DOI： 10.21203/rs.3.rs-2586527/v1

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

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

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

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

PubMed

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

DOI： 10.1038/s10038-022-01059-4

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Other Link： https://www.nature.com/articles/s10038-022-01059-4

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

Aim

Eating disorders (EDs) are complex, multifactorial psychiatric conditions. Previous studies identified pathogenic copy number variations associated with NDDs (NDD‐CNVs) in ED patients. However, no statistical evidence for an association between NDD‐CNVs and EDs has been demonstrated. Therefore, we examined whether NDD‐CNVs confer risk for EDs.

Methods

Using array comparative genomic hybridization (aCGH), we conducted a high‐resolution CNV analysis of 71 severe female ED patients and 1045 female controls. According to the American College of Medical Genetics guidelines, we identified NDD‐CNVs or pathogenic/likely pathogenic CNVs in NDD‐linked loci. Gene set analysis was performed to examine the involvement of synaptic dysfunction in EDs. Clinical data were retrospectively examined for ED patients with NDD‐CNVs.

Results

Of the samples analyzed with aCGH, 70 severe ED patients (98.6%) and 1036 controls (99.1%) passed our quality control filtering. We obtained 189 and 2539 rare CNVs from patients and controls, respectively. NDD‐CNVs were identified in 10.0% (7/70) of patients and 2.3% (24/1036) of controls. Statistical analysis revealed a significant association between NDD‐CNVs and EDs (odds ratio = 4.69, P = 0.0023). NDD‐CNVs in ED patients included 45,X and deletions at KATNAL2, DIP2A, PTPRT, RBFOX1, CNTN4, MACROD2, and FAM92B. Four of these genes were related to synaptic function. In gene set analysis, we observed a nominally significant enrichment of rare exonic CNVs in synaptic signaling in ED patients (odds ratio = 2.55, P = 0.0254).

Conclusion

Our study provides the first preliminary evidence that NDD‐CNVs may confer risk for severe EDs. The pathophysiology may involve synaptic dysfunction.

DOI： 10.1111/pcn.13430

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/pcn.13430

Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science (PLoS)  

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

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

PubMed

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Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/09540261.2022.2072193

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

DOI： 10.1111/pcn.13309

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Publishing type：Research paper (scientific journal)  

DOI： 10.1111/pcn.13483

Scopus

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

Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays an essential role in correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal, and postmortem studies. Recently, increasing attention has been given to rare single-nucleotide variants (SNVs) found by deep sequencing of candidate genes. In this study, we performed exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency <1%. We detected two rare missense mutations (G382C, V129I) and then performed a genetic association study in a sample comprising 1763 SCZ, 380 ASD, and 2190 healthy control subjects. Although no statistically significant association with the detected mutations was observed for either SCZ or ASD, G382C was found only in the case group, and in silico analyses and in vitro functional assays suggested that G382C alters the function of the DAB1 protein. The rare variants of DAB1 found in the present study should be studied further to elucidate their potential functional relevance to the pathophysiology of SCZ and ASD.

DOI： 10.1038/s41439-020-00125-7

PubMed

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

© 2020, The Author(s). 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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PubMed

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

<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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Other Link： http://www.nature.com/articles/s41398-020-01107-7

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

Creatine transporter deficiency (CTD) is an example of X-linked intellectual disability syndromes, caused by mutations in SLC6A8 on Xq28. Although this is the second most frequent genetic cause of intellectual disabilities in Europe or America after Fragile X syndrome, information on the morbidity of this disease is limited in Japan. Using the HPLC screening method we have established recently, we examined samples of urine of 105 patients (73 males and 32 females) with developmental disabilities at our medical center. And we have found a family with three ID boys with a novel missense mutation in SLC6A8. This is the second report of a Japanese family case of CTD. A systematic diagnostic system of this syndrome should be established in Japan to enable us to estimate its frequency and treatment.

DOI： 10.1016/j.braindev.2013.08.004

PubMed

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DOI： 10.11249/jsbpjjpp.33.3_117

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J-GLOBAL

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Publisher：Elsevier {BV}  

DOI： 10.1016/j.ajp.2020.102443

Scopus

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Publisher：Elsevier {BV}  

DOI： 10.1016/S2215-0366(20)30314-X

Scopus

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Language：Japanese   Publisher：(公財)日本精神衛生会  

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Publisher：Royal College of Psychiatrists  

DOI： 10.1192/bji.2020.8

Scopus

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DOI： 10.5692/clinicalneurol.cn-001240

Scopus

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Language：Japanese   Publisher：(株)羊土社  

＜Point＞●発達障害の特性を有する方の身体診療時には、本人、家族、そして医療者ともに困難を感じることが少なくない●本人の能力や特性に合わせた配慮をすることで、その困難は解消されることも多い●感覚過敏への対応、見通しをもちやすくするための対応、そして視覚認知の強さなどの強みを活かした対応などを意識するとよい●能力や特性の個人差は大きく、診察のしかたについて家族ともよく相談をするとよい(著者抄録)

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Language：Japanese   Publisher：(株)羊土社  

＜Point＞●発達障害の特性を有する方の身体診療時には、本人、家族、そして医療者ともに困難を感じることが少なくない●本人の能力や特性に合わせた配慮をすることで、その困難は解消されることも多い●感覚過敏への対応、見通しをもちやすくするための対応、そして視覚認知の強さなどの強みを活かした対応などを意識するとよい●能力や特性の個人差は大きく、診察のしかたについて家族ともよく相談をするとよい(著者抄録)

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Language：Japanese  

DOI： 10.20615/jscap.58.3_389

CiNii Books

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Language：Japanese   Publisher：全国患者図書サービス連絡会  

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Language：Japanese   Publisher：神奈川県立こども医療センター  

患児の安全と持続点滴の拘束から解放するため末梢静脈路の間欠注入ロックは有用である。その方法にはヘパリン生食によるロックと生理食塩水によるロックがある。当院では主にヘパリン生食が用いられているが、両者の利点と欠点について検討した。末梢静脈路の維持において、開通率や静脈炎の頻度は両者に差はないが、ヘパリンロックに比べ生食ロックは安全かつ経済的であると考えられた。ヘパリンロックに比べて生食ロックではルート内に血栓が作られやすいので右左シャントを持つ先天性心疾患の児ではヘパリンロックを用いた方が良いと考えられた。いずれの方法をとる際も陽圧をかけながらロックすることが重要である。(著者抄録)

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Language：Japanese   Publisher：神奈川県立こども医療センター  

2009年に大流行したパンデミックインフルエンザA(H1N1)の多くは軽症例であったが、急速に呼吸不全をきたす重症例がみられた。当センターでは3次医療機関として主に重症例の診療にあたった。今回、当科で経験した重症例の臨床像を明らかにするため、挿管群と非挿管群に分けて比較し、呼吸管理を要する児の危険因子を検討した。両群とも男児が多く、喘息の既往を持つ例が多かった。症状発現後、急速に呼吸不全に至ったが、治療開始後は両群とも比較的速やかに症状は改善したことから早期介入が重要であると考えられた。重症化の危険因子については、酸素化障害のみ重要な臨床指標であることが明らかとなった。他の予後因子を明らかにするには、軽症例と重症例を比較検討する必要がある。(著者抄録)

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Event date： 2023.5

Language：English   Presentation type：Symposium, workshop panel (public)  

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Event date： 2023.5

Language：English   Presentation type：Poster presentation  

Venue：Kyoto   Country：Japan  

Event date： 2023.2

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：名古屋   Country：Japan  

Event date： 2023.2

Presentation type：Oral presentation (general)  

Event date： 2022.12

Language：English   Presentation type：Poster presentation  

Venue：DUBAI   Country：United Arab Emirates  

Event date： 2022.11

Language：Japanese   Presentation type：Poster presentation  

Venue：松本   Country：Japan  

Event date： 2022.11

Presentation type：Poster presentation  

Venue：東京  

Event date： 2022.11

Presentation type：Poster presentation  

Venue：東京  

Event date： 2022.7

Presentation type：Oral presentation (general)  

Event date： 2022.7

Venue：名古屋  

Event date： 2022.3

Presentation type：Oral presentation (general)  

Venue：名古屋   Country：Japan  

Event date： 2021.11

Presentation type：Oral presentation (general)  

Venue：Web  

Event date： 2021.11

Presentation type：Oral presentation (general)  

Venue：Web  

Event date： 2021.10

Presentation type：Poster presentation  

Venue：横浜  

Event date： 2021.10

Presentation type：Poster presentation  

Event date： 2021.9

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Venue：京都  

Event date： 2021.7

Presentation type：Poster presentation  

Event date： 2018.7

Presentation type：Symposium, workshop panel (public)  

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Event date： 2016.9

Presentation type：Oral presentation (general)  

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Event date： 2015.11

Presentation type：Symposium, workshop panel (public)  

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Event date： 2013.10

Presentation type：Symposium, workshop panel (public)  

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