patients or controls. Conclusion: Our data does not support the role of the rare compound heterozygous SPATA7 missense variations p.Asp134Gly and p.Ile332Thr in conferring a substantial risk of schizophrenia.

DOI： 10.2147/NDT.S218773

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Perineuronal nets comprise chondroitin sulfate moieties and their core proteins, and their neuropathological alterations have been implicated in schizophrenia. To explore the molecular mechanism of the perineuronal net impairments in schizophrenia, we measured the immunoreactivity of chondroitin sulfate moieties, major components of perineuronal nets, in three brain regions (postmortem dorsolateral prefrontal cortex, caudate nucleus, and hippocampus) of schizophrenia patients and control subjects. Immunoblotting for chondroitin 4-sulfate and chondroitin 6-sulfate moieties revealed a significant increase in intensity of a 180 kD band of chondroitin 4-sulfate immunoreactivity in the hippocampus of patients, although we detected no significant alteration in their immunoreactivities with any other molecular sizes or in other brain regions. The levels of immunoreactivity were not correlated with postmortem interval, age, or storage time. We failed to find such an increase in a similar molecular range of the chondroitin 4-sulfate immunoreactivity in the hippocampus of the rats chronically treated with haloperidol. These results suggest that the level alteration of the chondroitin 4-sulfate moiety might contribute to the perineuronal net abnormality found in patients with schizophrenia.

DOI： 10.1016/j.psychres.2018.10.062

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DOI： 10.1111/eip.12472

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Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders.

DOI： 10.1016/j.celrep.2018.08.022

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Several previous studies have investigated an association between leukocyte telomere length (LTL) and schizophrenia (SCZ). However, results have been largely inconsistent, partially due to the relatively small sample sizes in each study and heterogeneity caused by various uncontrolled confounders (e.g., duration of illness or hospitalization, lifetime antipsychotic dose, and LTL assay methods). Here, we investigate the association of LTL with SCZ with the quantitative polymerase chain reaction method in independent cohorts consisting of 1241 patients with SCZ and 1042 controls (the largest independent sample in this field). Furthermore, we examined whether duration of hospitalization and lifetime antipsychotic dose had an effect on LTL in SCZ. In all samples, we observed significantly longer LTL in patients with SCZ relative to controls. In subgroup analyses, we observed that longer telomeres in SCZ were only visible in elderly patients and not in patients under 50 years old. Moreover, significantly longer LTL in elderly patients with SCZ was only specific to those with long-term hospitalization, but not outpatients or those with short-term hospitalization. This may be because the former received more appropriate lifestyle management. Meanwhile, lifetime antipsychotic dose had no effect on LTL. Our findings suggest that consideration of the effect of age and duration of hospitalization on LTL may improve our understanding of controversial results obtained in previous studies of telomeres in SCZ.

DOI： 10.1016/j.jpsychires.2018.05.014

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BACKGROUND: Numerous studies have suggested that an immune system imbalance plays an important role in schizophrenia. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine. It plays multiple roles in various biological processes, including inflammation and neurogenesis. Furthermore, several exhaustive serum proteomic profiling studies have identified MIF as a potential biomarker of schizophrenia. Here, we investigate MIF protein levels in serum and postmortem prefrontal cortex in patients with schizophrenia and controls. Moreover, we investigate the association of two functional polymorphisms in the MIF gene promoter region (MIF-794CATT5-8 microsatellite and MIF-173G/C single-nucleotide polymorphism [SNP]) with schizophrenia. METHODS: We measured serum MIF levels with an enzyme-linked immunosorbent assay (ELISA) (51 patients vs. 86 controls) and postmortem brain MIF levels with a western blotting assay (18 patients vs. 22 controls). Subsequently, we genotyped the MIF-794CATT5-8 microsatellite with a fluorescence-based fragment assay and the MIF-173G/C SNP with a TaqMan SNP genotyping assay (1483 patients vs. 1454 controls). RESULTS: Serum MIF levels were significantly higher in patients with schizophrenia than in controls (p=0.00118), and were positively correlated with antipsychotic dose (Spearman's r=0.222, p=0.0402). In addition, an earlier age of onset was observed in patients with a high serum MIF level (≥40ng/mL) than those with a low serum MIF level (<40ng/mL) (p=0.0392). However, postmortem brain MIF levels did not differ between patients with schizophrenia and controls. The association study revealed that the CATT6-G haplotype was nominally significantly associated with schizophrenia (p=0.0338), and that the CATT6 allele and CATT6-G haplotype were significantly associated with female adolescent-onset schizophrenia (AsOS) (corrected p=0.0222 and p=0.0147, respectively). CONCLUSIONS: These results suggest that serum MIF level is a potential pharmacodynamic and/or monitoring marker of schizophrenia, and is related to a novel antipsychotic effect beyond dopamine antagonism. Furthermore, the MIF gene polymorphisms are associated with the risk for schizophrenia especially in adolescent females, and are potential stratification markers of schizophrenia. Further studies of MIF are warranted to elucidate the pathophysiology of schizophrenia and the effects of antipsychotics.

DOI： 10.1016/j.pnpbp.2018.01.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Aim: Rare gene variations are thought to confer substantial risk for schizophrenia. We performed a three-stage study to identify rare variations that have a strong impact on the risk of developing schizophrenia.
Methods: In the first stage, we prioritized rare missense variations using whole-exome sequencing (WES) data from three families, consisting of a proband, an affected sibling, and parents. In the second stage, we performed targeted resequencing of the PDCD11 coding region in 96 patients. In the third stage, we conducted an association study of rare PDCD11 variations with schizophrenia in a total of 1357 patients and 1394 controls.
Results: Via WES, we identified two rare missense PDCD11 variations, p.(Asp961Asn) and p.(Val1240Leu), shared by two affected siblings within families. Targeted resequencing of the PDCD11 coding region identified three rare non-synonymous variations: p.(Asp961Asn), p.(Phe1835del), and p.(Arg1837His). The case-control study demonstrated no significant associations between schizophrenia and four rare PDCD11 variations: p.(Asp961Asn), p.(Val1240Leu), p.(Phe1835del), and p.(Arg1837His).
Conclusion: Our data do not support the role of rare PDCD11 variations in conferring substantial risk for schizophrenia in the Japanese population.

DOI： 10.1111/pcn.12564

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Aim: Rare variations are suggested to play a role in the genetic etiology of schizophrenia; to further investigate their role, we performed a three-stage study in a Japanese population.
Methods: In the first stage, we performed whole-exome sequencing (WES) of two parent-affected offspring trios. In the second stage, we resequenced the FBXO18 coding region in 96 patients. In the third stage, we tested rare non-synonymous FBXO18 variations for association with schizophrenia in two independent populations comprising a total of 1376 patients and 1496 controls.
Results: A rare frameshift variation (L116fsX) in the FBXO18 gene was recurrently identified by WES in both trios. Resequencing FBXO18 coding regions, we detected three rare non-synonymous variations (V15L, L116fsX, and V1006I). However, there were no significant associations between these rare FBXO18 variations and schizophrenia in the case-control study.
Conclusion: Our present study does not provide evidence for the contribution of rare non-synonymous FBXO18 variations to the genetic etiology of schizophrenia in the Japanese population. However, to draw a definitive conclusion, further studies should be performed using sufficiently large sample sizes.

DOI： 10.1111/pcn.12526

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Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (&lt; 100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio = 3.04, P = 9.3 x 10 (-9), 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e. g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio = 2.79, P = 0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e. g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

DOI： 10.1038/mp.2016.88

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Language：Japanese   Publisher：(公社)日本精神神経学会  

自閉スペクトラム症の多発罹患家系において,稀な変異が発症に重要な役割を果たすことが示唆されている.自閉スペクトラム症の稀なリスク変異を同定するため,われわれは4人の罹患者(同胞2人,母方いとこ2人)を有する多発罹患家系の全エクソームシークエンスおよび症例・対照サンプル(243対667)を用いたフォローアップ研究を実施した.多発罹患家系の4人(発端者,罹患同胞,非罹患同胞,保因者と推定される母)について全エクソームシークエンスを行ったところ,2つの稀な短縮型変異(RPS24遺伝子Q191X変異とCD300LF遺伝子P261fsX266変異)を同定した.これらの変異は,フォローアップ研究の910サンプルでは検出されなかった.本研究により,2つの稀な短縮型変異(RPS24遺伝子Q191X変異とCD300LF遺伝子P261fsX266変異)が自閉スペクトラム症の候補リスク変異であることが示唆された.(著者抄録)

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Rare genomic variations inherited in multiplex schizophrenia families are suggested to play a role in the genetic etiology of the disease. To identify rare variations with large effects on the risk of developing schizophrenia, we performed whole-exome sequencing (WES) in two affected and one unaffected individual of a multiplex family with 10 affected individuals. We also performed follow-up resequencing of the unc-13 homolog B (Caenorhabditis elegans) (UNC13B) gene, a potential risk gene identified by WES, in the multiplex family and undertook a case-control study to investigate association between UNC13B and schizophrenia. UNC13B coding regions (39 exons) from 15 individuals of the multiplex family and 111 affected offspring for whom parental DNA samples were available were resequenced. Rare missense UNC13B variations identified by resequencing were further tested for association with schizophrenia in two independent case-control populations comprising a total of 1,753 patients and 1,602 controls. A rare missense variation (V1525M) in UNC13B was identified by WES in the multiplex family; this variation was present in five of six affected individuals, but not in eight unaffected individuals or one individual of unknown disease status. Resequencing UNC13B coding regions identified five rare missense variations (T103M, M813T, P1349T, I1362T, and V1525M). In the case-control study, there was no significant association between rare missense UNC13B variations and schizophrenia, although single-variant meta-analysis indicated that M813T was nominally associated with schizophrenia. These results do not support a contribution of rare missense UNC13B variations to the genetic etiology of schizophrenia in the Japanese population. (c) 2016 Wiley Periodicals, Inc.

DOI： 10.1002/ajmg.b.32444

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Rare inherited variations in multiplex families with schizophrenia are suggested to play a role in the genetic etiology of schizophrenia. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES) in three families, each with two affected siblings. We also performed a three-stage follow-up case-control study in a Japanese population with a total of 2617 patients and 2396 controls. WES identified 15 rare truncating variations that were variously present in the two affected siblings in each family. These variations did not necessarily segregate with schizophrenia within families, and they were different in each family. In the follow-up study, four variations (NWDI W169X, LCORL R7fsX53, CAMK2B L497fsX497, and C9orf89 Q102X) had a higher mutant allele frequency in patients compared with controls, although these associations were not significant in the combined population, which comprised the first-, second- and third-stage populations. These results do not support a contribution of the rare truncating variations identified in the three families to the genetic etiology of schizophrenia. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.psychres.2015.12.011

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Rare variations contribute substantially to autism spectrum disorder (ASD) liability. We recently performed whole-exome sequencing in two families with affected siblings and then carried out a follow-up study and identified ceroid-lipofuscinosis neuronal 8 (epilepsy, progressive with mental retardation) (CLN8) as a potential genetic risk factor for ASD. To further investigate the role of CLN8 in the genetic etiology of ASD, we performed resequencing and association analysis of CLN8 with ASD in a Japanese population. Resequencing the CLN8 coding region in 256 ASD patients identified five rare missense variations: g.1719291G&gt;A (R24H), rs201670636 (F39L), rs116605307 (R97H), rs143701028 (T108M) and rs138581191 (N152S). These variations were genotyped in 568 patients (including the resequenced 256 patients) and 1017 controls. However, no significant association between these variations and ASD was identified. This study does not support a contribution of rare missense CLN8 variations to ASD susceptibility in the Japanese population.

DOI： 10.1371/journal.pone.0144624

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DOI： 10.1016/j.psychres.2015.07.016

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Two truncating variations (WDR90 V1125fs and EFCAB5 L1210fs), identified by whole-exome sequencing in a family with a monozygotic twin pair concordant for autism spectrum disorder (ASD), were not detected in 257 ASD patients, 677 schizophrenia patients or 667 controls in a follow-up study. Thus, these variations were exclusively identified in the family, suggesting that rare truncating variations may have a role in the genetic etiology of ASD, at least in a subset of ASD patients. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.psychres.2015.07.018

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AimsRare heterozygous truncating variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare heterozygous truncating variations, we performed whole-exome sequencing (WES) in a multiplex ASD family with four affected individuals (two siblings and two maternal cousins), and a follow-up case-control study in a Japanese population.
MethodsWES was performed in four individuals (a proband, his affected and unaffected siblings, and their putative carrier mother) from the multiplex ASD family. Rare heterozygous truncating variations prioritized in WES were genotyped in 243 patients and 667 controls.
ResultsBy WES of the multiplex family, we prioritized two rare heterozygous truncating variations, RPS24Q191X and CD300LFP261fsX266. However, we did not identify these variations in patients or controls in the follow-up study.
ConclusionsOur findings suggest that two rare heterozygous truncating variations (RPS24Q191X and CD300LFP261fsX266) are risk candidates for ASD.

DOI： 10.1111/pcn.12274

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Background: Cytogenomic mutations and chromosomal abnormality are implicated in the neuropathology of several brain diseases. Cell heterogeneity of brain tissues makes their detection and validation difficult, however. In the present study, we analyzed gene dosage alterations in brain DNA of schizophrenia patients and compared those with the copy number variations (CNVs) identified in schizophrenia patients as well as with those in Asian lymphocyte DNA and attempted to obtain hints at the pathological contribution of cytogenomic instability to schizophrenia.
Results: Brain DNA was extracted from postmortem striatum of schizophrenia patients and control subjects (n = 48 each) and subjected to the direct two color microarray analysis that limits technical data variations. Disease-associated biases of relative DNA doses were statistically analyzed with Bonferroni's compensation on the premise of brain cell mosaicism. We found that the relative gene dosage of 85 regions significantly varied among a million of probe sites. In the candidate CNV regions, 26 regions had no overlaps with the common CNVs found in Asian populations and included the genes (i.e., ANTXRL, CHST9, DNM3, NDST3, SDK1, STRC, SKY) that are associated with schizophrenia and/or other psychiatric diseases. The majority of these candidate CNVs exhibited high statistical probabilities but their signal differences in gene dosage were less than 1.5-fold. For test evaluation, we rather selected the 10 candidate CNV regions that exhibited higher aberration scores or larger global effects and were thus confirmable by PCR. Quantitative PCR verified the loss of gene dosage at two loci (1p36.21 and 1p13.3) and confirmed the global variation of the copy number distributions at two loci (11p15.4 and 13q21.1), both indicating the utility of the present strategy. These test loci, however, exhibited the same somatic CNV patterns in the other brain region.
Conclusions: The present study lists the candidate regions potentially representing cytogenomic CNVs in the brain of schizophrenia patients, although the significant but modest alterations in their brain genome doses largely remain to be characterized further.

DOI： 10.1186/s13039-015-0144-5

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Language：Japanese   Publisher：日本シミュレーション医療教育学会  

新潟大学医学部医学科(本学科)では、医学への興味を高め、本学科への進学希望者を増加させることを目的として、シミュレータ体験を中心とした体験講座を開催している。その効果を検討するため、2012-2013年度に体験講座に参加した高校生87人、ならびに2014年度の本学科入学者123人に対して、アンケート調査を実施し、解析した。高校生に対するシミュレータ実習を含む体験講座の評価は良く、参加者の医療関係職を希望する気持ちの強さは有意に増加した(P&lt;0.001)。2014年度本学科入学者のうち69人(56%)は、全国の医学科で開催されている体験講座に参加した経験があり、そのなかで本学科の体験講座に参加した34人中28人の学生は、医学科進学を考える上で影響を受けたと回答した。(著者抄録)

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DOI： 10.1002/ajmg.b.32303

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AimsThe oxytocin receptor (OXTR) is implicated in the pathophysiology of autism spectrum disorder (ASD). A recent study found a rare non-synonymous OXTR gene variation, rs35062132 (R376G), associated with ASD in a Japanese population. In order to investigate the association between rare non-synonymous OXTR variations and ASD, we resequenced OXTR and performed association analysis with ASD in a Japanese population.
MethodsWe resequenced the OXTR coding region in 213 ASD patients. Rare non-synonymous OXTR variations detected by resequencing were genotyped in 213 patients and 667 controls.
ResultsWe detected three rare non-synonymous variations: rs35062132 (R376G/C), rs151257822 (G334D), and g.8809426G&gt;T (R150S). However, there was no significant association between these rare non-synonymous variations and ASD.
ConclusionsOur present study does not support the contribution of rare non-synonymous OXTR variations to ASD susceptibility in the Japanese population.

DOI： 10.1111/pcn.12205

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Rare inherited variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in the genetic etiology of ASD. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES) in two families, each with three affected siblings. We also performed a two-stage follow-up case-control study in a Japanese population. WES of the six affected siblings identified six novel rare missense variations. Among these variations, CLN8 R24H was inherited in one family by three affected siblings from an affected father and thus co-segregated with ASD. In the first stage of the follow-up study, we genotyped the six novel rare missense variations identified by WES in 241 patients and 667 controls (the Niigata sample). Only CLN8 R24H had higher mutant allele frequencies in patients (1/482) compared with controls (1/1334). In the second stage, this variation was further genotyped, yet was not detected in a sample of 309 patients and 350 controls (the Nagoya sample). In the combined Niigata and Nagoya samples, there was no significant association (odds ratio = 1.8, 95% confidence interval = 0.1-29.6). These results suggest that CLN8 R24H plays a role in the genetic etiology of ASD, at least in a subset of ASD patients.

DOI： 10.1371/journal.pone.0119413

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BACKGROUND: Cadherin13 (CDH13) is a glycosylphosphatidylinositol-anchored cell adhesion molecule that plays a crucial role in morphogenesis and the maintenance of neuronal circuitry. CDH13 has been implicated in the susceptibility to a variety of psychiatric diseases. A recent genome-wide association study using Danish samples showed, for the first time, the involvement of a single nucleotide polymorphism (SNP) of CDH13 (intronic SNP rs8057927) in schizophrenia. Here, we investigated the association between other SNPs of CDH13 and schizophrenia and tried to replicate the association for the SNP of rs8057927, in the Japanese population. METHODS: Using TaqMan(®) SNP genotyping assays, five tag SNPs (rs12925602, rs7193788, rs736719, rs6565051, and rs7204454) in the promoter region of CDH13 were examined for their association with schizophrenia in two independent samples. The first sample comprised 665 patients and 760 controls, and the second sample comprised 677 patients and 667 controls. One tag SNP for rs8057927 was also examined for the association with schizophrenia in the first sample set. RESULTS: A GACAG haplotype of the five SNPs in the promoter region of CDH13 was significantly associated with schizophrenia in the first sample set (P=0.016 and corrected P=0.098). A combined analysis of the GACAG haplotype with the second sample set enhanced the significance (P=0.0026 and corrected P=0.021). We found no association between rs8057927 and schizophrenia in the first sample set. CONCLUSION: Our results suggest that CDH13 may contribute to the genetic risk of schizophrenia. Further replication on the association of CDH13 with schizophrenia and functional studies are required to confirm the current findings.

DOI： 10.2147/NDT.S84736

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Language：Japanese   Publisher：新潟県医師会  

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Background: Genome-wide association studies (GWAS) and gene expression analyses have revealed that single nucleotide polymorphisms (SNPs) associated with multifactorial diseases, such as schizophrenia, are significantly more likely to be associated with expression quantitative trait loci (eQTL). It was recently suggested that an immune system imbalance plays an important role in the pathogenesis of schizophrenia. Interleukin-19 is a novel cytokine that may play multiple roles in immune regulation and various diseases.
Method: We selected eight tag SNPs in the eQTL of the IL-19 gene. Seven of the SNPs are putative cis-acting SNPs. Then, we conducted a case-control study using two independent samples. The first sample comprised 567 schizophrenia patients and 710 controls, and the second sample comprised 677 schizophrenia patients and 667 controls.
Result: We identified the TGAA haplotype as being significantly associated with schizophrenia (p = 0.0036 and corrected p = 0.0264), although a combined analysis of the TGAA haplotype with the replication samples exhibited a nominally significant difference (p = 0.022 and corrected p = 0.235).
Conclusions: These results suggest that the IL-19 gene might slightly contribute to the genetic risk of schizophrenia. Thus, further research on the association of eQTL SNPs with schizophrenia is warranted. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pnpbp.2013.12.006

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DOI： 10.1016/j.psychres.2013.12.029

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DOI： 10.1016/j.ajp.2013.10.013

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Language：Japanese   Publisher：新潟医学会  

統合失調症は複数の遺伝要因と環境要因が相互に影響し合って発症する複雑な脳疾患であると考えられている. 統合失調症の分子病態はいまだ明らかでないが, 筆者らはその一端を解明しつつある. 統合失調症のサイトカイン仮説に基づいて, 統合失調症患者の死後脳や末梢血におけるサイトカイン発現異常を明らかにするとともに, 高い妥当性を有する統合失調症の動物モデルとして新生仔期サイトカイン投与動物を作成した. また, ゲノム解析により疾患感受性座位を同定し, ごく一部ではあるが遺伝要因を明らかにした. さらに, 統合失調症の血液検査キットの開発を目指して, 末梢血トランスクリプトーム解析に基づく診断分類予測モデルを構築し, このモデルにより高い感度・特異度をもって患者群と対照群を判別できることを示した. 統合失調症の分子病態を完全に解明し, 妥当性の高い診断法や根治的な治療法の開発につなげるために, 今後も研究を進めていくことが必要である.

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ObjectiveInterleukin-1 beta (IL-1) has been implicated in the pathophysiology of schizophrenia. To assess whether the IL1B gene confers increased susceptibility to schizophrenia, we conducted case-control and family-based studies and an updated meta-analysis.
MethodsWe tested the association between IL1B and schizophrenia in 1229 case-control and 112 trio samples using 12 markers, including common tagging single nucleotide variations (SNVs) and a rare non-synonymous variation detected by resequencing the coding regions. We also performed a meta-analysis of rs16944 using a total of 8724 case-control and 201 trio samples from 16 independent populations.
ResultsWe found no significant associations between any of the 12 SNVs examined and schizophrenia in either case-control or trio samples. Moreover, our meta-analysis results showed no significant association between the common SNV, rs16944, and schizophrenia.
ConclusionsThe present study does not support a role for IL1B in schizophrenia susceptibility. Copyright (c) 2013 John Wiley & Sons, Ltd.

DOI： 10.1002/hup.2365

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DOI： 10.1111/pcn.12081

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Recent genetic analyses have implicated several candidate susceptibility variants for schizophrenia. The single nucleotide polymorphism (SNP) rs7294919 is likely a schizophrenia-susceptibility variant according to its significant association with hippocampal volume, hippocampus function, and cognitive performance as well as the nominal association with schizophrenia. However, all previous analyses were conducted only in Europeans, and whether rs7294919 is associated with schizophrenia in other populations are yet to be tested. Here, we conducted a case-control analysis of rs7294919 with schizophrenia in six independent Chinese (N = 3) and Japanese (N = 3) samples, including a total of 7,352 cases and 10,824 controls. The results of our association analysis were not able to confirm the association of rs7294919 with schizophrenia (p = 0.51 in total samples, odds ratio = 1.02 for allele[C]). The absence of rs7294919's association in Chinese and Japanese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating associations of schizophrenia across different ethnic populations.

DOI： 10.1371/journal.pone.0080696

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DOI： 10.1016/j.schres.2013.08.028

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DOI： 10.1111/pcn.12080

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Stigma toward schizophrenia is an important area of research as it is frequently a barrier to early intervention. This study attempted to identify factors underlying stigma in Japan. Because even adolescents can develop schizophrenia, 357 Japanese parents of high school students were enrolled. All parents lived outside the areas affected by the Tohoku earthquake that occurred on March 11, 2011 (ie, parts of Iwate, Miyagi, and Fukushima prefectures). Factor analysis using the Link Devaluation-Discrimination Measure identified two factors: comparison with an able-bodied person and non-comparison with an able-bodied person. Regression analysis revealed that family structure had independent effects on factor 2 (p <0.05), and ANOVA showed that education had independent effects on factor 2 (p<0.05). These results suggest that education programs that seek to counteract stigma should target curricula in high schools and vocational schools.

DOI： 10.5539/gjhs.v5n6p46

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1097/YPG.0b013e328360c8be

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DOI： 10.1016/j.psychres.2012.11.007

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DOI： 10.1038/mp.2012.74

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objectives To search for schizophrenia susceptibility loci, we carried out a case-control study using 28601 microsatellite markers distributed across the entire genome. Materials and methods To control the highly multiple testing, we designed three sequential steps of screening using three independent sets of pooled samples, followed by the confirmatory step using an independent sample set (&gt;2200 case-control pairs). Results The first screening using pooled samples of 157 case-control pairs showed 2966 markers to be significantly associated with the disorder (P &lt; 0.05). After the second and the third screening steps using pooled samples of 150 pairs each, 374 markers remained significantly associated with the disorder. We individually genotyped all screening samples using a total of 1536 tag single nucleotide polymorphisms (SNPs) located in the vicinity of similar to 200 kb from the 59 positive microsatellite markers. Of the 167 SNPs that replicated the significance, we selected 31 SNPs on the basis of the levels of P values for the confirmatory association test using an independent-sample set. The best association signal was observed in rs13404754, located in the upstream region of SLC23A3. We genotyped six additional SNPs in the vicinity of rs13404754. Significant associations were observed in rs13404754, rs6436122, and rs1043160 in the cumulative samples (2617 cases and 2698 controls) (P = 0.005, 0.035, and 0.011, respectively). These SNPs are located in the linkage disequilibrium block of 20 kb in size containing SLC23A3, CNPPD1, and FAM134A genes. Conclusion Genome-wide association study using microsatellite markers suggested SLC23A3, CNPPD1, and FAM134A genes as candidates for schizophrenia susceptibility in the Japanese population. Psychiatr Genet 23: 117-123 (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. Psychiatric Genetics 2013, 23:117-123

DOI： 10.1097/YPG.0b013e32835fe4f1

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MicroRNA may play a role in the pathophysiology of schizophrenia. A recent meta-analysis of genome-wide association studies indicated a significant association between schizophrenia and a common intronic variation in MIR137HG (microRNA 137 host gene) encoding the primary microRNA-137. To explore additional risk variations for schizophrenia, we resequenced MIR137 and performed an association analysis in 1321 Japanese individuals. By resequencing, we detected four sequence variations in the 5' and 3' flanking regions. There were no significant associations between these variations and schizophrenia. Our resequencing and association analysis of MIR137 failed to find additional risk variations for schizophrenia. © 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.

DOI： 10.1111/pcn.12047

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Brain-derived neurotrophic factor (BDNF) has been suggested to play a role in the pathophysiology of schizophrenia. The C270T polymorphism (rs56164415) in the BDNF 5-non-coding region has been extensively investigated for an association with schizophrenia, but with conflicting results. An updated meta-analysis was therefore performed of 13 casecontrol association studies (3505 patients and 3992 controls). An association was found between the T allele and schizophrenia. The association was significant in the East Asian population, but not in the Caucasian population. It is suggested that the BDNF C270T polymorphism contributes to schizophrenia susceptibility, especially in East Asian subjects.

DOI： 10.1111/pcn.12018

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Background: Cell adhesion molecules (CAMs) play pivotal role in the development of the central nervous system (CNS) and have also been reported to play role in the pathophysiology of schizophrenia. Missense mutations in the CAMs genes might alter the binding of their ligands, increasing the vulnerability to develop schizophrenia.
Methods: We selected 15 missense mutations in the CAMs genes of the CNS reported in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and examined the association between these mutations and schizophrenia in 278 patients and 284 control subjects (first batch). We also genotyped the positive single nucleotide polymorphisms (SNPs) in 567 patients and 710 control subjects (second batch) and in 635 patients and 639 control subjects (replication samples).
Results: Genotypic and allelic distributions of rs2298033 in the ITGA8 gene between the schizophrenia and control groups were significantly different in the first batch (p = 0.005 and 0.007, respectively). Gender-based analysis revealed that the allelic and genotypic distributions of rs2298033 in the ITGA8 were significantly different between the schizophrenia and control groups among females in both batches (p = 0.010, 0.011 and 0.0086, 0.010, respectively) but not among males. Combine analysis of rs2298033 with the replication samples revealed a more significant differences (p = 0.0032; 0.0035 in the overall subjects and p = 0.0024; 0.0025 in the female subjects, respectively). The significant differences for rs2802808 of the NFASC gene were only observed in the female subgroup of the first batch.
Conclusion: These results suggest that the ITGA8 gene might have gender-specific roles in the development of schizophrenia. Further replication and functional studies are required to confirm these findings. (c) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.pnpbp.2012.11.002

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Significant variabilities exist in psychotropic disposition and response. Numerous polymorphisms in the genes coding for specific cytochrome P-450 metabolizing enzymes and the ABCB1 transporter residing at the blood-brain barrier have been studied for their possible roles in individualized psychotropic drug therapy. Although molecular diagnostics are available for CYP2D6 and CYP2C19 genotyping, current data provide evidence for their use primarily in predicting adverse drug effects and possibly increasing compliance in subsets of populations. The involvement of the serotonergic system, especially the 5-HT2C receptor, provides convincing evidence of a genetic basis in predicting antipsychotic-induced weight gain. On the other hand, prediction of psychotropic drug effects based on polymorphisms in multiple drug targets within the brain is limited by methodological and clinical problems, especially with the candidate gene approach. Nevertheless, the lack of novel new drugs in psychiatry underscores the importance of refining current molecular approaches to provide insights into etiologies of mental disorders and their treatment. © 2013 Copyright © 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/B978-0-12-391918-2.00006-8

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DOI： 10.1111/j.1440-1819.2012.02396.x

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DOI： 10.1016/j.schres.2012.06.043

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Language：Japanese   Publisher：(株)星和書店  

臨床に従事する精神科医師として、合理的な薬物治療を実践するための根拠や理論を理解することは重要である。多くの精神疾患の正確な病態はいまだ不明であり、数多くの病態仮説が提唱されている。統合失調症に関しては、現在でも最も有力な仮説であるドパミン仮説に基づいて多くの抗精神病薬が開発されてきたが、十分な利益を受けられない患者が存在する。ドパミン仮説を超えた新規の作用機序をもつ統合失調症治療薬の開発が進められているが、今のところ成功には至っていない。ゲノム多様性に関する研究により統合失調症の遺伝要因が明らかにされつつあり、その発症機序が解明されれば、根治療法の開発につながる可能性がある。(著者抄録)

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Language：English   Publisher：Scientific Research Publishing  

DOI： 10.4236/health.2012.47061

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Language：English   Publisher：Canadian Center of Science and Education  

DOI： 10.5539/gjhs.v4n4p42

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Language：English   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.psychres.2011.11.005

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DOI： 10.1016/j.schres.2012.01.034

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We conducted a detailed association analysis between the tryptophan hydroxylase 2 gene and autism spectrum disorders in a Japanese population using 19 markers, including tagging single nucleotide polymorphisms and a novel missense variation, p.R225Q identified through exon resequencing. However, we failed to obtain supportive evidence for an association. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.psychres.2011.09.001

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Glutamate is one of the key molecules involved in signal transduction in the brain, and dysfunction of glutamate signaling could be linked to schizophrenia. The SLC1A1 gene located at 9p24 encodes the glutamate transporter EAAT3/EAAC1. To investigate the association between the SLC1A1 gene and schizophrenia in the Japanese population, we genotyped 19 tagging single nucleotide polymorphisms (tagSNPs) in the SLC1A1 gene in 576 unrelated individuals with schizophrenia and 576 control subjects followed by replication in an independent case-control study of 1,344 individuals with schizophrenia and 1,344 control subjects. In addition, we determined the boundaries of the copy number variation (CNV) region in the first intron (Database of Genomic Variants, chr9:4516796-4520549) and directly genotyped the CNV because of significant deviation from the Hardy-Weinberg equilibrium. The CNV was not associated with schizophrenia. Four SNPs showed a possible association with schizophrenia in the screening subjects and the associations were replicated in the same direction (nominal allelic P < 0.05), and, among them, an association with rs7022369 was replicated even after Bonferroni correction (allelic nominal P = 5 × 10(-5) , allelic corrected P = 2.5 × 10(-4) , allelic odds ratio, 1.30; 95% CI: 1.14-1.47 in the combined subjects). Expression analysis quantified by the real-time quantitative polymerase chain reaction in the postmortem prefrontal cortex of 43 Japanese individuals with schizophrenia and 11 Japanese control subjects revealed increased SLC1A1 expression levels in individuals homozygous for the rs7022369 risk allele (P = 0.003). Our findings suggest the involvement of SLC1A1 in the pathogenesis of schizophrenia.

DOI： 10.1002/ajmg.b.31249

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Language：English   Publisher：Canadian Center of Science and Education  

DOI： 10.5539/gjhs.v4n1p33

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

As schizophrenia-like symptoms are produced by administration of phencyclidine (PCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, PCP-responsive genes could be involved in the pathophysiology of schizophrenia. We injected PCP to Wistar rats and isolated five different parts of the brain in 1 and 4 hr after the injection. We analyzed the gene expression induced by the PCP treatment of these tissues using the AGILENT rat cDNA microarray system. We observed changes in expression level in 90 genes and 21 ESTs after the treatment. Out of the 10 genes showing &gt;2-fold expressional change evaluated by qRT-PCR, we selected 7 genes as subjects for the locus-wide association study to identify susceptibility genes for schizophrenia in the Japanese population. In haplotype analysis, significant associations were detected in combinations of two SNPs of BTG2 (P = 1.4 x 10(-6)), PDE4A (P = 1.4 x 10(-6)), and PLAT (P = 1 x 10(-3)), after false discovery rate (FDR) correction. Additionally, we not only successfully replicated the haplotype associations in PDE4A (P = 6.8 x 10(-12)) and PLAT (P = 0.015), but also detected single-point associations of one SNP in PDE4A (P = 0.0068) and two SNPs in PLAT (P = 0.0260 and 0.0104) in another larger sample set consisting of 2,224 cases and 2,250 controls. These results indicate that PDE4A and PLAT may be susceptibility genes for schizophrenia in the Japanese population. (C) 2011 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.b.31233

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Language：Japanese   Publisher：先端医学社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Endocannabinoids, anandamide, and 2-arachidonoyl glycerol are involved in food intake and appetite. Although anandamide is now thought to be a ligand for vanilloid receptor, receptors that are targets of anandamide could play a similar role in eating behaviors and related disorders. This study therefore focused on the receptor, which is called G-protein-coupled receptor 55 (GPR55) that had recently been reported to have binding affinity for endocannabinoids. Functional analysis of the sole missense polymorphism, rs3749073 (Gly195Val) in the GPR55 gene was performed by detecting the phosphorylation level of extracellular signal-regulated kinase (ERK) in Chinese-Hamster-Ovary (CHO) cells engineered to express human GPR55. Val195 type GPR55 appeared to induce less phosphorylated ERK than Gly195 type GPR55 when CHO cells were treated with anandamide and lysophosphatidylinositol (LPI). An association between the functional Gly195Val polymorphism and anorexia nervosa was tested in a female Japanese population comprising 235 patients and 1244 controls. The Val195 allele and homozygote of the Val195 allele were more abundant in the group of patients diagnosed with anorexia nervosa (P = 0.023, Odds ratio 5 1.31 (95% Cl = 1.03-1.37), P = 0.0048, OR = 2.41 (95% Cl = 1.34-4.34), respectively). In conclusion, the low-functioning Val195 allele of GPR55 appears to be a risk factor for anorexia nervosa. Synapse 65: 103-108, 2011. (c) 2010 Wiley-Liss, Inc.

DOI： 10.1002/syn.20821

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DOI： 10.1111/j.1440-1819.2011.02210.x

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Background: Stigma toward schizophrenia is a substantial barrier to accessing care and adhering to treatment. Provisions to combat stigma are important, but in Japan and other developed countries there are few such provisions in place that target parents of adolescents. The attitudes of parents are important to address as first schizophrenic episodes typically occur in adolescence. In overall efforts to develop an education program and provisions against stigma, here we examined the relationship between stigma toward schizophrenia and demographic characteristics of parents of junior and senior high school students in Japan. The specific hypothesis tested was that contact and communication with a person with schizophrenia would be important to reducing stigma. A questionnaire inquiring about respondent characteristics and which included a survey on stigma toward schizophrenia was completed by 2690 parents. Results: The demographic characteristics significantly associated with the Devaluation- Discrimination Measure were family income, occupation, presence of a neighbor with schizophrenia, and participation in welfare activities for people with mental illness (p &lt
0.05). The mean ±SD score was 32.74 ± 5.66 out of a maximum of 48 points on the Link Devaluation- Discrimination Measure. Conclusions: Stigma toward schizophrenia among parents of junior and senior high school students was in fact significantly stronger among members of the general public who had had contact with individuals with schizophrenia. In addition, stigma was associated with family income. © 2011 Yoshii et al
licensee BioMed Central Ltd.

DOI： 10.1186/1756-0500-4-558

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Language：English   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.schres.2010.08.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Many gene variants are involved in the susceptibility to schizophrenia and some of them are expected to be associated with other human characters. Recently reported meta-analysis of genetic associations revealed nucleotide variants in synaptic vesicular transport/Golgi apparatus genes with schizophrenia. In this study, we selected the dymeclin gene (DYM) as a candidate gene for schizophrenia. The DYM gene encodes dymeclin that has been identified to be associated with the Golgi apparatus and with transitional vesicles of the reticulum-Golgi interface. A three-step case-control study of total of 2105 Japanese cases of schizophrenia and 2087 Japanese control subjects was carried out for tag single-nucleotide polymorphisms (SNPs) in the DYM gene and an association between an SNP, rs833497, and schizophrenia was identified (allelic P-2 x 10(-5), in the total sample). DYM is the causal gene for Dyggve-Melchior-Clausen syndrome and this study shows the second neuropsychiatric disorder in which the DYM gene is involved. The present data support the involvement of Golgi function and vesicular transport in the presynapse in schizophrenia. Journal of Human Genetics (2010) 55, 631-634; doi:10.1038/jhg.2010.72; published online 17 June 2010

DOI： 10.1038/jhg.2010.72

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Language：Japanese   Publisher：日本臨床社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Background: Chromosome 22q11 deletion syndrome (22q11DS) increases the risk of development of schizophrenia more than 10 times compared with that of the general population, indicating that haploinsufficiency of a subset of the more than 20 genes contained in the 22q11DS region could increase the risk of schizophrenia. In the present study, we screened for genes located in the 22q11DS region that are expressed at lower levels in postmortem prefrontal cortex of patients with schizophrenia than in those of controls. Methods: Gene expression was screened by Illumina Human-6 Expression BeadChip arrays and confirmed by real-time reverse transcription-polymerase chain reaction assays and Western blot analysis. Results: Expression of GNB1L was lower in patients with schizophrenia than in control subjects in both Australian (10 schizophrenia cases and 10 controls) and Japanese (43 schizophrenia cases and 11 controls) brain samples. TBX1 could not be evaluated due to its low expression levels. Expression levels of the other genes were not significantly lower in patients with schizophrenia than in control subjects. Association analysis of tag single-nucleotide polymorphisms in the GNB1L gene region did not confirm excess homozygosity in 1918 Japanese schizophrenia cases and 1909 Japanese controls. Haloperidol treatment for 50 weeks increased Gnb1l gene expression in prefrontal cortex of mice. Conclusions: Taken together with the impaired prepulse inhibition observed in heterozygous Gnb1l knockout mice reported by the previous study, the present findings support assertions that GNB1L is one of the genes in the 22q11DS region responsible for increasing the risk of schizophrenia.

DOI： 10.1093/schbul/sbn160

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Neuregulin-1 (NRG1) gene is implicated in the etiology or neuropathology of schizophrenia, although its biological contribution to this illness is not fully understood. We have established an enzyme-linked immunosorbent assay (ELISA), which recognizes the NRG1 beta 1 immunoglobulin-like (Ig) domain, and measured soluble Ig-NRG1 immunoreactivity in the sera of chronic schizophrenia patients (n = 40) and healthy volunteers (n = 59). ELISA detected remarkably high concentrations of Ig-NRG1 immunoreactivity in human serum (mean 5.97 +/- A 0.40 ng/mL, similar to 213 +/- A 14 pM). Gender and diagnosis exhibited significant effects on serum Ig-NRG1 immunoreactivity. Mean Ig-NRG1 immunoreactivity in the schizophrenia group was 63.2% of that measured in the control group. Ig-NRG1 immunoreactivity in women was 147.1% of that seen in men. We also attempted to correlate six SNPs of NRG1 genome with serum Ig-NRG1 immunoreactivity. Analysis of covariance with compensation for gender identified a significant interaction between diagnosis and SNP8NRG243177 allele. The T allele of this SNP significantly contributed to the disease-associated decrease in Ig-NRG1 immunoreactivity. Although we hypothesized a chronic influence of antipsychotic medications, there was no significant effect of chronic haloperidol treatment on serum Ig-NRG1 immunoreactivity in monkeys. These findings suggest that serum NRG1 levels are decreased in patients with chronic schizophrenia and influenced by their SNP8NRG243177 alleles.

DOI： 10.1007/s00702-010-0418-3

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Gene expression profiling with microarray technology suggests that peripheral blood cells might be a surrogate for postmortem brain tissue in studies of schizophrenia. The development of an accessible peripheral biomarker would substantially help in the diagnosis of this disease. We used a bioinformatics approach to examine whether the gene expression signature in whole blood contains enough information to make a specific diagnosis of schizophrenia. Unpaired t-tests of gene expression datasets from 52 antipsychotics-free schizophrenia patients and 49 normal controls identified 792 differentially expressed probes. Functional profiling with DAVID revealed that eleven of these genes were previously reported to be associated with schizophrenia, and 73 of them were expressed in the brain tissue. We analyzed the datasets with one of the supervised classifiers, artificial neural networks (ANNs). The samples were subdivided into training and testing sets. Quality filtering and stepwise forward selection identified 14 probes as predictors of the diagnosis. ANNs were then trained with the selected probes as the input and the training set for known diagnosis as the output. The constructed model achieved 91.2% diagnostic accuracy in the training set and 87.9% accuracy in the hold-out testing set. On the other hand, hierarchical clustering, a standard but unsupervised classifier, failed to separate patients and controls. These results suggest analysis of a blood-based gene expression signature with the supervised classifier, ANNs, might be a diagnostic tool for schizophrenia. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2009.12.024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

The adenylate cyclase-activating polypeptide 1 (ADCYAP1) gene encodes a neuropeptide with neurotransmission activity, which is known as the pituitary adenylate cyclase-activating polypeptide. Associations of two polymorphisms, rs1893154 and rs2856966 (Asp54Gly), in the ADCYAP1 gene with schizophrenia were reported earlier by a Japanese case-control study. In this study, we tried to confirm the association in 2027 Japanese patients with schizophrenia and 2058 controls. The power to detect an association was more than 0.9. However, we did not detect allelic associations of rs1893154 with schizophrenia (P=0.36). Although rs2856966 was nominally significant (P=0.045), the association was in the opposite direction from that reported earlier. Combined data and meta-analysis of the two studies comprising nearly 6000 Japanese case-control patients did not show significant associations (P=0.53-0.86). It is concluded that single-nucleotide polymorphisms, including Asp54Gly, of the ADCYAP1 gene are unlikely to play a sizeable role in the genetic susceptibility to schizophrenia. Psychiatr Genet 20:123-125 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

DOI： 10.1097/YPG.0b013e32833a1f52

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The pathogenesis of schizophrenia has yet to be fully characterized. Gene-environment interactions have been found to play a crucial role in the vulnerability to this disease. Among various environmental factors, inflammatory immune processes have been most clearly implicated in the etiology and pathology of schizophrenia. Cytokines, regulators of immune/inflammatory reactions and brain development, emerge as part of a common pathway of genetic and environmental components of schizophrenia. Maternal infection, obstetric complications, neonatal hypoxia and brain injury all recruit cytokines to mediate inflammatory processes. Abnormal expression levels of specific cytokines such as epidermal growth factor, interleukins (IL) and neuregulin-1 are found both in the brain and peripheral blood of patients with schizophrenia. Accordingly, cytokines have been proposed to transmit peripheral immune/inflammatory signals to immature brain tissue through the developing blood-brain barrier, perturbing structural and phenotypic development of the brain. This cytokine hypothesis of schizophrenia is also supported by modeling experiments in animals. Animals treated with specific cytokines of epi

DOI： 10.1111/j.1440-1819.2010.02094.x

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BACKGROUND: Neural endocannabinoid function appears to be involved in schizophrenia. Two endocannabinoid receptors, CB1 and CB2, are found in the brain and elsewhere in the body. We investigated roles of CB2 in schizophrenia. MATERIALS AND METHODS: An association study was performed between tag single nucleotide polymorphisms (SNPs) in the CNR2 gene encoding the CB2 receptor and schizophrenia in two independent case-control populations. Allelic differences of associated SNPs were analyzed in human postmortem brain tissues and in cultured cells. Prepulse inhibition and locomotor activity in C57BL/6JJmsSlc mice with CB2 receptor antagonist AM630 administration was examined. RESULTS: The analysis in the first population revealed nominally significant associations between schizophrenia and two SNPs, and the associations were replicated in the second population. The R63 allele of rs2501432 (R63Q) (p = .001), the C allele of rs12744386 (p = .005) and the haplotype of the R63-C allele (p = 5 x 10(-6)) were significantly increased among 1920 patients with schizophrenia compared with 1920 control subjects in the combined population. A significantly lower response to CB2 ligands in cultured

DOI： 10.1016/j.biopsych.2009.09.024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Several genome-wide linkage studies have suggested linkage between markers on the long arm of chromosome 22 and schizophrenia. It has also been reported that 22q11.2 deletions increase the risk of schizophrenia. Therefore, 22q is a candidate region for schizophrenia. To search for genetic susceptibility loci for schizophrenia on 22q, we conducted a three-stage case-control association study in Japanese individuals. In the first stage, we examined 13 microsatellite markers on 22q in 766 individuals (340 patients with schizophrenia and 426 control individuals) and found a potential association of AFM262VH5 (D22S283) with schizophrenia. In the second stage, we performed fine mapping of the myosin heavy chain 9, non-muscle (MYH9) gene, where AFM262VH5 is located, using 25 tagging single nucleotide polymorphisms (SNPs). We obtained potential associations between three SNPs in MYH9 and schizophrenia in 1193 individuals (595 patients and 598 controls), which included the individuals analyzed in the first stage. In the third stage, however, we could not replicate these associations in 4694 independent individuals (2288 patients and 2406 controls). Our results suggest that MYH9 does not confer increased susceptibility to schizophrenia in the Japanese population, although we could not exclude possible contributions of other genes on 22q to the pathogenesis of schizophrenia. (C) 2010 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2010.01.023

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Calcineurin (CN) is a calcium/calmodulin-dependent serine/threonine protein phosphatase and regulates neuronal structure, neurotransmission and activity-dependent gene expression. Several studies have indicated that CN signaling is likely to be involved in the pathogenesis of schizophrenia. The gene encoding CN-binding protein 1 (CABIN1) is located on 22q11.23, one of the common susceptibility loci for schizophrenia. Therefore, CABIN1 is a promising functional and positional candidate gene for schizophrenia. To assess whether CABIN1 is implicated in vulnerability to schizophrenia, we conducted a case-control association study between CABIN1 and schizophrenia. The results showed no evidence of an association between CABIN1 and schizophrenia using 11 tagging single nucleotide polymorphisms in 1193 Japanese subjects. Our results suggest that CABIN1 may not confer increased susceptibility for schizophrenia in the Japanese population. Journal of Human Genetics (2010) 55, 179-181; doi: 10.1038/jhg.2009.136; published online 15 January 2010

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Language：Japanese   Publisher：(株)星和書店  

レビー小体型認知症(dementia with Lewy bodies:DLB)は、認知機能の動揺、繰り返す幻視、特発性のパーキンソニズムを中核的特徴とする変性疾患である。DLBではアセチルコリンエステラーゼ阻害薬であるdonepezil(DPZ)の有効性が示唆されており、適応外ではあるが比較的広く用いられている。しかし臨床現場においてDPZの副作用としてパーキンソニズムは消化器症状ほど十分には認識されていない。今回われわれは、パーキンソニズムがDPZ中止により一旦は軽減したものの再投与により悪化したDLBの1例を経験した。DPZがコリン神経伝達を増強することで黒質線条体経路におけるドパミン神経伝達の減弱が生じ、パーキンソニズムが悪化したと推察される。DLBに対してDPZを投与する際には、パーキンソニズムを惹起あるいは悪化させる可能性に留意して注意深く観察することが必要である。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The dopamine D3 receptor (DRD3) has been suggested to be involved in the pathophysiology of schizophrenia. DRD3 has been tested for an association with schizophrenia, but with conflicting results. A recent meta-analysis suggested that the haplotype T-T-T-G for the SNPs rs7631540-rs1486012-rs2134655-rs963468 may confer protection against schizophrenia. However, almost all previous studies of the association between DRD3 and schizophrenia have been performed using a relatively small sample size and a limited number of markers. To assess whether DRD3 is implicated in vulnerability to schizophrenia, we conducted case-control association studies and performed an updated meta-analysis. In the first population (595 patients and 598 controls), we examined 16 genotyped single nucleotide polymorphisms (SNPs), including tagging SNPs selected from the HapMap database and SNPs detected through resequencing, as well as 58 imputed SNPs that are not directly genotyped. To confirm the results obtained, we genotyped the SNPs rs7631540-rs1486012-rs2134655-rs963468 in a second, independent population (2126 patients and 2228 controls). We also performed an updated meta-analysis of the haplotype, combining the results obtained in five populations, with a total sample size of 7551. No supportive evidence was obtained for an association between DRD3 and schizophrenia in our Japanese subjects. Our updated meta-analysis also failed to confirm the existence of a protective haplotype. To draw a definitive conclusion, further studies using larger samples and sufficient markets should be carried out in various ethnic populations. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2009.10.016

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Language：English   Publisher：Blackwell Publishing Ltd  

The pathogenesis of schizophrenia has yet to be fully characterized. Gene-environment interactions have been found to play a crucial role in the vulnerability to this disease. Among various environmental factors, inflammatory immune processes have been most clearly implicated in the etiology and pathology of schizophrenia. Cytokines, regulators of immune/inflammatory reactions and brain development, emerge as part of a common pathway of genetic and environmental components of schizophrenia. Maternal infection, obstetric complications, neonatal hypoxia and brain injury all recruit cytokines to mediate inflammatory processes. Abnormal expression levels of specific cytokines such as epidermal growth factor, interleukins (IL) and neuregulin-1 are found both in the brain and peripheral blood of patients with schizophrenia. Accordingly, cytokines have been proposed to transmit peripheral immune/inflammatory signals to immature brain tissue through the developing blood-brain barrier, perturbing structural and phenotypic development of the brain. This cytokine hypothesis of schizophrenia is also supported by modeling experiments in animals. Animals treated with specific cytokines of epidermal growth factor, IL-1, IL-6, and neuregulin-1 as embryos or neonates exhibit schizophrenia-like behavioral abnormalities after puberty, some of which are ameliorated by treatment with antipsychotics. In this review, we discuss the neurobiological mechanisms underlying schizophrenia and novel antipsychotic candidates based on the cytokine hypothesis. © 2010 Japanese Society of Psychiatry and Neurology.

DOI： 10.1111/j.1440-1819.2010.02094.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Recent progress in genotyping technology and the development of public databases has enabled large-scale genome-wide association tests with diseases. We performed a two-stage genome-wide association study (GWAS) of bipolar disorder (BD) in Japanese cohorts. First we used Affymetrix 100K GeneChip arrays in the analysis of 107 cases with bipolar I disorder and 107 controls, and selected markers that were nominally significant (P&lt;0.01) in at least one of the three models (1,577 markers in total). In the follow-up stage, we analyzed these markers using an Illumina platform (1,526 markers; 51 markers were not designable for the platform) and an independent sample set, which consisted of 395 cases (bipolar I + II) and 409 controls. We also assessed the population stratification of current samples using principal components analysis. After the two-stage analysis, 89 markers remained nominally significant (allelic P &lt; 0.05) with the same allele being consistently over-represented in both the first and the follow-up stages. However, none of these were significant after correction for multiple-testing by false discovery rates. Sample stratification was virtually negligible. Collectively, this is the first GWAS of BD in the Japanese population. But given the small sample size and the limited genomic coverage, these results should be taken as preliminary. (C) 2009 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.b.30941

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Language：Japanese   Publisher：Japanese Society of Biological Psychiatry  

DOI： 10.11249/jsbp.20.213

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Peptidylarginine deiminases (PADIs), five isoforms of which have been identified, catalyze the conversion of arginine residues to citrulline residues in proteins. Recent studies have revealed that abnormal activation of PADI2, the gene for which is expressed throughout the nervous system, is likely to be related to the pathogenesis of neuropsychiatric diseases with neurodegenerative processes, such as Alzheimer&apos;s disease and multiple sclerosis. Such a progressive neurodegenerative process could be involved in the etiology and/or course of schizophrenia, and PADI2 may be a candidate gene for schizophrenia. To assess whether PADI2 has a role in vulnerability to schizophrenia, we conducted a two-stage case-control association study in Japanese individuals. In a screening population of 534 patients and 559 control individuals, we examined eight single-nucleotide polymorphisms (SNPs) including four haplotype tag SNPs and four coding SNPs in PADI2. There was a potential association of a synonymous SNP in exon 7 with schizophrenia. However, we could not replicate this association in a confirmatory population of 2126 patients and 2228 control individuals. The results of this study suggest that PADI2 does not contribute to genetic susceptibility to schizophrenia. Journal of Human Genetics (2009) 54, 430-432; doi: 10.1038/jhg.2009.52; published online 29 May 2009

DOI： 10.1038/jhg.2009.52

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Chromatin remodeling may play a role in the neurobiology of schizophrenia and the process, therefore, may be considered as a therapeutic target. The SMARCA2 gene encodes BRM in the SWI/SNF chromatin-remodeling complex, and associations of single nucleotide polymorphisms (SNPs) to schizophrenia were found in two linkage disequilibrium blocks in the SMARCA2 gene after screening of 11 883 SNPs (rs2296212; overall allelic P = 5.8 x 10(-5)) and subsequent screening of 22 genes involved in chromatin remodeling (rs3793490; overall allelic P = 2.0 x 10(-6)) in a Japanese population. A risk allele of a missense polymorphism (rs2296212) induced a lower nuclear localization efficiency of BRM, and risk alleles of intronic polymorphisms (rs3763627 and rs3793490) were associated with low SMARCA2 expression levels in the postmortem prefrontal cortex. A significant correlation in the fold changes of gene expression from schizophrenic prefrontal cortex (from the Stanley Medical Research Institute online genomics database) was seen with suppression of SMARCA2 in transfected human cells by specific siRNA, and of orthologous genes in the prefrontal cortex of Smarca2 knockout mice. Smarca2 knockout mice showed impaired social interaction and prepulse inhibition. Psychotogenic drugs lowered Smarca2 expression while antipsychotic drugs increased it in the mouse brain. These findings support the existence of a role for BRM in the pathophysiology of schizophrenia.

DOI： 10.1093/hmg/ddp166

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There is strong evidence for a negative association between schizophrenia and rheumatoid arthritis ( RA). However, the mechanism for this association is unknown. We hypothesize that these two diseases share susceptibility genes. Recently, extensive studies have identified some RA susceptibility genes, including NFKBIL1, SLC22A4, RUNX1, FCRL3 and PADI4, in the Japanese population. To assess whether polymorphisms in these RA susceptibility genes are implicated in vulnerability to schizophrenia, we conducted a two-stage case-control association study in Japanese subjects. In a screening population of 534 patients and 559 control subjects, we examined eight polymorphisms in RA susceptibility genes and found a potential association of padi4_94 in PADI4 with schizophrenia. However, we could not replicate this association in a confirmatory population of 2126 patients and 2228 control subjects. The results of this study suggest that these polymorphisms in RA susceptibility genes do not contribute to genetic susceptibility to schizophrenia.

DOI： 10.1038/jhg.2008.4

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Chromatin remodeling may play a role in the neurobiology of schizophrenia and the process, therefore, may be considered as a therapeutic target. The SMARCA2 gene encodes BRM in the SWI/SNF chromatin-remodeling complex, and associations of single nucleotide polymorphisms (SNPs) to schizophrenia were found in two linkage disequilibrium blocks in the SMARCA2 gene after screening of 11 883 SNPs (rs2296212
overall allelic P = 5.8 × 10-5) and subsequent screening of 22 genes involved in chromatin remodeling (rs3793490
overall allelic P = 2.0 × 10-6) in a Japanese population. A risk allele of a missense polymorphism (rs2296212) induced a lower nuclear localization efficiency of BRM, and risk alleles of intronic polymorphisms (rs3763627 and rs3793490) were associated with low SMARCA2 expression levels in the postmortem prefrontal cortex. A significant correlation in the fold changes of gene expression from schizophrenic prefrontal cortex (from the Stanley Medical Research Institute online genomics database) was seen with suppression of SMARCA2 in transfected human cells by specific siRNA, and of orthologous genes in the prefrontal cortex of Smarca2 knockout mice. Smarca2 knockout mice showed impaired social interaction and prepulse inhibition. Psychotogenic drugs lowered Smarca2 expression while antipsychotic drugs increased it in the mouse brain. These findings support the existence of a role for BRM in the pathophysiology of schizophrenia. © The Author 2009. Published by Oxford University Press. All rights reserved.

DOI： 10.1093/hmg/ddp166

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1097/YPG.0b013e328306c7dc

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Interleukin 2 (IL-2) and IL-4 are pleiotropic cytokines regulating Th1/Th2 balance and have a regulatory activity in brain function. Thus these cytokines have been implicated in the pathophysiology of schizophrenia. The latest studies provided controversial results regarding the genetic associations of these cytokines. The functional polymorphisms, IL2-330T/G and IL4-590C/T, were associated with schizophrenia in a German population, although contradictory findings were also reported in a Korean population. To ascertain whether IL2 and IL4 contribute to vulnerability to schizophrenia, we conducted a moderate-scale case-control (536 patients and 510 controls) association study for seven polymorphisms in Japanese subjects. There were no significant associations of these genes with schizophrenia using either single marker or haplotype analyses. The present study suggests that IL2 and IL4 do not contribute to vulnerability to schizophrenia in the Japanese population.

DOI： 10.1007/s00406-008-0813-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：DR DIETRICH STEINKOPFF VERLAG  

Interleukin 2 (IL-2) and IL-4 are pleiotropic cytokines regulating Th1/Th2 balance and have a regulatory activity in brain function. Thus these cytokines have been implicated in the pathophysiology of schizophrenia. The latest studies provided controversial results regarding the genetic associations of these cytokines. The functional polymorphisms, IL2-330T/G and IL4-590C/T, were associated with schizophrenia in a German population, although contradictory findings were also reported in a Korean population. To ascertain whether IL2 and IL4 contribute to vulnerability to schizophrenia, we conducted a moderate-scale case-control (536 patients and 510 controls) association study for seven polymorphisms in Japanese subjects. There were no significant associations of these genes with schizophrenia using either single marker or haplotype analyses. The present study suggests that IL2 and IL4 do not contribute to vulnerability to schizophrenia in the Japanese population.

DOI： 10.1007/s00406-008-0813-z

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Language：Japanese   Publisher：(株)星和書店  

Paroxetine(PRX)とnortriptyline(NT)はチトクロームP450(CYP)2D6によって主に代謝され、PRXは強いCYP2D6阻害作用を有する。今回我々は、PRX30mg/日とNT100mg/日の併用時に振戦が出現し、NTの中止により改善がみられた1例を経験した。NT25mg,PRX30mgの最終服用24時間後に測定したNTの血漿濃度は120ng/mLであり、シミュレーション・カーブからは、有害事象が出現した日の早朝には血漿NT濃度が310ng/mL以上になっていたと推計された。PRXによるCYP2D6阻害や同酵素の飽和によりNTの代謝が阻害されたため、血漿NT濃度が上昇し、PRXとの相乗効果で錐体外路症状が惹起されたものと推察された。薬物併用時に有害事象が生じた場合には、therapeutic drug monitoringが薬物相互作用の検出に有用と考えられた。(著者抄録)

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Language：Japanese   Publisher：(株)メディカルレビュー社  

統合失調症に対する疫学研究から、妊娠母体のウイルス感染や周産期障害が本疾患の発症リスクを上昇させることが報告されている。それゆえ、免疫・炎症と統合失調症との関係が仮説され、その媒介分子であるサイトカインに注目が集まっている。サイトカインは、免疫系での分子群に加えて、細胞増殖因子や神経栄養因子などを含めると、その総数は100近くに及び、種々の神経細胞の分化、発達、細胞死を調節していることが知られていた。したがって、サイトカインの機能障害は、脳発達や脳機能障害に結び付くのである。本章では、統合失調症の発症や病態に関与するかもしれないサイトカインに着目して、その活性の相違点やその動物モデルについて紹介したい。(著者抄録)

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DOI： 10.1111/j.1440-1819.2008.01762.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Chromosome 1p13 is linked with schizophrenia in Japanese families, and one of the candidate genes in this region is the netrinG1 (NTNG1) gene at 1p13.3. Associations of 56 tag single-nucleotide polymorphisms (SNPs) with schizophrenia were explored by transmission disequilibrium analysis in 160 Japanese trios and by case-control analysis in 2174 Japanese cases and 2054 Japanese controls. An association between SNP rs628117 and schizophrenia was identified by case-control comparison (nominal allelic p = 0.0009; corrected p = 0.006). The associated polymorphism is located in intron 9 and in the haplotype block encompassing the alternatively spliced exons of the gene. Allelic association of a different SNP in the same haplotype block in Japanese families was previously reported. These findings support that the NTNG1 gene is associated with schizophrenia in the Japanese. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2008.02.053

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Systematic linkage disequilibrium (LD) mapping of 8p12-21 in the Icelandic population identified neuregulin 1 (NRG1) as a pdrne candidate gene for schizophrenia. However, results of replication studies have been inconsistent, and no large sample analyses have been reported. Therefore, we designed this study with the aim of assessing this putative association between schizophrenia and NRG1 (especially HAP(ICE) region and exon region) using a gene-based association approach in the Japanese population.
This study was a two-stage association analysis with a different panel of samples, in which the significant association found in the first-set screening samples (1126 cases and 1022 controls) was further assessed in the confirmation samples (1262 cases and 1172 controls, and 166 trio samples). In the first-set scan, 60 SNPs (49 tagging SNPs from HapMap database, four SNPs from other papers, and seven SNPs detected in the mutation scan) were examined.
One haplotype showed a significant association in the first-set screening samples (Global P-value= 0.0244, uncorrected). However, we could not replicate this association in the following independent confirmation samples. Moreover, we could not find sufficient evidence for association of the haplotype identified as being significant in the first-set samples by imputing ungenotyped SNPs from HapMap database.
These results indicate that the positionally and functionally attractive regions of NRG1 are unlikely to contribute to susceptibility to schizophrenia in the Japanese population. Moreover, the nature of our results support that two-stage analysis with large sample size is appropriate to examine the susceptibility genes for common diseases. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2008.01.010

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Introduction: Glutamate dysfunction has been implicated in the pathophysiology of schizophrenia. The metabotropic glutamate receptors (rnGluRs) are G-protein-coupled receptors. GRM7, the gene that encodes mGluR7, is expressed in many regions of the human central nervous system. The GRM7 gene is located on human chromosome 3p26, which has been suggested by linkage analysis to contain a susceptibility locus for schizophrenia.
Methods: We screened for mutations in all exons, exori/intron junctions, and promoter regions of the GRM7 gene in Japanese patients with schizophrenia and evaluated associations between the detected polymorphisms and schizophrenia. We examined the influence of one polymorphism associated with schizophrenia on the expression of GRM7 by dual-luciferase assay in transfected cells.
Results: Twenty-five polymorphisms/mutations were detected in GRM7. Case-control analysis revealed a potential association of a synonymous polymorphism (371 T/C, rs3749380) in exon 1 with schizophrenia in our case-control study of 2293 Japanese patients with schizophrenia and 2382 Japanese control subjects (allelic p=0.009). Dual-luciferase assay revealed suppression of transcription activity by exon 1 containing this polymorphism and a statistically significant difference in the promoter activity between the T and C alleles.
Conclusions: Our results support the possible association of a GRM7 gene polymorphism with genetic susceptibility to schizophrenia. (C) 2008 Elsevier B.V All rights reserved.

DOI： 10.1016/j.schres.2008.01.027

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The GRM3 gene, which encodes a metabotropic glutamate receptor, is an important candidate gene for susceptibility to schizophrenia. Two single nucleotide polymorphisms (SNPs), rs1468412 and rs2299225 in intron 3, were reported to be associated with schizophrenia in Japanese and Chinese populations, respectively. Haplotypes with these SNPs were also reported to be associated with schizophrenia. In the present study, we attempted to replicate these single marker and haplotype associations in a case-control study of 1,916 Japanese patients with schizophrenia and 1,915 Japanese control subjects. In addition to these two SNPs, we genotyped rs274622 in the promoter region of GRM3. In the present study, none of these polymorphisms were associated with schizophrenia (rs274622, allelic P = 0.68; rs1468412, allelic P = 0.74; rs2299225, allelic P = 0.20). Haplotypes constructed with these SNPs also were not associated with schizophrenia (P = 0.18-0.84). Meta-analysis of five case-control studies of more than 3,000 patients with schizophrenia and more than 3,000 control subjects did not support the associations of rs1468412 and rs2299225 with schizophrenia. Our data indicate that SNPs previously reported to be associated with schizophrenia do not contribute to genetic susceptibility to schizophrenia. (C) 2007 Wiley-Liss, Inc.

DOI： 10.1002/ajmg.b.30610

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Serotonin (5-hydroxytryptamine [5-HT]) may be implicated in both the pathophysiology of schizophrenia and in mediating atypical antipsychotic drug effects. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme involved in the synthesis of 5-HT. Some genetic variants of the TPHI gene have been tested for their associations with schizophrenia, but with conflicting results. To assess whether TPHI is implicated in vulnerability to schizophrenia, we conducted a case-control association study (409 patients and 440 controls) for six single nucleotide polymorphisms in Japanese subjects and performed an updated meta-analysis. There were no significant associations between the polymorphisms or haplotypes of TPHI and schizophrenia in our Japanese subjects. Our updated meta-analysis, which included six population-based case-control studies, suggests the possible involvement of the TPHI 218A allele in susceptibility to schizophrenia. To draw any conclusion, however, further studies using larger sample sizes should be carried out in various ethnic populations. (C) 2007 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2007.08.002

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Olanzapine(OLZ)は体重増加や糖脂質代謝異常といったメタボリックシンドローム(MS)につながる病態を惹き起こす危険性があり、血中プロラクチン(PRL)濃度を有意に上昇させるという報告もなされている。このためOLZによるこれらの有害事象には十分な注意を払う必要がある。今回我々はOLZ投与中にMSを指摘され、aripiprazole(ARP)への置換によりMSと高PRL血症が改善した51歳、女性の統合失調症の1例を経験した。ARPはMSや高PRL血症を惹起する可能性が低いことが二重盲検比較試験により確認されており、各種ガイドラインでもこれらの病態を有する場合、ARPの投与が推奨されている。ただし、ARPの投与時にも、定期的な体重測定、糖脂質代謝異常のモニタリング、生活指導が必要である。また、今後もARPの特に長期安全性について症例を蓄積することが重要と思われる。(著者抄録)

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Tumor necrosis factor-alpha (TNF-alpha) is a pleiotrophic cytokine and exerts neuroprotective and neurodegenerative effects in brain, Several studies have indicated that TNF-alpha is likely related to the pathogenesis of schizophrenia. Recent genetic investigations have revealed that a TNF-alpha gene promoter polymorphism (-G308A) is associated with schizophrenia, although negative findings have also been reported. To assess whether the TNF-alpha gene promoter variants including -G308A could be implicated in vulnerability to schizophrenia, we conducted a case-control association analysis (265 cases and 424 controls) and the transmission disequilibrium test (TDT) analysis (83 trios) for four polymorphisms (-G238A, -G308A, -C857T and -T1031C) in Japanese subjects. In a case-control analysis, there was no significant association between the promoter polymorphisms or haplotypes in the TNF-alpha gene and schizophrenia. In the TDT analysis, we also did not observe transmission distortion. Our results suggest that the above four polymorphisms in the promoter region of the TNF-alpha gene appear not to confer increased susceptibility for schizophrenia in a Japanese population. (C) 2006 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.psychres.2006.03.009

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DOI： 10.1016/j.schres.2007.05.032

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Interleukin-1 (IL1) is an inflammatory cytokine and exerts neurodegenerative effects in the brain. Several studies have indicated that IL1 is likely to be involved in the pathogenesis of schizophrenia. Recent genetic studies have revealed that the IL1 gene complex (IL,1 alpha, IL1, beta and IL1 receptor antagonist) was associated with schizophrenia, although contradictory findings have also been reported. To assess whether the IL1 gene complex was implicated in vulnerability to schizophrenia, the authors conducted a case-control association study (416 patients with schizophrenia and 440 control subjects) for nine polymorphisms in Japanese subjects. The authors found no association between the IL1 gene complex polymorphisms and schizophrenia using either single-marker or haplotype analyses. The results of the present study suggest that the IL1 gene complex does not play a major role in conferring susceptibility to schizophrenia in the Japanese population.

DOI： 10.1111/j.1440-1819.2007.01671.x

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Catechol-O-methyltransferase (COMT) is one of the enzymes that degrade catecholamine neurotransmitters including dopamine. The COMT gene is located on 22q11.2, a common susceptibility locus for schizophrenia. Therefore, COMT is a strong functional and positional candidate gene for schizophrenia. A common functional polymorphism (rs4680, Val 158Met) has been extensively tested for an association with schizophrenia, but with conflicting results. Recent studies indicate that if COMT is implicated in susceptibility to schizophrenia, this cannot be wholly accounted for by the Va1158Met polymorphism. To assess this view, the authors conducted a case-control association study (399 patients with schizophrenia and 440 control subjects) for five functional polyrnorphisms (rs2075507, rs737865, rs6267, rs4680 and rs165599) in Japanese subjects. There were no significant associations found between the polyrnorphisms or haplotypes of COMT and schizophrenia. The present study shows that these five functional COMT polymorphisms do not play a major role in conferring susceptibility to schizophrenia in Japanese. (C) 2007 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2007.03.015

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There is cumulative evidence that neuregulin I (NRG1) is a susceptibility gene for schizophrenia. Postmortem studies on brains from schizophrenia patients have revealed changes in the mRNA expression levels of v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3), one of the NRG1 receptor genes. These observations suggest that NRG1-ERBB signaling is involved in the pathogenesis of schizophrenia. To assess whether the ERBB3 gene could be implicated in vulnerability to schizophrenia, we conducted a case-control (399 patients and 438 controls) association study in Japanese subjects. There were no significant association between the polymorphisms or haplotypes of ERBB3 and schizophrenia. The present study shows that ERBB3 does not play a major role in conferring susceptibility to schizophrenia in the Japanese population. (c) 2007 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2007.01.001

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The functional promoter polymorphism -116C/G of the X-box binding protein 1 (XBP1) gene was found to be associated with schizophrenia in Han Chinese and Japanese subjects, although contradictive negative findings were also reported in European populations. To confirm this association in a Japanese population, the authors conducted a case-control association study. There was no significant difference in both genotype and allele frequencies between the patients and control subjects, suggesting that the XBP1 -116C/G polymorphism might not confer increased susceptibility for schizophrenia in a Japanese population. However, further studies using a larger sample with detailed clinical data should be performed in several populations.

DOI： 10.1111/j.1440-1819.2006.01570.x

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抗精神病薬による性機能障害は比較的頻度が高く,服薬アドヒアランスや生活の質(QOL)を低下させる重大な有害事象であるにもかかわらず,臨床場面では十分な注意が払われていない.今回我々は,risperidone(RIS)2mg/日にて精神病症状は改善し病識も得られたが勃起障害のために服薬を拒否するようになり,olanzapine(OLZ)10mg/日に変更したところ勃起障害が消失し服薬アドヒアランスも保たれた,38歳男性の統合失調症の1例を経験した.他の非定型抗精神病薬と比較し,RISはドパミンD2およびα1アドレナリン受容体遮断作用が強く,高プロラクチン血症をきたしやすいために性機能障害を惹起しやすいと考えられている.RISによる性機能障害に対してはOLZやquetiapineへの変更が有効である可能性が示唆されており,今後の更なる症例の蓄積と大規模な臨床研究が期待される(著者抄録)

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Brain-derived neurotrophic factor (BDNF) plays important roles in the survival, maintenance and growth of neurons. Several studies have indicated that BDNF is likely to be related to the pathogenesis of schizophrenia. Recent genetic analyses have revealed that BDNF gene polymorphisms are associated with schizophrenia, although contradictory negative findings have also been reported. To assess whether three BDNF gene polymorphisms (rs988748, C132T and rs6265) could be implicated in vulnerability to schizophrenia, we conducted a case-control association analysis (349 patients and 423 controls) in Japanese subjects. We found no association between these BDNF gene polymorphisms and schizophrenia using both single-marker and haplotype analyses. The results of the present study suggest that these three BDNF gene polymorphisms do not play major roles in conferring susceptibility to schizophrenia in a Japanese population. However, further studies assessing the associations between these BDNF gene polymorphisms and schizophrenia should be performed in several other ethnic populations. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.schres.2006.03.011

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Language：Japanese   Publisher：医学書院  

進行性核上性麻痺(PSP)に対してミルナシプランの単剤投与(25mg/日)を行ったところ,意欲低下,姿勢反射障害,眼球運動障害などに改善がみられたPSPの1例(66歳男性)を報告した.投与開始4日後には姿勢反射障害や眼球運動障害が改善し,3週目からは意欲の向上もみられた.本症例はミルナシプラン単剤投与による効果がみられた点で意義があると考えられ,ミルナシプランはPSPの治療に有効である可能性が示唆された

DOI： 10.11477/mf.1405100253

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DOI： 10.1111/j.1440-1819.2006.01470.x

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Language：Japanese   Publisher：日本生物学的精神医学会  

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2003年度の1年間に,新潟県立新発田病院精神科への院内他科より診療依頼のあった初診患者194人を外来群(94人)と入院群(100人)の2群に分け,それぞれの臨床特徴について検討を行った.外来群の平均年齢[標準偏差]は52.3[23.5]歳と入院群に比し10歳以上若く,女性の比率が高かった(1:2.1).また他施設精神科を受診中だった者(精神科受診群)の割合は,入院群(18.0%)が外来群(3.2%)よりも有意に高かった.依頼科については,両群ともに内科系が6割強,外科系が4割弱と同じ割合であったが,入院群では内科が半数を超えたのに対し,外来群では神経内科や脳外科のいわゆる&quot;神経系の科&quot;からの依頼が3分の1以上であった.診断カテゴリーについて,外来群では気分障害や身体表現性障害が,入院群ではせん妄および痴呆が半数弱を占めた.入院群の中でも精神科受診群では気分障害や精神病性障害が,非受診群ではせん妄および痴呆,アルコール関連障害が多かった.以上より,外来と入院,精神科受診状況の違いにより診断カテゴリーに一定の傾向が存在すること等をわれわれ精神科医は把握して他科医師の啓蒙を行うなど,より効率的で質の高いコンサルテーション・リエゾン活動への努力が重要と思われた(著者抄録)

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ドーパミン機能を調節しているEGFに着目することで,類縁分子を含めたEGFファミリーによるドーパミン神経の発達調節メカニズムを明らかにするとともに,ドーパミン関連脳機能そのものへの影響を動物モデルで評価する計画を立案した.EGFファミリーの脳内分布と中枢神経に対するEGFの栄養活性の詳細を,初代培養の中脳神経細胞とラット脳内投与法を用いて調べた.モノアミン神経細胞種のうちドーパミン神経がEGFファミリーに対する反応が大きく,作用はドーパミン神経上に多く発現するErbB1受容体への直接作用と考えられた.他の栄養因子GDNFなどとは異なり,神経の生存より発達分化促進作用が顕著で,in vivoにおいてもEGFのドーパミン神経への刺激作用を確認した.統合失調症における「ドーパミン機能障害仮説」と「脳発達障害仮説」の両方を支持した

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Epidermal growth factor (EGF) signal regulates the development of dopaminergic neurons and monoamine metabolism. It is suggested that EGF protein levels are decreased in the brain and blood of patients with schizophrenia. A recent study has reported that a polymorphism in EGF gene (rs4444903) is associated with schizophrenia in Finnish men. To confirm this association for another population in larger samples, we conducted a case-control association study on a Japanese population (337 cases and 421 controls). No significant difference was observed in both the allelic and genotype distribution between cases and controls in women, men and total samples. Our results suggest that the polymorphism in EGF gene might not confer increased susceptibility for schizophrenia in a Japanese population. (c) 2005 Lippincott Williams E Wilkins.

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症例は31歳の男性,統合失調症の外来患者である.Risperidone(RIS)の投与が開始されて11ヵ月後,4mg/日に増量されたころから多飲水が出現し,数度のけいれん発作がみられた.9mg/日に漸増された1ヵ月後に,水中毒に伴う意識障害を呈し入院となった.筋強剛,発汗,CK上昇,褐色尿などが認められ,悪性症候群と横紋筋融解症を併発した.呼吸不全や急性腎不全も合併したが,人工呼吸器管理および血液透析などの集中治療により良好な経過をとった.本症例ではRISの増量に一致して多飲水が出現・増悪したことから,RISにより多飲水が惹起された可能性が示唆される.多飲水は抗精神病薬の慢性的なドパミンD2受容体遮断により惹起されるという仮説が提唱されている.RISは非定型抗精神病薬のなかではD2受容体遮断作用が強く,高用量になるほどその作用が増すことは,この仮説に合致する(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Maternal stress, viral infection, and obstetric complications, which trigger cytokine signaling, are hypothesized to be involved in schizophrenia and its related disorders. The etiologic contribution of individual cytokines to such psychiatric disorders, however, remains to be evaluated. To estimate the impact of peripheral cytokine challenge on neurobehavioral development, we examined effects of four proinflammatory cytokines on rat neonates and their later behavioral performance. Sublethal doses of interleukin-1alpha, interleukin-2, interleukin-6, or interferon-gamma were subcutaneously administered to rat pups for 9 days. These animals displayed alterations in physical development, including lower weight gain and/or accelerated eyelid opening. In addition, behavioral abnormalities related to fear/anxiety levels and sensorimotor gating emerged at different developmental stages, depending on the cytokine species administered. During juvenile stages, neonatal interleukin-2 treatment increased exploratory locomotor activity, whereas other cytokine treatments did not. At the post-puberty stage, however, the interleukin-2-induced abnormal motor activity became undetectable, whereas interleukin-1alpha-treated rats developed abnormalities in startle response, prepulse inhibition (PPI), and social interaction. Subchronic treatment of an anti-psychotic drug, clozapine, ameliorated the impairment of prepulse inhibition without altering startle responses. These animal experiments illustrate that, during early postnatal development, inflammatory cytokine challenge in the periphery can induce future psychobehavioral and/or cognitive impairments with various latencies, although the pathologic mechanisms underlying these abnormalities remain to be determined. (C) 2004 Elsevier Ireland Ltd and The Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2004.05.010

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Cytokines have been implicated in the etiology or pathology of various psychiatric diseases of developmental origin such as autism and schizophrenia. Leukemia inhibitory factor (LIF) is induced by a variety of brain insults and known to have many influences on mature and immature nervous system. Here, we assessed the neurobehavioral and pathological consequences of peripheral administration of LIF in newborn rats. Subcutaneous LIF injection induced STAT3 phosphorylation in many brain regions and increased glial fibrillary acidic protein (GFAP) immunoreactivity in the neocortex, suggesting that LIF had direct effects in the central nervous system. The LIF-treated rats displayed decreased motor activity during juvenile stages, and developed abnormal prepulse inhibition in the acoustic startle test during and after adolescence. They displayed normal learning ability in active avoidance test, however. Brain neuronal structures and startle responses were grossly normal, except for the cortical astrogliosis during neonatal LIF administration. These results indicate that LIF induction in the periphery of the infant has a significant, but discrete impact on neurobehavioral development. (C) 2003 Elsevier Ireland Ltd and The Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/j.neures.2003.12.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Interleukin-1 (IL-1) mediates psychological stress responses by regulating monoamine metabolism and secretion of corticotropin-releasing factor, and is therefore, implicated in various psychiatric diseases. To evaluate the contribution of IL-1 signaling to the brain pathology of schizophrenia, we measured protein and/or mRNA levels for IL-1beta and endogenous IL-1 receptor antagonist (IL-1RA) in the postmortem brain tissues of prefrontal and parietal cortex, putamen, and hypothalamus. Both protein and mRNA levels of IL-1RA were specifically decreased in the prefrontal cortex of schizophrenic patients, whereas IL-1beta levels were not significantly altered in all the regions examined. The IL-1RA decrease was not correlated with the dose of antipsychotics given to patients. There was no influence of this illness on protein levels for IL-1 receptor type I in the prefrontal cortex, either. In contrast, IL-1RA serum levels were increased in schizophrenic patients, especially in drug-free patients, as reported previously. These findings suggest that chronic schizophrenia down-regulates IL-1RA production the prefrontal cortex, irrespective of its impact on the periphery. IL-1RA reduction might reflect an immunopathologic trait of the prefrontal region in schizophrenic patients. (C) 2003 Elsevier Science Ireland Ltd and Japan Neuroscience Society. All rights reserved.

DOI： 10.1016/S0168-0102(03)00093-2

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DOI： 10.1016/S0920-9964(03)80878-2

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Neurotrophic factors regulate neuronal development as well as synaptic plasticity, and their impairment is often implicated as a cause of schizophrenia. Among various neurotrophic molecules, brain-derived neurotrophic factor (BDNF) levels have been found to be increased in the corticolimbic regions of patients' brains. In the present study, we assessed peripheral BDNF levels in whole blood as well as in the serum of two independent groups of schizophrenic patients (n = 34 in each group) and healthy volunteers (n = 35 and n = 27, respectively). BDNF protein levels in fresh serum and blood of the patients and volunteers were measured using a two-site enzyme immunoassay and correlated with the number and decay of platelets. In addition to the studies of patients and volunteers, neuroleptic effects on BDNF levels were assessed by administering haloperidol to adult rats for 2 weeks or 5 months. The major findings were as follows: BDNF levels were significantly reduced in the serum of schizophrenic patients (P &lt; 0.005, Mann-Whitney U-test) but not in their whole blood. Antipsychotic dose did not correlate with serum BDNF levels. Moreover, chronic administration of haloperidol failed to decrease serum BDNF levels in adult rats. Abnormal levels of BDNF are evident not only in the brain of schizophrenic patients, but also in their peripheral blood. The BDNF reduction in serum but not in whole blood suggests a potential deficit in neurotrophic factor release in patients with schizophrenia. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0165-1781(02)00127-0

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＜文献概要＞ポイント ◆COVID-19パンデミック下で医療従事者の約25%が不安や抑うつを有している.◆専門職による心理的介入だけでなく基本的なセルフケアの確保など現場の医療従事者が求める支援の実施が重要である.◆医療従事者は偏見や差別にさらされており,これらの克服など行政的な取り組みも必要である.

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DOI： 10.4238/2012.April.27.13

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新潟大学医学部医学科(本学科)では、医学への興味を高め、本学科への進学希望者を増加させることを目的として、シミュレータ体験を中心とした体験講座を開催している。その効果を検討するため、2012-2013年度に体験講座に参加した高校生87人、ならびに2014年度の本学科入学者123人に対して、アンケート調査を実施し、解析した。高校生に対するシミュレータ実習を含む体験講座の評価は良く、参加者の医療関係職を希望する気持ちの強さは有意に増加した(P<0.001)。2014年度本学科入学者のうち69人(56%)は、全国の医学科で開催されている体験講座に参加した経験があり、そのなかで本学科の体験講座に参加した34人中28人の学生は、医学科進学を考える上で影響を受けたと回答した。(著者抄録)

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