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DOI： 10.1371/journal.pone.0036836

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DOI： 10.1007/s00213-012-2885-8

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DOI： 10.1002/ajmg.b.32049

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DOI： 10.1016/j.pnpbp.2011.11.016

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DOI： 10.1007/BF03325260

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DOI： 10.1038/mp.2012.74

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DOI： 10.1371/journal.pone.0050220

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DOI： 10.1111/j.1440-1819.2012.02362.x

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DOI： 10.1371/journal.pone.0034725

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DOI： 10.1136/bmjopen-2012-001340

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DOI： 10.1093/schbul/sbs038

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DOI： 10.1136/bmjopen-2011-000596

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DOI： 10.5363/tits.16.7_20

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DOI： 10.1016/j.pnpbp.2011.04.003

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DOI： 10.1016/j.jad.2010.06.015

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DOI： 10.1002/hup.1205

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DOI： 10.1016/j.jpsychores.2011.02.001

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DOI： 10.1016/j.biopsych.2010.07.010

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DOI： 10.1111/j.1440-1819.2011.02238.x

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DOI： 10.1371/journal.pone.0028929

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DOI： 10.1016/j.schres.2010.07.011

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DOI： 10.1038/jhg.2010.110

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DOI： 10.1093/schbul/sbq118

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DOI： 10.1038/jhg.2009.139

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DOI： 10.1002/ajmg.b.31048

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DOI： 10.1038/jhg.2010.38

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DOI： 10.1016/j.biopsych.2009.08.034

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DOI： 10.1016/j.schres.2010.01.014

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DOI： 10.1016/j.schres.2009.03.040

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DOI： 10.1016/j.neures.2009.09.1441

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DOI： 10.1016/j.schres.2007.10.028

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DOI： 10.1097/WNR.0b013e3282f600b4

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

DOI： 10.18999/nagjms.70.1-2.11

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DOI： 10.1016/j.neulet.2008.04.010

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DOI： 10.1016/j.schres.2008.01.010

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DOI： 10.1007/s10038-008-0318-7

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

DOI： 10.1097/YPG.0b013e3280ae6cd8

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

DOI： 10.1097/WNR.0b013e3280586890

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

DOI： 10.1007/s10038-007-0142-5

Language：English   Publisher：BMC Medical Education  

Background: Problem-Based Learning (PBL) requires active communication and learner autonomy, which can be challenging in cultural contexts that emphasize group harmony and indirect communication, such as Japan. This challenge is often amplified when PBL is conducted in a non-native language (English), potentially inducing “foreign language anxiety.” While the COVID-19 pandemic necessitated a shift to online learning, the specific impact of this format on psychological barriers and student engagement in high-context cultures remains underexplored. We investigated whether the online format could reduce these transactional distances and enhance learning outcomes compared to traditional in-person PBL. Methods: We conducted a naturalistic, historical control study comparing fourth-year medical students at Nagoya University during a Child and Adolescent Psychiatry curriculum. The 2019 cohort (n = 109) participated in-person, while the 2021 cohort (n = 100) participated online. We administered a 15-item questionnaire assessing satisfaction, engagement, and case suitability. Beyond standard descriptive comparisons, we applied a novel multidimensional statistical framework. This included Ordered Logistic Regression adjusted for age and sex to identify predictors of satisfaction, Exploratory Factor Analysis (EFA) to validate the instrument’s latent structure, and K-means Clustering to identify distinct student “phenotypes” based on response patterns. Results: The online cohort reported significantly higher satisfaction across most domains (Odds Ratios 0.36–0.51, p < 0.05). Factor analysis identified two primary dimensions—“Perceived Learning Efficacy” and “Engagement”—while “Communication Skills” (Question 4) emerged as an independent outlier, failing to load on either dimension. Cluster analysis identified two distinct student phenotypes: a “Traditional/Dissatisfied” profile (Cluster 1: n = 77, 69% from the in-person group, predominantly male and older) and a “Digital/Satisfied” profile (Cluster 2: n = 127, 57% from the online group, predominantly female and younger). Conclusions: Online delivery of PBL was associated with significantly higher student satisfaction and engagement scores in this Japanese context. Because the study is observational (historical-cohort comparison with no randomisation), this association cannot be attributed causally to the modality, and the role of reduced foreign-language anxiety is an interpretive hypothesis that the present design does not directly test. The identification of distinct student phenotypes suggests that demographic factors (gender, age) and delivery modality interact to shape the learning experience. These findings advocate for a tailored pedagogical approach, where digital formats serve as a “safe harbor” for students with high communication apprehension.

DOI： 10.1186/s12909-026-09517-9

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Language：English   Publisher：BMC Medical Education  

Background: Pharmacology education faces challenges due to evolving student learning behaviors. This study examined the feasibility of identifying which student-level characteristics, academic background and learning activities were associated with performance at the pharmacology exam using routinely-collected data. Methods: In a prospective cohort study of second-year medical students at Caen Normandie University (2024–2025), we analyzed in-person lecture, online resource, and peer tutoring mock exam attendance, as well as use of student-written lecture support, and pharmacology exam outcomes. The primary outcome was final pharmacology exam score (over 20points), according to pedagogical methods, estimated through multivariate linear regression. Results: Participants (164 out-of 250 eligible students(66%)) were well representative of 2^ndyear medical students, with two thirds of women, high prior academic achievement, and a median age of 19. In the univariate analysis, higher in-person lecture attendance was significantly associated with a higher score at the pharmacology exam (+ 0.41points for each additional 10h of attendance, 95%Confidence Interval (CI): + 0.05 to + 0.77). Similarly, the number of online resources downloaded showed a positive association in univariate analysis (+ 0.53points for each additional 10downloads, 95%CI: + 0.09 to + 0.97). In-person lecture attendance remained significant in the multivariate model (+ 0.46points, 95%CI:0.03–0.88). Peer tutoring exam attendance and student-written lecture support use were not associated with a significant change in exam score. In-person lecture attendance exhibited a U-shaped relationship with exam performance: initial declines (up to 10h) preceded gradual improvement, plateauing at 25–30 h (spline regression, p < 0.05). Prior academic achievement (baccalaureate distinction, rapid first-year completion) and curriculum (first-year major being health-science) were significantly associated with higher exam score. Conclusions: This pilot study demonstrates the feasibility and value of quantitatively evaluating pharmacology education among French medical students. Academic background and pedagogical methods seem to influence pharmacology exam success. Broader replication, and long-term follow-up are needed to confirm these insights and identify determinants of student success more robustly.

DOI： 10.1186/s12909-026-09454-7

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Publisher：Nature Medicine  

The past decade has seen remarkable progress in identifying genes that, when impacted by deleterious coding variation, confer high likelihood for autism spectrum disorder (ASD), intellectual disability and other associated developmental disorders. However, most underlying gene discovery efforts have focused on individuals of European ancestry, limiting insights into genetic liability across diverse populations. To help address this, the Genomics of Autism in Latin American Ancestries (GALA) Consortium was formed, presenting here the largest sequencing study of autism in Latin American individuals (n > 15,000, including 4,717 participants with an ASD diagnosis). We identified 35 genome-wide significant (false discovery rate < 0.05) autism-associated genes, with substantial overlap with findings from European cohorts, and highly constrained genes showing consistent signal across populations. The results provide support for emerging (for example, MARK2, YWHAG, PACS1, RERE, SPEN, GSE1, GLS, TNPO3 and ANKRD17) and established autism genes and for the utility of genetic testing approaches for deleterious variants in individuals from diverse backgrounds; the results also demonstrate the ongoing need for more inclusive genetic research and testing. We conclude that the biology of autism is consistent across populations, with no detectable influence of ancestry.

DOI： 10.1038/s41591-026-04228-6

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Language：English   Publisher：Scientific Reports  

Depressive symptomatology is prevalent among oncology patients and may influence the perception of adverse drug reactions (ADRs) to anticancer drugs. Understanding this relationship is crucial for optimizing treatment strategies and improving ADR management. This pharmacovigilance study analyzed VigiBase^® data from 1968 (year of its establishment) to 2024. Focusing on reports involving antineoplastic or immunomodulating agents, a case/non-case disproportionality analysis was conducted to assess the reporting and seriousness of ADRs in patients receiving antidepressants. Multivariable analyses were performed for all ADRs and the most frequently reported ADRs. Reporting Odds Ratios (RORs) were considered significant if the 95% credible interval lower bound exceeded 1. Among 8,804,863 reports, 428,102 involved patients receiving antidepressants. Antidepressant use was associated with a higher likelihood of serious ADRs reporting(58%vs45%; adjusted-ROR:1.78, 95%CI:1.76–1.79). Increased reporting was observed for most tested ADRs, including fatigue(ROR:2.19, 95%CI:2.13–2.25), pain(ROR:2.79, 95%CI:2.69–2.89), and headache(ROR:2.56, 95%CI:2.46–2.62). The timing of antidepressant initiation did not significantly impact ADR reporting. Antidepressant use in oncology patients is associated with increased ADR reporting and seriousness, emphasizing the need for heightened clinical vigilance. Effective management of depressive symptomatology may improve ADR perception, treatment adherence, and patient well-being. Prospective studies are required to confirm these findings and inform targeted interventions.

DOI： 10.1038/s41598-025-28563-9

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Publisher：American Journal of Human Genetics  

(The American Journal of Human Genetics 110, 963–978; June 1, 2023) The article was updated after publication to remove photographs of one individual from Figure 4.

DOI： 10.1016/j.ajhg.2025.10.010

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Publisher：American Journal of Human Genetics  

Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals using a liability model with differing thresholds. Given the sex differences in the rates of cognitive impairment among autistic individuals, we also compared effect sizes of rare variants between individuals with and without cognitive impairment or motor delay. Although these variants mediated different likelihoods of autism with versus without cognitive or motor difficulties, their effect sizes on the liability scale did not differ significantly by sex exome wide or in genes sex-differentially expressed in the cortex. De novo mutations were enriched in genes with male-biased expression in the adult cortex, but these genes did not show a significant sex difference on the liability scale, nor did the liability conferred by these genes differ significantly from other genes with similar loss-of-function intolerance and sex-averaged cortical expression. Exome-wide female bias in de novo protein-truncating mutation rates on the observed scale was driven by high-confidence and syndromic autism-predisposition genes. In summary, autosomal rare and damaging coding variants confer similar liability for autism in females and males.

DOI： 10.1016/j.ajhg.2025.01.016

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Publisher：Nature Genetics  

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.

DOI： 10.1038/s41588-022-01104-0

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Language：Japanese   Publisher：東京 : ニューサイエンス社  

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Publisher：openRxiv  

<jats:title>Summary</jats:title>
<jats:p>
We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate
<jats:italic>de novo</jats:italic>
and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive
<jats:italic>de novo</jats:italic>
variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.
</jats:p>

DOI： 10.1101/484113

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Publisher：Lancet Psychiatry  

DOI： 10.1016/S2215-0366(16)30409-6

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Publisher：Lancet Psychiatry  

DOI： 10.1016/S2215-0366(16)30409-6

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Publisher：Lancet Psychiatry  

DOI： 10.1016/S2215-0366(16)30409-6

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Publisher：Lancet Psychiatry  

DOI： 10.1016/S2215-0366(16)30409-6

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Publisher：Lancet Psychiatry  

DOI： 10.1016/S2215-0366(16)30409-6

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Language：English  

DOI： 10.1016/S2215-0366(16)30409-6

PubMed

Language：English  

DOI： 10.1016/S2215-0366(16)30409-6

PubMed

Language：English  

DOI： 10.1016/S2215-0366(16)30409-6

PubMed

Language：English  

DOI： 10.1016/S2215-0366(16)30409-6

PubMed

Language：English  

DOI： 10.1016/S2215-0366(16)30409-6

PubMed

DOI： 10.1016/S2215-0366(16)30409-6

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PubMed

DOI： 10.1016/S2215-0366(16)30409-6

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PubMed

DOI： 10.1016/S2215-0366(16)30409-6

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PubMed

DOI： 10.1016/S2215-0366(16)30409-6

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PubMed

DOI： 10.1016/S2215-0366(16)30409-6

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Publisher：(株)学研メディカル秀潤社  

DOI： 10.15105/j01677.2015211569

CiNii Research

Language：Japanese   Publisher：東京 : 先端医学社  

CiNii Research

Language：Japanese   Publisher：東京 : 先端医学社  

CiNii Research

Language：Japanese   Publisher：京都大学霊長類研究所  

CiNii Research

Language：Japanese   Publisher：京都大学霊長類研究所  

CiNii Research

Publisher：Hepato Gastroenterology  

Oncolytic virus therapy is a promising new therapeutic method, one of an eagerly anticipated class of biological therapies against cancer. There are many different classes of oncolytic virus. One of these, herpes oncolytic virus, is strongly oncolytic and has a large DNA genome as 150k bp. HF10 is a spontaneous mutant of herpes simplex virus -1 (HSV-1) that replicates within tumors and destroys cancers without damaging normal tissue and organs. Clinical trials of HF10 are underway in Japan and the United States. The first pilot study of HF10 was initiated in Japan in 2003. This study examined the safety and efficacy of HF10 in the treatment of breast cancer and head and neck cancers; the trial also included careful dose escalation studies. In 2005, a clinical trial using HF10 to treat pancreatic cancer was initiated. screened In this Japanese study, 17 patients received HF10 in their tumor sites. A clinical trial in the United States is also ongoing to evaluate safety, tolerability and evidence of antitumor activity in patients with refractory superficial solid tumors. Here, we report the evaluation of the 17 patients treated in Japan. Among the patients, 6 had recurrent breast cancer, 3 had recurrent head and neck cancer, and 8 had non-resectable pancreatic cancer. No severe adverse side effects have been observed, and some therapeutic potential has been reported based on pathological findings, tumor markers, and diagnostic radiography. Those results should encourage further clinical trials of HF10 around the world.

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Language：Japanese   Publisher：東京 : 先端医学社  

CiNii Research

Language：Japanese   Publisher：京都大学霊長類研究所  

CiNii Research

Language：Japanese   Publisher：京都大学霊長類研究所  

CiNii Research

Language：Japanese   Publisher：東京 : シーエムシー出版  

CiNii Research

Language：Japanese   Publisher：東京 : 先端医学社  

CiNii Research

Language：Japanese   Publisher：東京 : 先端医学社  

CiNii Research

Language：English   Publisher：Tokyo : Springer Nature  

資料形態 : テキストデータ プレーンテキスト

CiNii Research

Language：English   Publisher：Tokyo : Springer Nature  

資料形態 : テキストデータ プレーンテキスト

CiNii Research

Language：English   Publisher：Tokyo : Springer Nature  

資料形態 : テキストデータ プレーンテキスト

CiNii Research

Publisher：Nagoya Journal of Medical Science  

Genetic factors are thought to be involved in the development of treatment-resistant schizophrenia (TRS). Since several antipsychotic drugs inhibit the release of neurotransmitters via the serotonin receptors 3 (5-HT3), a dysfunction of this kind of receptor might be associated with the development of TRS. Thus, single-marker and haplotype analyses of the tag-single nucleotide polymorphisms (SNPs) of the 5-HT3B subunit gene (HTR3B) were performed in TRS (n = 101) and non-TRS (n = 244) patients. The deletion allele at the 3 bp-insertion/deletion polymorphism site (-100_-102delAAG) located in the putative HTR3B promoter region is significantly more frequent in the TRS group than the insertion allele by a single-marker comparison (p = 0.031). In addition, luciferase promoter assays showed that the deletion allele exhibited significantly higher transcriptional activity than the insertion allele in COS7 cells (p < 0.05). These results suggest that HTR3B is involved in the development of TRS in the Japanese population.

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Language：English   Publisher：Tokyo : Springer Nature  

資料形態 : テキストデータ プレーンテキスト

CiNii Research

Language：English   Publisher：Tokyo : Springer Nature  

資料形態 : テキストデータ プレーンテキスト

CiNii Research

Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ime5030077

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DOI： 10.1016/j.clnu.2025.06.011

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DOI： 10.1101/2025.05.08.25327243

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DOI： 10.3390/ime4020013

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

AIM: Autism spectrum disorder (ASD) is a genetically and phenotypically heterogeneous neurodevelopmental disorder with a strong genetic basis. Conducting the first comprehensive whole-genome sequencing (WGS) analysis of Japanese ASD trios, this study aimed to elucidate the clinical significance of pathogenic variants and enhance the understanding of ASD pathogenesis. METHODS: WGS was performed on 57 Japanese patients with ASD and their parents, investigating variants ranging from single-nucleotide variants to structural variants (SVs), short tandem repeats (STRs), mitochondrial variants, and polygenic risk score (PRS). RESULTS: Potentially pathogenic variants that could explain observed phenotypes were identified in 18 patients (31.6%) overall and in 10 of 23 patients (43.5%) with comorbid intellectual developmental disorder (IDD). De novo variants in PTEN, CHD7, and HNRNPH2 were identified in patients referred for genetic counseling who exhibited previously reported phenotypes, including one patient with ASD who had profound IDD and macrocephaly with PTEN L320S. Analysis of the AlphaFold3 protein structure indicated potential inhibition of intramolecular interactions within PTEN. SV analysis identified deletions in ARHGAP11B and TMLHE. A pathogenic de novo mitochondrial variant was identified in a patient with ASD who had a history of encephalitis and cognitive decline. GO enrichment analysis of genes with nonsense variants and missense variants (Missense badness, PolyPhen-2, and Constraint >1) showed associations with regulation of growth and ATP-dependent chromatin remodeler activity. No reportable results were obtained in the analysis of STR and PRS. CONCLUSION: Characterizing the comprehensive genetic architecture and phenotypes of ASD is a fundamental step towards unraveling its complex biology.

DOI： 10.1111/pcn.13767

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DOI： 10.1093/ijnp/pyae059.102

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

DOI： 10.3389/fnins.2025.1542260

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

AIM: Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population. METHODS: Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%. RESULTS: The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05). CONCLUSION: We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD.

DOI： 10.1111/pcn.13752

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

DOI： 10.2147/AMEP.S526211

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Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ime3040038

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

Recent genetic studies have found common genomic risk variants among psychiatric disorders, strongly suggesting the overlaps in their molecular and cellular mechanism. Our research group identified the variant in ASTN2 as one of the candidate risk factors across these psychiatric disorders by whole-genome copy number variation analysis. However, the alterations in the human neuronal cells resulting from ASTN2 variants identified in patients remain unknown. To address this, we used patient-derived and genome-edited iPS cells with ASTN2 deletion; cells were further differentiated into neuronal cells. A comprehensive gene expression analysis using genome-edited iPS cells with variants on both alleles revealed that the expression level of ZNF558, a gene specifically expressed in human forebrain neural progenitor cells, was greatly reduced in ASTN2-deleted neuronal cells. Furthermore, the expression of the mitophagy-related gene SPATA18, which is repressed by ZNF558, and mitophagy activity were increased in ASTN2-deleted neuronal cells. These phenotypes were also detected in neuronal cells differentiated from patient-derived iPS cells with heterozygous ASTN2 deletion. Our results suggest that ASTN2 deletion is related to the common pathogenic mechanism of psychiatric disorders by regulating mitophagy via ZNF558.

DOI： 10.1038/s41398-024-02962-4

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

Psychiatric disorders are highly inheritable, and most psychiatric disorders exhibit genetic overlap. Recent studies associated the 3q29 recurrent deletion with schizophrenia (SCZ) and autism spectrum disorder (ASD). In this study, we investigated the association of genes in the 3q29 region with SCZ and ASD. TM4SF19 and PAK2 were chosen as candidate genes for this study based on evidence from previous research. We sequenced TM4SF19 and PAK2 in 437 SCZ cases, 187 ASD cases and 524 controls in the Japanese population. Through targeted sequencing, we identified 6 missense variants among the cases (ASD & SCZ), 3 missense variants among controls, and 1 variant common to both cases and controls; however, no loss-of-function variants were identified. Fisher's exact test showed a significant association of variants in TM4SF19 among cases (p=0.0160). These results suggest TM4SF19 variants affect the etiology of SCZ and ASD in the Japanese population. Further research examining 3q29 region genes and their association with SCZ and ASD is thus needed.

DOI： 10.18999/nagjms.86.2.216

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

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

Whole genome analysis has identified rare copy number variations (CNV) that are strongly involved in the pathogenesis of psychiatric disorders, and 3q29 deletion has been found to have the largest effect size. The 3q29 deletion mice model (3q29-del mice) has been established as a good pathological model for schizophrenia based on phenotypic analysis; however, circadian rhythm and sleep, which are also closely related to neuropsychiatric disorders, have not been investigated. In this study, our aims were to reevaluate the pathogenesis of 3q29-del by recreating model mice and analyzing their behavior and to identify novel new insights into the temporal activity and temperature fluctuations of the mouse model using a recently developed small implantable accelerometer chip, Nano-tag. We generated 3q29-del mice using genome editing technology and reevaluated common behavioral phenotypes. We next implanted Nano-tag in the abdominal cavity of mice for continuous measurements of long-time activity and body temperature. Our model mice exhibited weight loss similar to that of other mice reported previously. A general behavioral battery test in the model mice revealed phenotypes similar to those observed in mouse models of schizophrenia, including increased rearing frequency. Intraperitoneal implantation of Nano-tag, a miniature acceleration sensor, resulted in hypersensitive and rapid increases in the activity and body temperature of 3q29-del mice upon switching to lights-off condition. Similar to the 3q29-del mice reported previously, these mice are a promising model animals for schizophrenia. Successive quantitative analysis may provide results that could help in treating sleep disorders closely associated with neuropsychiatric disorders.

DOI： 10.1038/s41398-023-02679-w

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Aim: The present study aimed to examine the association between copy number variations (CNVs) in parkin (PRKN) and schizophrenia (SCZ) and autism spectrum disorder (ASD) in a large case–control sample.
Method: Array comparative genomic hybridization was performed on 3111 cases with SCZ, 1236 cases with ASD, and 2713 controls. We systematically prioritized likely pathogenic CNVs (LP-CNVs) in PRKN and examined their association with SCZ and ASD.
Results: In total, 3014 SCZ cases (96.9%), 1205 ASD cases (97.5%), and 2671 controls (98.5%) passed quality control. We found that monoallelic carriers of LP-CNVs in PRKN were common (70/6890, 1.02%) and were not at higher risk of SCZ (p = 0.29) or ASD (p = 0.72). We observed that the distribution pattern of LP-CNVs in the Japanese population was consistent with those in other populations. We also identified a patient diagnosed with SCZ and early-onset Parkinson's disease carrying biallelic pathogenic CNVs in PRKN. The absence of Parkinson's symptoms in 10 other monoallelic carriers of the same pathogenic CNV further reflects the lack of effect of monoallelic pathogenic variants in PRKN in the absence of a second hit.
Conclusion: The present findings suggest that monoallelic CNVs in PRKN do not confer a significant risk for SCZ or ASD. However, further studies to investigate the association between biallelic CNVs in PRKN and SCZ and ASD are warranted.

DOI： 10.1002/npr2.12370

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DOI： 10.1080/10872981.2023.2202459

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DOI： 10.1002/npr2.12340

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DOI： 10.1097/JCP.0000000000001682

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DOI： 10.1007/s00439-023-02569-7

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DOI： 10.1016/j.ajhg.2023.04.008

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BACKGROUND: Chromosome 16p13.11 duplication is a well-known genetic risk factor for schizophrenia (SCZ) (odds ratio = 1.84). However, no case reports focusing on patients with SCZ and 16p13.11 duplication have been published. Therefore, here, we report the detailed clinical cases of four patients with SCZ and 16p13.11 duplication who were identified in our previous whole-genome copy number variant (CNV) study. CASE PRESENTATION: In the four patients with SCZ and 16p13.11 duplication detected by array comparative genomic hybridization, one patient was found to have treatment-resistant SCZ and an additional pathogenic rare CNV. Two of the four patients in this study had environmental risk factors that may have been involved in the development of SCZ. CONCLUSIONS: The results of this case series suggest that a genetic cohort study would be useful for evaluating which genetic and environmental risk factors could better explain the variable expressivity of 16p13.11 duplication. Furthermore, this work could be useful for elucidating the pathophysiology of SCZ.

DOI： 10.1002/npr2.12334

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DOI： 10.1038/s10038-022-01059-4

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DOI： 10.21203/rs.3.rs-2586527/v1

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DOI： 10.1111/pcn.13494

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DOI： 10.1111/pcn.13474

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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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DOI： 10.1111/pcn.13430

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Abstract

Autism spectrum disorder (ASD) is a highly heritable, complex disorder in which rare variants contribute significantly to disease risk. Although many genes have been associated with ASD, there have been few genetic studies of ASD in the Japanese population. In whole exomes from a Japanese ASD sample of 309 cases and 299 controls, rare variants were associated with ASD within specific neurodevelopmental gene sets, including highly constrained genes, fragile X mental retardation protein target genes, and genes involved in synaptic function, with the strongest enrichment in trans-synaptic signaling (p = 4.4 × 10⁻⁴, Q-value = 0.06). In particular, we strengthen the evidence regarding the role of ABCA13, a synaptic function-related gene, in Japanese ASD. The overall results of this case-control exome study showed that rare variants related to synaptic function are associated with ASD susceptibility in the Japanese population.

DOI： 10.1038/s41398-022-02033-6

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Other Link： https://www.nature.com/articles/s41398-022-02033-6

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DOI： 10.1111/pcn.13361

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DOI： 10.1111/pcn.13367

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DOI： 10.1111/appy.12509

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DOI： 10.1097/YPG.0000000000000313

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A number of genomic mutations that are thought to be strongly involved in the development of schizophrenia (SCZ) and autism spectrum disorder (ASD) have been identified. Abnormalities involving oligodendrocytes have been reported in SCZ, and as a related gene, oligodendrocyte lineage transcription factor 2 (OLIG2) has been reported to be strongly associated with SCZ. In this study, based on the common disease-rare variant hypothesis, target sequencing of candidate genes was performed to identify rare mutations with a high effect size and the possibility that the identified mutations may increase the risks of SCZ and ASD in the Japanese population. In this study, the exon region of OLIG2 was targeted; 370 patients with SCZ and 192 with ASD were subjected to next-generation sequencing. As a result, one rare missense mutation (A33T) was detected. We used the Sanger method to validate this missense mutation with a low frequency (<1%), and then carried out a genetic association analysis involving 3299 unrelated individuals (1447 with SCZ, 380 with ASD, and 1472 healthy controls) to clarify whether A33T was associated with SCZ or ASD. A33T was not found in either case group, and in only one control. We did not find evidence that p.A33T is involved in the onset of ASD or SCZ; however, associations with this variant need to be evaluated in larger samples to confirm our results.

DOI： 10.18999/nagjms.84.2.260

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DOI： 10.1111/pcn.13329

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DOI： 10.1111/pcn.13324

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Several large-scale whole-exome sequencing studies in patients with schizophrenia (SCZ) and autism spectrum disorder (ASD) have identified rare variants with modest or strong effect size as genetic risk factors. Dysregulation of cellular calcium homeostasis might be involved in SCZ/ASD pathogenesis, and genes encoding L-type voltage-gated calcium channel (VGCC) subunits Cav1.1 (CACNA1S), Cav1.2 (CACNA1C), Cav1.3 (CACNA1D), and T-type VGCC subunit Cav3.3 (CACNA1I) recently were identified as risk loci for psychiatric disorders. We performed a screening study, using the Ion Torrent Personal Genome Machine (PGM), of exon regions of these four candidate genes (CACNA1C, CACNA1D, CACNA1S, CACNA1I) in 370 Japanese patients with SCZ and 192 with ASD. Variant filtering was applied to identify biologically relevant mutations that were not registered in the dbSNP database or that have a minor allele frequency of less than 1% in East-Asian samples from databases; and are potentially disruptive, including nonsense, frameshift, canonical splicing site single nucleotide variants (SNVs), and non-synonymous SNVs predicted as damaging by five different in silico analyses. Each of these filtered mutations were confirmed by Sanger sequencing. If parental samples were available, segregation analysis was employed for measuring the inheritance pattern. Using our filter, we discovered one nonsense SNV (p.C1451* in CACNA1D), one de novo SNV (p.A36V in CACNA1C), one rare short deletion (p.E1675del in CACNA1D), and 14 NSstrict SNVs (non-synonymous SNV predicted as damaging by all of five in silico analyses). Neither p.A36V in CACNA1C nor p.C1451* in CACNA1D were found in 1871 SCZ cases, 380 ASD cases, or 1916 healthy controls in the independent sample set, suggesting that these SNVs might be ultra-rare SNVs in the Japanese population. The neuronal splicing isoform of Cav1.2 with the p.A36V mutation, discovered in the present study, showed reduced Ca2+-dependent inhibition, resulting in excessive Ca2+ entry through the mutant channel. These results suggested that this de novo SNV in CACNA1C might predispose to SCZ by affecting Ca2+ homeostasis. Thus, our analysis successfully identified several ultra-rare and potentially disruptive gene variants, lending partial support to the hypothesis that VGCC-encoding genes may contribute to the risk of SCZ/ASD.

DOI： 10.1038/s41398-022-01851-y

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DOI： 10.1080/09540261.2022.2072193

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DOI： 10.1111/pcn.13309

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Background

Most sequencing studies of schizophrenia (SCZ) have focused on de novo genetic variants due to interpretability. However, investigating shared rare variants among patients in the same multiplex family is also important. Relatively large-scale analyses of SCZ multiplex families have been done in Caucasian populations, but whether detected variants are also pathogenic in the Japanese population is unclear because of ethnic differences in rare variants.

Materials and methods

We performed whole-exome sequencing (WES) of 14 Japanese SCZ multiplex families. After quality control and filtering, we identified rare variants shared among affected persons within the same family. A gene ontology (GO) analysis was performed to identify gene categories possibly affected by these candidate variants.

Results

We found 530 variants in 486 genes as potential candidate variants from the 14 SCZ multiplex families examined. The GO analysis demonstrated significant enrichment in calcium channel activity.

Conclusion

This study provides supporting evidence that calcium ion channel activity is involved in SCZ. WES of multiplex families is a potential means of identifying disease-associated rare variants for SCZ.

DOI： 10.1371/journal.pone.0268321

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DOI： 10.1007/s00787-021-01788-5

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DOI： 10.1016/j.neures.2020.11.008

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DOI： 10.2147/AMEP.S333958

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<title>Abstract</title>Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (<italic>KDM4C</italic>) have been suggested to confer a risk for such disorders. However, rare genetic variants in <italic>KDM4C</italic> have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in <italic>KDM4C</italic> and SCZ (<italic>p</italic> = 0.003) and ASD (<italic>p</italic> = 0.04). We also observed a significant association between deletions in <italic>KDM4C</italic> and SCZ (corrected <italic>p</italic> = 0.04). Next, to explore the contribution of single nucleotide variants in <italic>KDM4C</italic>, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with <italic>KDM4C</italic> deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between <italic>KDM4C</italic> CNVs and these two disorders and for their potential functional effect on histone methylation patterns.

DOI： 10.1038/s41398-020-01107-7

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DOI： 10.1038/s41439-020-00125-7

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<title>Abstract</title>
<sec>
<title>Background</title>
Rare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in <italic>NRXN1</italic>, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ.


</sec>
<sec>
<title>Methods</title>
To discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced <italic>NRXN1</italic> coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detected here on cell surface expression, interaction with NLGN1, and synaptogenic activity was analyzed using an in vitro functional assay and in silico three-dimensional (3D) structural modeling.


</sec>
<sec>
<title>Results</title>
Through mutation screening, we regarded three ultra-rare missense variants (T737M, D772G, and R856W), all of which affected the LNS4 domain of <italic>NRXN1</italic>α isoform<italic>,</italic> as disease-associated variants. Diagnosis of individuals with T737M, D772G, and R856W was 1ASD and 1SCZ, 1ASD, and 1SCZ, respectively. We observed the following phenotypic and functional burden caused by each variant. (i) D772G and R856W carriers had more serious social disabilities than T737M carriers. (ii) In vitro assay showed reduced cell surface expression of NRXN1α by D772G and R856W mutations. In vitro functional analysis showed decreased NRXN1α-NLGN1 interaction of T737M and D772G mutants. (iii) In silico 3D structural modeling indicated that T737M and D772G mutations could destabilize the rod-shaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal.


</sec>
<sec>
<title>Conclusions</title>
The combined data suggest that missense variants in <italic>NRXN1</italic> could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ.


</sec>

DOI： 10.1186/s11689-020-09325-2

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An amendment to this paper has been published and can be accessed via a link at the top of the paper.

DOI： 10.1038/s41593-020-0681-z

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Language：Japanese   Publisher：日本神経精神薬理学会・日本生物学的精神医学会・日本精神薬学会  

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Schizophrenia (SCZ) is known to be a heritable disorder; however, its multifactorial nature has significantly hampered attempts to establish its pathogenesis. Therefore, in this study, we performed genome-wide copy-number variation (CNV) analysis of 2940 patients with SCZ and 2402 control subjects and identified a statistically significant association between SCZ and exonic CNVs in the ARHGAP10 gene. ARHGAP10 encodes a member of the RhoGAP superfamily of proteins that is involved in small GTPase signaling. This signaling pathway is one of the SCZ-associated pathways and may contribute to neural development and function. However, the ARHGAP10 gene is often confused with ARHGAP21, thus, the significance of ARHGAP10 in the molecular pathology of SCZ, including the expression profile of the ARHGAP10 protein, remains poorly understood. To address this issue, we focused on one patient identified to have both an exonic deletion and a missense variant (p.S490P) in ARHGAP10. The missense variant was found to be located in the RhoGAP domain and was determined to be relevant to the association between ARHGAP10 and the active form of RhoA. We evaluated ARHGAP10 protein expression in the brains of reporter mice and generated a mouse model to mimic the patient case. The model exhibited abnormal emotional behaviors, along with reduced spine density in the medial prefrontal cortex (mPFC). In addition, primary cultured neurons prepared from the mouse model brain exhibited immature neurites in vitro. Furthermore, we established induced pluripotent stem cells (iPSCs) from this patient, and differentiated them into tyrosine hydroxylase (TH)-positive neurons in order to analyze their morphological phenotypes. TH-positive neurons differentiated from the patient-derived iPSCs exhibited severe defects in both neurite length and branch number; these defects were restored by the addition of the Rho-kinase inhibitor, Y-27632. Collectively, our findings suggest that rare ARHGAP10 variants may be genetically and biologically associated with SCZ and indicate that Rho signaling represents a promising drug discovery target for SCZ treatment.

DOI： 10.1038/s41398-020-00917-z

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OBJECTIVE: Neurodevelopmental disorders (NDDs) often associate with epilepsy or craniofacial malformations. Recent large-scale DNA analyses identified hundreds of candidate genes for NDDs, but a large portion of the cases still remain unexplained. We aimed to identify novel candidate genes for NDDs. METHODS: We performed exome sequencing of 95 patients with NDDs including 51 with trigonocephaly and subsequent targeted sequencing of additional 463 NDD patients, functional analyses of variant in vitro, and evaluations of autism spectrum disorder (ASD)-like phenotypes and seizure-related phenotypes in vivo. RESULTS: We identified de novo truncation variants in nine novel genes; CYP1A1, C14orf119, FLI1, CYB5R4, SEL1L2, RAB11FIP2, ZMYND8, ZNF143, and MSX2. MSX2 variants have been described in patients with cranial malformations, and our present patient with the MSX2 de novo truncation variant showed cranial meningocele and partial epilepsy. MSX2 protein is known to be ubiquitinated by an E3 ubiquitin ligase PJA1, and interestingly we found a PJA1 hemizygous p.Arg376Cys variant recurrently in seven Japanese NDD patients; five with trigonocephaly and one with partial epilepsy, and the variant was absent in 886 Japanese control individuals. Pja1 knock-in mice carrying p.Arg365Cys, which is equivalent to p.Arg376Cys in human, showed a significant decrease in PJA1 protein amount, suggesting a loss-of-function effect of the variant. Pja1 knockout mice displayed moderate deficits in isolation-induced ultrasonic vocalizations and increased seizure susceptibility to pentylenetetrazole. INTERPRETATION: These findings propose novel candidate genes including PJA1 and MSX2 for NDDs associated with craniofacial abnormalities and/or epilepsy.

DOI： 10.1002/acn3.51093

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INTRODUCTION: A history of major depressive disorder before pregnancy is one risk factor for peripartum depression. Therefore, the purpose of the present study was to examine the validation and factor structure of the Japanese version of the Inventory to Diagnose Depression, Lifetime version (IDDL) for pregnant women. METHODS: The study participants were 556 pregnant women. Factor analysis was performed to identify the factor structure, construct validity was examined based on the results of the factor analysis, and reliability was examined using Cronbach's α coefficient. RESULTS: Based on the results of the factor analysis of the IDDL, a bifactor model composed of a single general dimension along with the following five factors was extracted: (1) depression, anxiety, and irritability (items 1, 2, 8-10, and 19-21); (2) retardation, decreased concentration, indecisiveness, and insomnia (items 4, 11, 12, and 17); (3) decrease in appetite/significant weight loss (items 13 and 14); (4) increase in appetite/significant weight gain (items 15 and 16); and (5) diminished interest, pleasure, and libido (items 5-7). Cronbach's α coefficients for these five factors were as follows: 0.910, 0.815, 0.780, 0.683, and 0.803, respectively. CONCLUSIONS: The reliability, construct validity, and factor structure of the Japanese version of the IDDL were confirmed in pregnant women.

DOI： 10.1371/journal.pone.0234240

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Introduction: The aim of the present study was to elucidate the foreseeable risk factors for suicidal ideation among Japanese perinatal women. Methods: This cohort study was conducted in Nagoya, Japan, from July 2012 to March 2018. The Edinburgh Postnatal Depression Scale (EPDS) questionnaire was conducted at four time points: early pregnancy, late pregnancy, 5 days postpartum, and 1 month postpartum. A total of 430 women completed the questionnaires. A logistic regression analysis was performed using the presence of suicidal ideation on the EPDS as an objective variable. The explanatory variables were age, presence of physical or mental disease, smoking and drinking habits, education, hospital types, EPDS total score in early pregnancy, bonding, and quality and amount of social support, as well as the history of major depressive disorder (MDD). Results: The rate of participants who were suspected of having suicidal ideation at any of the four time points was 11.6% (n=52), with the highest (n=25, 5.8%) at late pregnancy. For suicidal ideation, education level (OR: 1.19; 95% CI: 1.00-1.41; p=0.047), EPDS total points in the pregnancy period (OR: 1.25; 95% CI: 1.16-1.34; p < 0.000), a history of MDD (OR: 2.16; 95% CI: 1.00-4.79; p=0.049), and presence of mental disease (OR: 2.39; 95% CI: 1.00-5.70; p=0.049) were found to be risk factors for suicidal ideation. Age [odds ratio (OR): 0.88; 95% confidence interval (CI): 0.80-0.95; p=.002] and quality of social support (OR: 0.77; 95% CI: 0.60-0.99; p=.041) were found to be protective factors. Conclusion: Based on these results, effective preventive interventions, such as increasing the quality of social support and confirming the history of depression, should be carried out in pregnant depressive women at the early stage of the perinatal period.

DOI： 10.3389/fpsyt.2020.00441

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AIM: A Japanese individual with schizophrenia harboring a novel exonic deletion in RELN was recently identified by genome-wide copy-number variation analysis. Thus, the present study aimed to generate and analyze a model mouse to clarify whether Reln deficiency is associated with the pathogenesis of schizophrenia. METHODS: A mouse line with a novel RELN exonic deletion (Reln-del) was established using the CRISPR/Cas9 method to elucidate the underlying molecular mechanism. Subsequently, general behavioral tests and histopathological examinations of the model mice were conducted and phenotypic analysis of the cerebellar granule cell migration was performed. RESULTS: The phenotype of homozygous Reln-del mice was similar to that of reeler mice with cerebellar atrophy, dysplasia of the cerebral layers, and abrogated protein levels of cerebral reelin. The expression of reelin in heterozygous Reln-del mice was approximately half of that in wild-type mice. Conversely, behavioral analyses in heterozygous Reln-del mice without cerebellar atrophy or dysplasia showed abnormal social novelty in the three-chamber social interaction test. In vitro reaggregation formation and neuronal migration were severely altered in the cerebellar cultures of homozygous Reln-del mice. CONCLUSION: The present results in novel Reln-del mice modeled after our patient with a novel exonic deletion in RELN are expected to contribute to the development of reelin-based therapies for schizophrenia.

DOI： 10.1111/pcn.12993

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BACKGROUND: This paper is a systematic review and meta-analysis of the efficacy of available medications for the treatment of restricted/repetitive behavior (RRBs) in Autism Spectrum Disorder (ASD). METHOD: We searched MEDLINE, Embase, PsycINFO, The Cochrane Library (Cochrane Database of Systematic Reviews (CDRS), the Cochrane Central Register of Controlled Trials (CENTRAL), database of Abstracts of Reviews of Effects (DARE)), Scopus, Epistimonikos, Clinicaltrials.gov, and included all randomized controlled trials published after 1993 that were directed at RRBs in patients with ASD of all ages. We extracted the relevant data from the published studies with a predefined data extraction form and assessed the risk of bias. The primary outcomes were change in restricted/repetitive behavior. We performed a meta-analysis using the random effect model and included studies with given mean and standard deviation. This study is registered with PROSPERO number CRD42018092660). RESULTS: We identified 14 randomized controlled trials that met initial inclusion criteria. After closer inspection, nine trials - involving 552 patients in total - were included in the final analysis. The meta-analysis found no significant difference between medications (including fluvoxamine, risperidone, fluoxetine, citalopram, oxytocin, N-Acetylcysteine, buspirone) and placebo in the treatment of RRBs in ASD (P = 0.20). Similarly, the sub-group meta-analysis also showed no significant difference between Selective Serotonin Reuptake Inhibitor (SSRIs) and placebo in the treatment of RRBs in ASD (P = 0.68). There was no evidence of publication bias. CONCLUSION: This meta-analysis finds little support for the routine use of medications to treat restricted/repetitive behaviors in Autism Spectrum Disorder. Further research of large, balanced trials with precise assessment tools and long-term follow-up are needed. TRIAL REGISTRATION: The study protocol is registered in PROSPERO (Reference number: CRD42018092660).

DOI： 10.1186/s12888-020-2477-9

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DOI： 10.1016/j.cell.2019.12.036

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Genetic studies have identified rare RELN variants as risk factors for psychiatric disorders. However, additional genetic factors appear to be necessary for disease onset. Detailed genetic information and the use of patient-derived neuronal cells may thus enable to discover these disease-related additional factors. Here, we performed whole-genome sequencing of a schizophrenia patient with a rare RELN deletion and his healthy mother, and examined the phenotypes of 3D-cultured neuronal cells derived from induced pluripotent stem cells of this patient. Our results revealed that, along with the RELN deletion, neuronal death was promoted in this patient; thus, neuronal death may be a vulnerable factor for schizophrenia.

DOI： 10.1016/j.schres.2019.10.038

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Background: The Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) is a multidimensional rating scale designed for the fast, easy and reliable assessment of extrapyramidal symptoms (EPSs) induced by antipsychotics. Aim: The aim of this study was to validate the level of inter-rater and test-retest reliability of the Norwegian translation of this scale. Methods: A total of 125 video clips showing a variety of or no signs of EPSs were used in the present study. The participants recorded were Japanese psychiatric patients receiving first- and/or second-generation antipsychotics. A total of 103 patients (47 males and 56 females), diagnosed with schizophrenia (n = 68) or mood disorders (n = 35) appeared in the video clips. Their mean age was 48.7 ± 16.3 years (range 18-80) at the time of video recording. Inter-rater agreement was assessed with five raters and test-retest reliability with three. Results: Inter-rater reliability analyses showed interclass correlation coefficients (ICCs) ranging from 0.74 to 0.93 for each individual item. Test-retest reliability analysed independently for each rater ranged from 0.71 to 0.96. Conclusions: Inter-rater and test-retest agreement exhibited satisfactory ICC levels above 0.70. The Norwegian version of the DIEPSS is a reliable instrument for the assessment of drug-induced EPSs.

DOI： 10.1080/08039488.2019.1665708

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DOI： 10.1016/j.euroneuro.2019.08.099

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Introduction: The relationship between perinatal depressive symptoms, harm avoidance (HA), and a history of major depressive disorder (MDD) was examined in a prospective cohort study. Methods: This study was conducted from May 1, 2011, to December 31, 2016. A history of MDD was evaluated using the Inventory to Diagnose Depression, Lifetime version during pregnancy. Depressive state and HA were evaluated during pregnancy and at 1 month postnatal using the Edinburgh Postnatal Depression Scale (EPDS) and Temperament and Character Inventory, respectively. The relationship between these variances was examined using structural equation modeling. Results: A total of 338 participants with complete data were included in the present study. Pregnant women with compared with those without a history of MDD were observed to have a significantly higher intensity of HA and more severe depressive symptoms in both the prenatal and postnatal periods. A history of MDD affected the severity of depressive symptoms [standardized path coefficient (SPC) = 0.25, p < 0.001] and the intensity of HA during pregnancy (SPC = 0.36, p < 0.001). The intensity of HA during pregnancy affected that at 1 month postnatal (SPC = 0.78, p < 0.001), while the severity of depressive symptoms as assessed by the EPDS during pregnancy affected that at 1 month postnatal (SPC = 0.41, p < 0.001). The SPC for perinatal HA to postnatal depressive symptoms (SPC = 0.13, p = 0.014) was significant and higher than that for perinatal depressive symptoms to postnatal HA (SPC = 0.06, p = 0.087). Conclusion: The present results suggest that early intervention in pregnant women with a history of MDD or a high intensity of HA is important to prevent postnatal depressive symptoms.

DOI： 10.3389/fpsyt.2019.00515

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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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BACKGROUND: Postpartum depression (PPD) is a major depressive disorder that occurs after childbirth. Objective diagnostic and predictive methods for PPD are important for early detection and appropriate intervention. DNA methylation has been recognized as a potential biomarker for major depressive disorder. In this study, we used methylation analysis and peripheral blood to search for biomarkers that could to lead to the development a predictive method for PPD. METHODS: Study participants included 36 pregnant women (18 cases and 18 controls determined after childbirth). Genome-wide DNA methylation profiles were obtained by analysis with an Infinium Human Methylation 450BeadChip. The association of DNA methylation status at each DNA methylation site with PPD was assessed using linear regression analysis. We also conducted functional enrichment analysis of PPD using The Database for Annotation, Visualization and Integrated Discovery 6.8 to explore enriched functional-related gene groups for PPD. RESULTS: In the analysis with postpartum depressed state as an independent variable, the difference in methylation frequency between the postpartum non-depressed group and the postpartum depressed group was small, and sites with genome-wide significant differences were not confirmed. After analysis by The Database for Annotation, Visualization and Integrated Discovery 6.8, we revealed four gene ontology terms, including axon guidance, related to postpartum depression. CONCLUSIONS: These findings may help with the development of an objective predictive method for PPD.

DOI： 10.1186/s12888-019-2172-x

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

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BACKGROUND: New classification system Diagnostic and statistical manual of mental disorders. 5th ed.(DSM - 5) includes sensory problems as one of the symptoms in diagnostic profile of Autism Spectrum Disorder (ASD). Researching the effects of sensory integration treatment may improve new approaches to the individuals with ASD. The objective of this study is to determine the effects of Snoezelen, multisensory environment on the severity of ASD and stereotyped/repetitive behaviours in adolescents and adults using CARS scale. METHOD: The study involved 40 subjects with ASD associated with intellectual difficulties of both sexes, aged 15-35. The subjects were randomly divided into two groups: a control one (without treatment) and an experimental one (with treatment). The assessments were rated by CARS (Childhood Autism Rating Scale) before and after the three-month treatment. RESULTS: In the experimental group, there was a statistically significant difference of the total CARS score before and after the treatment (p < 0.0005). Comparing the results of both experimental and control groups, a statistically significant difference was found on total CARS score (p < 0.0005). Conslusion: The results in the present study indicate that the continual sessions in Snoezelen room had effects on reducing severity of ASD and repetitive and stereotyped behaviours on CARS scale.

DOI： 10.1016/j.ridd.2019.03.007

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

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The original Article required a few updates; one co-author name, which was given as Hiroki Kiumura, has been updated to Hiroki Kimura. Furthermore, supplementary information has been updated, and grant numbers have been added. These updates have been made to both the PDF and HTML versions of this Article.

DOI： 10.1038/s41398-019-0479-5

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Majority of head and neck cancer (HNC) patients are male, and more than 85% of patients with HNC have the habit of smoking and drinking. Due to the specific demographic characteristics, HNC patients are anticipated to have specific coping styles, affecting psychological distress, survival, and quality of life. We explored the subscales of the Mental Adjustment to Cancer (MAC) Scale in male patients with HNC, and then examined the correlation between revised subscales of the MAC scale and anxiety/depression. Participants were 150 male inpatients with HNC, and their demographic and medical data were obtained. Coping style was assessed by MAC scale. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Out of 40 items in the original MAC scale, 19 items were excluded by factor analysis, and the remaining 21 items were divided into three factors: Negative Adjustment, Positive Adjustment, and Abandonment. Negative and Positive Adjustments were similar to the copings of mixed gender patients with heterogeneous cancers, and Abandonment was a new subscale specific to male patients with HNC. This subscale had a weak positive correlation with anxiety and depression. Male HNC patients revealed a specific coping style of Abandonment, related with psychological distress. We believe that an understanding of the Abandonment coping style revealed in our study will improve the psychological support offered to male patients with HNC.

DOI： 10.18999/nagjms.81.2.249

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In a world of increasing academic mobility, most universities seek to give their students opportunities to experience education in different countries, which is especially true for senior research students. The Nagoya University Graduate School of Medicine started a joint degree program (JDP) for PhD students with the University of Adelaide, Faculty of Health Science (Australia) in 2015 and with Lund University Faculty of Medicine (Sweden) in 2017. Furthermore, we have started a new JDP with the University of Freiburg, Faculty of Medicine (Germany) in 2018. This article reports the issues specific to counterpart medical schools, including student’s recruitment, the curriculum, and the general differences between each schools. JDPs are not only important for educational collaboration, but also as a strategy to encourage international research collaboration, which is a core criterion to a university’s world-ranking reputation. Acquiring knowledge about educational strategies that are implemented in different foreign medical schools represents a unique opportunity to improve our own curriculum.

DOI： 10.18999/nagjms.81.2.183

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Although a number of studies have identified several convincing candidate genes or molecules, the pathophysiology of schizophrenia (SCZ) has not been completely elucidated. Therapeutic optimization based on pathophysiology should be performed as early as possible to improve functional outcomes and prognosis; to detect useful biomarkers for SCZ, which reflect pathophysiology and can be utilized for timely diagnosis and effective therapy. To explore biomarkers for SCZ, we employed fluorescence two-dimensional differential gel electrophoresis (2D-DIGE) of lymphoblastoid cell lines (LCLs) (1st sample set: 30 SCZ and 30 CON). Differentially expressed proteins were sequenced by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and identified proteins were confirmed by western blotting (WB) (1st and 2nd sample set: 60 SCZ and 60 CON). Multivariate logistic regression analysis was performed to identify an optimal combination of biomarkers to create a prediction model for SCZ. Twenty protein spots were differentially expressed between SCZ and CON in 2D-DIGE analysis and 22 unique proteins were identified by LC-MS/MS. Differential expression of eight of 22 proteins was confirmed by WB. Among the eight candidate proteins (HSPA4L, MX1, GLRX3, UROD, MAPRE1, TBCB, IGHM, and GART), we successfully constructed logistic regression models comprised of 4- and 6-markers with good discriminative ability between SCZ and CON. In both WB and gene expression analysis of LCL, MX1 showed reproducibly significant associations. Moreover, Mx1 and its related proinflamatory genes (Mx2, Il1b, and Tnf) were also up-regulated in poly I:C-treated mice. Differentially expressed proteins might be associated with molecular pathophysiology of SCZ, including dysregulation of immunological reactions and potentially provide diagnostic and prognostic biomarkers.

DOI： 10.1038/s41398-019-0461-2

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DOI： 10.1016/j.euroneuro.2018.08.490

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DOI： 10.1016/j.euroneuro.2017.08.415

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DOI： 10.1016/j.euroneuro.2017.08.085

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Early detection of perinatal depression is an urgent issue. Our study aimed to examine the construct validity and factor structure of the Japanese version of the Edinburgh Postnatal Depression Scale (EPDS) from a prospective cohort study from pregnancy to postpartum. A total of 1075 women completed all items of the EPDS at four time points: early pregnancy, late pregnancy, 5 days postpartum and 1 month postpartum. The participants were randomly divided into two sample sets. The first sample set (n = 304) was used for exploratory factor analysis, and the second sample set (n = 771) was used for confirmatory factor analysis. As a result, the Cronbach's alpha coefficients of the EPDS items were 0.762, 0.740, 0.765 and 0.772 at the four time points. From the confirmatory factor analysis of the EPDS in a sample set of Japanese women from pregnancy to postpartum, the following three factors were detected: depression (items 7, 9), anxiety (items 4, 5) and anhedonia (items 1, 2). In conclusion, the EPDS is a useful rating scale, and its factor structure is consistently stable during the whole peripartum period.

DOI： 10.1038/s41598-018-36101-z

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Myelinated axons segregate the axonal membrane into four defined regions: the node of Ranvier, paranode, juxtaparanode, and internode. The paranodal junction consists of specific component proteins, such as neurofascin155 (NF155) on the glial side, and Caspr and Contactin on the axonal side. Although paranodal junctions are thought to play crucial roles in rapid saltatory conduction and nodal assembly, the role of their interaction with neurons is not fully understood. In a previous study, conditional NF155 knockout in oligodendrocytes led to disorganization of the paranodal junctions. To examine if disruption of paranodal junctions affects neuronal gene expression, we prepared total RNA from the retina of NF155 conditional knockout, and performed expression analysis. We found that the expression level of 433 genes changed in response to paranodal junction ablation. Interestingly, expression of aquaporin 3 (AQP3) was significantly reduced in NF155 conditional knockout mice, but not in cerebroside sulfotransferase knockout (CST-KO) mice, whose paranodes are not originally formed during development. Copy number variations have an important role in the etiology of schizophrenia (SCZ). We observed rare duplications of AQP3 in SCZ patients, suggesting a correlation between abnormal AQP3 expression and SCZ. To determine if AQP3 over-expression in NF155 conditional knockout mice influences neuronal function, we performed adeno-associated virus (AAV)-mediated over-expression of AQP3 in the motor cortex of mice and found a significant increase in caspase 3-dependent neuronal apoptosis in AQP3-transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP3 expression, which is associated with paranodal disruption.

DOI： 10.1111/jnc.14553

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Oncolytic viral therapy has been accepted as a standard immunotherapy since talimogene laherparepvec (T-VEC, Imlygic®) was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for melanoma treatment in 2015. Various oncolytic viruses (OVs), such as HF10 (Canerpaturev-C-REV) and CVA21 (CAVATAK), are now actively being developed in phase II as monotherapies, or in combination with immune checkpoint inhibitors against melanoma. Moreover, in glioma, several OVs have clearly demonstrated both safety and a promising efficacy in the phase I clinical trials. Additionally, the safety of several OVs, such as pelareorep (Reolysin®), proved their safety and efficacy in combination with paclitaxel in breast cancer patients, but the outcomes of OVs as monotherapy against breast cancer have not provided a clear therapeutic strategy for OVs. The clinical trials of OVs against pancreatic cancer have not yet demonstrated efficacy as either monotherapy or as part of combination therapy. However, there are several oncolytic viruses that have successfully proved their efficacy in different preclinical models. In this review, we mainly focused on the oncolytic viruses that transitioned into clinical trials against melanoma, glioma, pancreatic, and breast cancers. Hence, we described the current status and future prospects of OVs clinical trials against melanoma, glioma, pancreatic, and breast cancers.

DOI： 10.3390/cancers10100356

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Enhanced carbonyl stress has been observed in a subgroup of patients with schizophrenia. Glyoxalase I, which is encoded by GLO1, is an enzyme that protects against carbonyl stress. In this study, we focused on the association between rare genetic variants of GLO1 and schizophrenia. First, we identified one heterozygous frameshift variant, p.P122fs, in 370 Japanese schizophrenia cases with allele frequencies of up to 1% by exon-targeted mutation screening of GLO1. We then performed an association analysis on 1282 cases and 1764 controls with this variant. The variant was found in three cases and eight controls. There was no statistically significant association between p.P122fs in GLO1 and schizophrenia (P=0.25). This frameshift variant in GLO1 might occur at near-polymorphic frequencies in the Japanese population, although further investigations using larger samples and biological analyses are needed to exclude the possibility of a low-penetrance genetic risk associated with this variant.

DOI： 10.1097/YPG.0000000000000204

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BACKGROUND: Although previous studies have reported associations between bonding failure, depression, social support among mothers, and perceived rearing, the causal relationships remain unclear. METHODS: A total of 855 women (mean age, 32.4 ± 4.4 years) completed the Mother-Infant Bonding Questionnaire (MIBQ), the Edinburgh Postnatal Depression Scale (EPDS), the Japanese version of the Social Support Questionnaire, and the Parental Bonding Instrument in early pregnancy before week 25 (T1) and at 1 month after delivery (T2). We created a path model to clarify the causal relationships between perinatal bonding failure, depression, social support, and perceived rearing during pregnancy and at 1 month after delivery. The model was tested using structural equation modeling. RESULTS: Our recursive model showed acceptable fit (chi-squared statistic/degree of freedom = 2.1, comparative fit index = 0.98, root mean square error of approximation = 0.04). It was revealed that: (1) at T1, higher overprotection significantly predicted MIBQ scores; (2) at T1, poorer social support significantly predicted both MIBQ and EPDS scores; and (3) at T1, both MIBQ and EPDS scores significantly predicted respective scores at T2. CONCLUSIONS: These results showed that bonding failure in the postpartum period was significantly influenced by mothers' own perceived rearing and social support during pregnancy. In addition, depression in the postpartum period was strongly influenced by social support during pregnancy. These findings suggest that psychosocial interventions that focus on both mothers' recollections of their own upbringing and social support during pregnancy are effective for preventing bonding failure and depression in the postpartum period.

DOI： 10.1016/j.jpsychires.2018.09.001

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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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Resting-state (rs) functional magnetic resonance imaging (fMRI) studies have revealed dysfunctional thalamocortical functional connectivity (FC) in schizophrenia. However, the relationship between thalamocortical FC and cognitive impairment has not been thoroughly investigated. We hypothesized that aberrant thalamocortical FC is related to attention deficits in schizophrenia. Thirty-eight patients with schizophrenia and 38 matched healthy controls underwent rs-fMRI and task fMRI while performing a Flanker task. We observed decreased left thalamic activation in patients with schizophrenia using task fMRI to determine the thalamic seed. A seed-based analysis using this seed was performed in the whole brain to assess differences in thalamocortical FC between the groups. Significantly worse performance was observed in the patient group. The rs-fMRI analysis revealed significantly increased FC between the left thalamus seed and the occipital cortices/postcentral gyri in patients when compared to controls. In the patient group, significant positive correlations were observed between the degree of FC from the left thalamus to the bilateral occipital gyri, which correspond to the visual cortex, and the Flanker effect. No significant correlation was detected in the control group. These results indicate that aberrant FC between the left thalamus and the visual cortex is related to attention deficits in schizophrenia.

DOI： 10.1016/j.pscychresns.2018.06.007

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Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.

DOI： 10.1038/s41598-018-31390-w

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This study aimed to assess the situation of postpartum depression and maternal bonding in Nagoya, a city distant from the epicenter of the Great East Japan Earthquake that occurred on March 11, 2011. Among the participants at 1 month after childbirth between March 11, 2010 and March 10, 2013 (n = 188), 152 fully responded to the Edinburgh Postnatal Depression Scale (EPDS) and Mother-Infant Bonding Questionnaire (MIBQ). They were divided into pre-quake (n = 58), and 0-6, 6-12, 12-18, and 18-24 months after the earthquake groups (n = 20, 26, 29, and 19, respectively). The rate of mothers who scored above the cutoff point for the EPDS increased from 12.1% in the pre-quake to 35.0% in the 0-6 months group (p = 0.022). The EPDS total and anxiety subscale scores (mean ± standard error) were also significantly different between the pre-quake and 0-6 months after the earthquake groups (4.45 ± 0.50 vs. 7.95 ± 1.47, p = 0.024; 2.16 ± 0.26 vs. 3.65 ± 0.57, p = 0.021, respectively). The EPDS total and anxiety scores were the highest for the 0-6 months group, followed by the 6-12, 12-18, 18-24 months groups (p = 0.019, p = 0.022). MIBQ scores did not differ between the pre-quake and 0-6 months groups. Depressive symptoms, mainly explained by anxiety, increased after the earthquake with no changes in maternal bonding.

DOI： 10.1038/s41598-018-30065-w

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Reelin is a protein encoded by the RELN gene that controls neuronal migration in the developing brain. Human genetic studies suggest that rare RELN variants confer susceptibility to mental disorders such as schizophrenia. However, it remains unknown what effects rare RELN variants have on human neuronal cells. To this end, the analysis of human neuronal dynamics at the single-cell level is necessary. In this study, we generated human-induced pluripotent stem cells carrying a rare RELN variant (RELN-del) using targeted genome editing; cells were further differentiated into highly homogeneous dopaminergic neurons. Our results indicated that RELN-del triggered an impaired reelin signal and decreased the expression levels of genes relevant for cell movement in human neurons. Single-cell trajectory analysis revealed that control neurons possessed directional migration even in vitro, while RELN-del neurons demonstrated a wandering type of migration. We further confirmed these phenotypes in neurons derived from a patient carrying the congenital RELN-del. To our knowledge, this is the first report of the biological significance of a rare RELN variant in human neurons based on individual neuron dynamics. Collectively, our approach should be useful for studying reelin function and evaluating mental disorder susceptibility, focusing on individual human neuronal migration.

DOI： 10.1038/s41398-018-0177-8

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AIM: Although the effects of psychotropics on driving ability have received much attention, little research is available on driving performance of stable outpatients with depression undergoing real-world treatment. This observational study investigated driving performance, cognitive functions, and depressive symptomatology of partly remitted outpatients with depression under daily-practice psychopharmacologic treatment. METHODS: Seventy stable outpatients with depression and 67 healthy volunteers were enrolled. Patients' prescriptions were not controlled in order to capture the real-world treatment environment. Participants underwent three driving tasks - road-tracking, car-following, and harsh-braking - using a driving simulator, and three cognitive tasks - Continuous Performance Test, Wisconsin Card Sorting Test, and Trail-Making Test. The Symptom Assessment Scale - Structured Interview Guide for the Hamilton Depression Rating Scale, Beck Depression Inventory-II, Social Adaptation Self-Evaluation Scale, and Stanford Sleepiness Scale were also completed. RESULTS: Although many patients received various pharmacologic treatments, there were no significant differences in the three driving tasks between outpatients with depression and healthy controls. Difficulty of maintaining set in the Wisconsin Card Sorting Test was significantly increased in patients with depression. Results on the Social Adaptation Self-Evaluation Scale were significantly associated with road-tracking and car-following performance, in contrast to results on the Hamilton Depression Rating Scale and the Beck Depression Inventory-II. CONCLUSION: We conclude that partly remitted depressive patients under steady-state pharmacologic treatment do not differ from healthy controls with respect to driving performance, which seems to be more affected by psychosocial functioning than by pharmacologic agents. This, however, should be investigated systematically in an off/on study.

DOI： 10.1111/pcn.12648

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Background: Adenosine kinase (ADK) is supposed to be a schizophrenia susceptibility gene based on the findings that ADK is an enzyme that catalyzes transfer of the gamma-phosphate from ATP to adenosine, which interacts with dopamine and glutamate neurotransmitters. However, no reports of schizophrenia cases with loss of function variants in the ADK region have been published. In our previous study investigating copy number variants in schizophrenia, we detected a copy number variant in the ADK region in 1 of 1699 schizophrenia patients. Methods: We validated the ADK deletion by determining the breakpoint. Then, we compared the relative expression of ADK in 32 schizophrenia patients, including a schizophrenia patient with deletion of ADK, with 29 healthy controls using lymphoblastoid cell lines. Furthermore, we evaluated the clinical phenotypes of the schizophrenia with ADK deletion. Result: We validated the copy number variants with Sanger sequencing and predicted that this copy number variant results in loss of function of ADK. Furthermore, expression analysis of mRNA from peripheral blood in this schizophrenia patient with the ADK deletion showed an extremely low level of ADK. Here we describe a case report of a patient with ADK deletion with phenotypes (schizophrenia, parkinsonism, epilepsy) that are predicted when ADK function is disrupted. Conclusion: Considering that the patient had a low ADK mRNA level and showed a phenotype that may be related to ADK deficiency, the copy number variants in the region of ADK may be strongly related to the phenotypes described here, such as schizophrenia, Parkinsonism, and epilepsy.

DOI： 10.1093/ijnp/pyx103

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Migfilin, encoded by FBLIM1 at the 1p36 locus, is a multi-domain adaptor protein essential for various cellular processes such as cell morphology and migration. Small deletions and duplications at the 1p36 locus, monosomy of which results in neurodevelopmental disorders and multiple congenital anomalies, have also been identified in patients with autism spectrum disorder (ASD). However, the impact of FBLIM1, the gene within 1p36, on the pathogenesis of ASD is unknown. In this study, we performed morphological analyses of migfilin to elucidate its role in brain development. Migfilin was detected specifically in the embryonic and perinatal stages of the mouse brain. Either silencing or overexpression of migfilin in embryos following in utero electroporation disrupted Neocortical neuronal migration. Additionally, neurite elongation was impaired when migfilin was silenced in cultured mouse hippocampal neurons. We then screened FBLIM1 for rare exonic deletions/duplications in 549 Japanese ASD patients and 824 controls, detecting one case of ASD and intellectual delay that harbored a 26-kb deletion at 1p36.21 that solely included the C-terminal exon of FBLIM1. The FBLIM1 mRNA expression level in this case was reduced compared to levels in individuals without FBLIM1 deletion. Our findings indicate that tightly regulated expression of migfilin is essential for neuronal development and that FBLIM1 disruption may be related to the phenotypes associated with ASD and related neurodevelopmental disorders.

DOI： 10.1002/jnr.24194

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Language：English   Publisher：Springer-Verlag Wien  

DOI： 10.1007/s00702-017-1828-2

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In schizophrenia (SCZ) and autism spectrum disorder (ASD), the dysregulation of glutamate transmission through N-methyl-D-aspartate receptors (NMDARs) has been implicated as a potential etiological mechanism. Previous studies have accumulated evidence supporting NMDAR-encoding genes' role in etiology of SCZ and ASD. We performed a screening study for exonic regions of GRIN1, GRIN2A, GRIN2C, GRIN2D, GRIN3A, and GRIN3B, which encode NMDAR subunits, in 562 participates (370 SCZ and 192 ASD). Forty rare variants were identified including 38 missense, 1 frameshift mutation in GRIN2C and 1 splice site mutation in GRIN2D. We conducted in silico analysis for all variants and detected seven missense variants with deleterious prediction. De novo analysis was conducted if pedigree samples were available. The splice site mutation in GRIN2D is predicted to result in intron retention by minigene assay. Furthermore, the frameshift mutation in GRIN2C and splice site mutation in GRIN2D were genotyped in an independent sample set comprising 1877 SCZ cases, 382 ASD cases, and 2040 controls. Both of them were revealed to be singleton. Our study gives evidence in support of the view that ultra-rare variants with loss of function (frameshift, nonsense or splice site) in NMDARs genes may contribute to possible risk of SCZ.

DOI： 10.1038/s41398-017-0061-y

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DOI： 10.1007/978-3-319-89488-1_14

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DOI： 10.1111/pcn.12541

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DOI： 10.1038/nn.4598

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DOI： 10.1038/s41598-017-08768-3

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DOI： 10.1038/tp.2017.170

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DOI： 10.1038/s41598-017-08706-3

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Language：English   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/tp.2017.173

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Other Link： http://www.nature.com/articles/tp2017173

Language：English   Publisher：Frontiers Media S.A.  

DOI： 10.3389/fonc.2017.00149

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

DOI： 10.1055/s-0042-116323

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Other Link： http://orcid.org/0000-0002-2539-1031

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DOI： 10.1038/mp.2016.88

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Language：English   Publisher：Elsevier Ltd  

DOI： 10.1016/S2215-0366(16)30409-6

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Language：English   Publisher：Elsevier Ltd  

DOI： 10.1016/S2215-0366(16)30409-6

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Language：English   Publisher：Elsevier Ltd  

DOI： 10.1016/S2215-0366(16)30409-6

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Language：English   Publisher：Elsevier Ltd  

DOI： 10.1016/S2215-0366(16)30409-6

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Language：English   Publisher：Elsevier Ltd  

DOI： 10.1016/S2215-0366(16)30409-6

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DOI： 10.1038/srep38222

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DOI： 10.1016/j.schres.2016.08.023

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nagoya University Graduate School of Medicine, School of Medicine  

MBD5 (Methyl-CpG-binding domain 5) is a critical gene for normal development. While deletion or duplication of MBD5 may contribute to a genetic predisposition to autism spectrum disorders (ASD), intellectual disability, or epilepsy, the impact of rare MBD5 single nucleotide variants (SNVs) on neurodevelopmental features, particularly features with late onset, has not been fully explored. In this study, we conducted exon-targeted resequencing of MBD5 with next-generation sequencing technology in 562 Japanese patients (192 with idiopathic ASD and 370 with schizophrenia (SCZ)) and detected 16 MBD5 SNVs with allele frequencies of ≤1%. We then performed phenotype analyses with 12 novel variants of these 16 SNVs. SCZ patients with these variants exhibited mainly within normal development ranges until the first psychosis and ASD patients with SNVs did not precisely overlap with the core characteristics described in previous literature as being associated with MBD5 SNVs. Our results suggested that MBD5 variants might contribute to a broad spectrum of neurodevelopmental pathophysiology. Further research and assessment of clinical diagnostic screening are necessary for understanding the burden of rare MBD5 SNVs for these neurodevelopmental disorders.

DOI： 10.18999/nagjms.78.4.465

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N-methyl-d-aspartate receptors (NMDARs) play a critical role in excitatory synaptic transmission and plasticity in the central nervous systems. Recent genetics studies in schizophrenia (SCZ) show that SCZ is susceptible to NMDARs and the NMDAR signaling complex. In autism spectrum disorder (ASD), several studies report dysregulation of NMDARs as a risk factor for ASD. To further examine the association between NMDARs and SCZ/ASD development, we conducted a mutation screening study of GRIN2B which encodes NR2B subunit of NMDARs, to identify rare mutations that potentially cause diseases, in SCZ and ASD patients (n = 574 and 152, respectively). This was followed by an association study in a large sample set of SCZ, ASD, and normal healthy controls (n = 4145, 381, and 4432, respectively). We identified five rare missense mutations through the mutation screening of GRIN2B. Although no statistically significant association between any single mutation and SCZ or ASD was found, one of its variant, K1292R, is found only in the patient group. To further examine the association between mutations in GRIN2B and SCZ/ASD development, a larger sample size and functional experiments are needed.

DOI： 10.1038/srep33311

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DOI： 10.1016/j.buildenv.2016.07.002

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Language：English  

DOI： 10.1111/pcn.12421

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Language：Japanese   Publisher：(一社)日本神経精神薬理学会  

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PSD-95 associated PSD proteins play a critical role in regulating the density and activity of glutamate receptors. Numerous previous studies have shown an association between the genes that encode these proteins and schizophrenia (SZ) and autism spectrum disorders (ASD), which share a substantial portion of genetic risks. We sequenced the protein-encoding regions of DLG1, DLG2, DLG4, DLGAP1, DLGAP2, and SynGAP in 562 cases (370 SZ and 192 ASD patients) on the Ion PGM platform. We detected 26 rare (minor allele frequency <1%), non-synonymous mutations, and conducted silico functional analysis and pedigree analysis when possible. Three variants, G344R in DLG1, G241S in DLG4, and R604C in DLGAP2, were selected for association analysis in an independent sample set of 1315 SZ patients, 382 ASD patients, and 1793 healthy controls. Neither DLG4-G241S nor DLGAP2-R604C was detected in any samples in case or control sets, whereas one additional SZ patient was found that carried DLG1-G344R. Our results suggest that rare missense mutations in the candidate PSD genes may increase susceptibility to SZ and/or ASD. These findings may strengthen the theory that rare, non-synonymous variants confer substantial genetic risks for these disorders.

DOI： 10.1038/srep27491

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

DOI： 10.1093/ijnp/pyw041.338

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DOI： 10.1371/journal.pgen.1005993

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DOI： 10.1371/journal.pone.0153224

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DOI： 10.1002/ajmg.b.32426

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Language：English   Publisher：BioMed Central Ltd.  

DOI： 10.1186/s40337-015-0077-8

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B-cell CLL/lymphoma 9 (BCL9) is located within the schizophrenia (SCZ) suspected locus chr1q21.1. A recent study reported that a single nucleotide polyphormism (SNP) within BCL9 (rs583583) is associated with negative symptoms of Schizophrenia, as measured by the Positive and Negative Syndrome Scale (PANSS), in the Caucasian population. We therefore investigated genetic association of rs583583, and its effect on negative symptoms in the Japanese patients. For association analysis, we used a Japanese sample set comprising 1089 SCZ and 950 controls (CON). Analysis of the effect of rs586586 on negative symptoms as examined by PANSS was investigated using 280 SCZ. Furthermore, for analysis of cognitive performance, we investigated 90 SCZ and 51 CON using the Continuous Performance Test (CPT-IP) and the Wisconsin Card Sorting Test (WCST) Keio version. We did not detect association between rs583583 and SCZ. Furthermore, rs583583 was not associated with PANSS negative scores or with CPT-IT or WCST cognitive tests. Considering the results of our previous study, combined with the results of the current study of rs583583, we argue that BCL9 most likely does not harbor a common genetic variant that can increase the risk for SCZ in the Japanese population.

DOI： 10.1038/srep15705

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

DOI： 10.1002/brb3.375

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DOI： 10.1111/pcn.12290

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DOI： 10.1007/s00213-014-3843-4

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DOI： 10.1038/srep10520

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DOI： 10.1016/j.vaccine.2014.12.036

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DOI： 10.1016/j.jpsychores.2015.02.006

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BACKGROUND: Nuclear distribution E homolog 1 (NDE1), located within chromosome 16p13.11, plays an essential role in microtubule organization, mitosis, and neuronal migration and has been suggested by several studies of rare copy number variants to be a promising schizophrenia (SCZ) candidate gene. Recently, increasing attention has been paid to rare single-nucleotide variants (SNVs) discovered by deep sequencing of candidate genes, because such SNVs may have large effect sizes and their functional analysis may clarify etiopathology. METHODS AND RESULTS: We conducted mutation screening of NDE1 coding exons using 433 SCZ and 145 pervasive developmental disorders samples in order to identify rare single nucleotide variants with a minor allele frequency ≤5%. We then performed genetic association analysis using a large number of unrelated individuals (3554 SCZ, 1041 bipolar disorder [BD], and 4746 controls). Among the discovered novel rare variants, we detected significant associations between SCZ and S214F (P = .039), and between BD and R234C (P = .032). Furthermore, functional assays showed that S214F affected axonal outgrowth and the interaction between NDE1 and YWHAE (14-3-3 epsilon; a neurodevelopmental regulator). CONCLUSIONS: This study strengthens the evidence for association between rare variants within NDE1 and SCZ, and may shed light into the molecular mechanisms underlying this severe psychiatric disorder.

DOI： 10.1093/schbul/sbu147

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Language：Japanese   Publisher：(株)学研メディカル秀潤社  

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DOI： 10.1016/j.pnpbp.2014.07.005

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DOI： 10.1038/nature13772

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BACKGROUND: The PTPRA gene, which encodes the protein RPTP-α, is critical to neurodevelopment. Previous linkage studies, genome-wide association studies, controlled expression analyses and animal models support an association with both schizophrenia and autism spectrum disorders, both of which share a substantial portion of genetic risks. METHODS: We sequenced the protein-encoding areas of the PTPRA gene for single nucleotide polymorphisms or small insertions/deletions (InDel) in 382 schizophrenia patients. To validate their association with the disorders, rare (minor allele frequency <1%), missense mutations as well as one InDel in the 3'UTR region were then genotyped in another independent sample set comprising 944 schizophrenia patients, 336 autism spectrum disorders patients, and 912 healthy controls. RESULTS: Eight rare mutations, including 3 novel variants, were identified during the mutation-screening phase. In the following association analysis, L59P, one of the two missense mutations, was only observed among patients of schizophrenia. Additionally, a novel duplication in the 3'UTR region, 174620_174623dupTGAT, was predicted to be located within a Musashi Binding Element. MAJOR CONCLUSIONS: No evidence was seen for the association of rare, missense mutations in the PTPRA gene with schizophrenia or autism spectrum disorders; however, we did find some rare variants with possibly damaging effects that may increase the susceptibility of carriers to the disorders.

DOI： 10.1371/journal.pone.0112531

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Language：Japanese   Publisher：(株)世論時報社  

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DOI： 10.1371/journal.pone.0103571

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DOI： 10.1371/journal.pone.0103941

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DOI： 10.1097/YPG.0000000000000043

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DOI： 10.1111/pcn.12171

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The ubiquitin ligase F-box protein 45 (FBXO45) is critical for synaptogenesis, neuronal migration, and synaptic transmission. FBXO45 is included in the 3q29 microdeletion region that confers a significant risk for schizophrenia, as shown by rare structural variant studies. Thus, FBXO45 is considered a prominent candidate for mediating schizophrenia pathogenesis. Here, we investigated rare, deleterious single nucleotide variants (SNVs) as well as small insertions and deletions (INDELs) in FBXO45 that may contribute to schizophrenia susceptibility. Using Sanger sequencing, we performed mutation screening in FBXO45 exon regions in 337 schizophrenia patients. Novel missense or nonsense variants were followed up with a genetic association study in an independent sample set of 601 schizophrenia patients and 916 controls, a case report for assessing the clinical consequence of the mutations, a pedigree study for measuring mutation inheritance in the proband's family, bioinformatics analyses for evaluating mutation effect on protein structure and function, and mRNA expression analysis for examining mutation transcriptional influence on FBXO45 expression. One heterozygous, novel, and rare missense mutation (R108C) was identified in a single schizophrenia patient and in his healthy mother. At age 20, this patient was diagnosed with paranoid schizophrenia and carried some clinical features of 3q29 deletion phenotypes, including premorbid IQ decline. With follow-up genotyping, this mutation was not found in either the schizophrenia group (0/601) or the healthy control group (0/916). Bioinformatics analyses predicted that R108C probably pathologically impacted the structure and function of the FBXO45 protein. The relative expression of FBXO45 in SCZ case with R108C mutation was relatively low when compared to 50 schizophrenia patients and 52 healthy controls. The R108C mutation in FBXO45 is a rare variant with a modest effect on schizophrenia risk that may disrupt the structure and function of the FBXO45 protein. Our findings also suggest that FBXO45 may be a new attractive candidate gene for schizophrenia.

DOI： 10.1016/j.schres.2014.04.032

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DOI： 10.1002/ajmg.b.32246

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DOI： 10.1186/1471-244X-14-173

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DOI： 10.1016/j.pnpbp.2014.02.005

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DOI： 10.5754/hge14104

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DOI： 10.1016/S0920-9964(14)70345-7

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