研究者詳細 - アレクシッチ　ブランコ

論文 - アレクシッチ　ブランコ

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Clinical characterization of patients with schizophrenia and 16p13.11 duplication: A case series 国際誌

Kimura, H; Kushima, I; Banno, M; Inada, T; Yoshimi, A; Aleksic, B; Ozaki, N

NEUROPSYCHOPHARMACOLOGY REPORTS 43 巻 ( 2 ) 頁： 267 - 271 2023年6月

記述言語：英語出版者・発行元：Wiley

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Case Presentation</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>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.</jats:p></jats:sec>

DOI： 10.1002/npr2.12334

The genetic architecture of schizophrenia: review of large-scale genetic studies

Kato, H; Kimura, H; Kushima, I; Takahashi, N; Aleksic, B; Ozaki, N

JOURNAL OF HUMAN GENETICS 68 巻 ( 3 ) 頁： 175 - 182 2023年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Human Genetics

Schizophrenia is a complex and often chronic psychiatric disorder with high heritability. Diagnosis of schizophrenia is still made clinically based on psychiatric symptoms; no diagnostic tests or biomarkers are available. Pathophysiology-based diagnostic scheme and treatments are also not available. Elucidation of the pathogenesis is needed for development of pathology-based diagnostics and treatments. In the past few decades, genetic research has made substantial advances in our understanding of the genetic architecture of schizophrenia. Rare copy number variations (CNVs) and rare single-nucleotide variants (SNVs) detected by whole-genome CNV analysis and whole-genome/-exome sequencing analysis have provided the great advances. Common single-nucleotide polymorphisms (SNPs) detected by large-scale genome-wide association studies have also provided important information. Large-scale genetic studies have been revealed that both rare and common genetic variants play crucial roles in this disorder. In this review, we focused on CNVs, SNVs, and SNPs, and discuss the latest research findings on the pathogenesis of schizophrenia based on these genetic variants. Rare variants with large effect sizes can provide mechanistic hypotheses. CRISPR-based genetics approaches and induced pluripotent stem cell technology can facilitate the functional analysis of these variants detected in patients with schizophrenia. Recent advances in long-read sequence technology are expected to detect variants that cannot be detected by short-read sequence technology. Various studies that bring together data from common variant and transcriptomic datasets provide biological insight. These new approaches will provide additional insight into the pathophysiology of schizophrenia and facilitate the development of pathology-based therapeutics.

DOI： 10.1038/s10038-022-01059-4

その他リンク： https://www.nature.com/articles/s10038-022-01059-4

Analysis of human neuronal cells carrying ASTN2 deletion: A cross-disorder risk variant of schizophrenia, autism spectrum disorder, and bipolar disorder

Yuko Arioka, Yu Hayashi, Hiroki Okumura, Itaru Kushima, Daisuke Mori, Tzuyao Lo, Gantsooj Otgonbayar, Hidekazu Kato, Yoshihiro Nawa, Hiroki Kimura, Branko Aleksic, Norio Ozaki

2023年2月

Clinical manifestations of schizophrenia in four patients with variants in voltage-gated calcium channel-encoding genes: a case series 国際誌

Lo, TY; Kushima, I; Aleksic, B; Yoshimi, A; Someya, T; Watanabe, Y; Ozaki, N

PSYCHIATRY AND CLINICAL NEUROSCIENCES 77 巻 ( 1 ) 頁： 57 - 59 2023年1月

X chromosome aneuploidies and schizophrenia: association analysis and phenotypic characterization

Kushima, I; Aleksic, B; Kimura, H; Nakatochi, M; Lo, T; Ikeda, M; Arai, M; Hashimoto, R; Numata, S; Okamura, Y; Obara, T; Inada, T; Ozaki, N

PSYCHIATRY AND CLINICAL NEUROSCIENCES 76 巻 ( 12 ) 頁： 667 - 673 2022年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley

<jats:sec><jats:title>Aim</jats:title><jats:p>The aims of the present study were: (i) to examine the association between schizophrenia (SCZ) and 47, XXY or 47, XXX in a large case–control sample; and (ii) to characterize the clinical features of patients with SCZ with these X chromosome aneuploidies.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>To identify 47, XXY and 47, XXX, array comparative genomic hybridization (aCGH) was performed in 3188 patients with SCZ and 3586 controls. We examined the association between 47, XXY and 47, XXX and SCZ in males and females separately using exact conditional tests to control for platform effects. Clinical data were retrospectively examined for patients with SCZ with X chromosome aneuploidies.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Of the analyzed samples, 3117 patients (97.8%) and 3519 controls (98.1%) passed our quality control. X chromosome aneuploidies were exclusively identified in patients: 47, XXY in seven patients (0.56%), 47, XXX in six patients (0.42%). Statistical analysis revealed a significant association between SCZ and 47, XXY (<jats:italic>P</jats:italic> = 0.028) and 47, XXX (<jats:italic>P</jats:italic> = 0.011). Phenotypic data were available from 12 patients. Treatment‐resistance to antipsychotics and manic symptoms were observed in six patients each (four with 47, XXY and two with 47, XXX for both), respectively. Statistical analysis revealed that treatment‐resistance to antipsychotics, mood stabilizer use, and manic symptoms were significantly more common in patients with 47, XXY than in male patients without pathogenic copy number variations.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>These findings indicate that both 47, XXY and 47, XXX are significantly associated with risk for SCZ. Patients with SCZ with 47, XXY may be characterized by treatment‐resistance and manic symptoms.</jats:p></jats:sec>

DOI： 10.1111/pcn.13474

Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder

Kushima, I; Nakatochi, M; Aleksic, B; Okada, T; Kimura, H; Kato, H; Morikawa, M; Inada, T; Ishizuka, K; Torii, Y; Nakamura, Y; Tanaka, S; Imaeda, M; Takahashi, N; Yamamoto, M; Iwamoto, K; Nawa, Y; Ogawa, N; Iritani, S; Hayashi, Y; Lo, TY; Otgonbayar, G; Furuta, S; Iwata, N; Ikeda, M; Saito, T; Ninomiya, K; Okochi, T; Hashimoto, R; Yamamori, H; Yasuda, Y; Fujimoto, M; Miura, K; Itokawa, M; Arai, M; Miyashita, M; Toriumi, K; Ohi, K; Shioiri, T; Kitaichi, K; Someya, T; Watanabe, Y; Egawa, J; Takahashi, T; Suzuki, M; Sasaki, T; Tochigi, M; Nishimura, F; Yamasue, H; Kuwabara, H; Wakuda, T; Kato, TA; Kanba, S; Horikawa, H; Usami, M; Kodaira, M; Watanabe, K; Yoshikawa, T; Toyota, T; Yokoyama, S; Munesue, T; Kimura, R; Funabiki, Y; Kosaka, H; Jung, MY; Kasai, K; Ikegame, T; Jinde, S; Numata, S; Kinoshita, M; Kato, T; Kakiuchi, C; Yamakawa, K; Suzuki, T; Hashimoto, N; Ishikawa, S; Yamagata, B; Nio, S; Murai, T; Son, S; Kunii, Y; Yabe, H; Inagaki, M; Goto, Y; Okumura, Y; Ito, T; Arioka, Y; Mori, D; Ozaki, N

BIOLOGICAL PSYCHIATRY 92 巻 ( 5 ) 頁： 362 - 374 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Biological Psychiatry

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

Contribution of copy number variations to the risk of severe eating disorders

Kushima, I; Imaeda, M; Tanaka, S; Kato, H; Oya-Ito, T; Nakatochi, M; Aleksic, B; Ozaki, N

PSYCHIATRY AND CLINICAL NEUROSCIENCES 76 巻 ( 9 ) 頁： 423 - 428 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley

<jats:sec><jats:title>Aim</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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, <jats:italic>P</jats:italic> = 0.0023). NDD‐CNVs in ED patients included 45,X and deletions at <jats:italic>KATNAL2</jats:italic>, <jats:italic>DIP2A</jats:italic>, <jats:italic>PTPRT</jats:italic>, <jats:italic>RBFOX1</jats:italic>, <jats:italic>CNTN4</jats:italic>, <jats:italic>MACROD2</jats:italic>, and <jats:italic>FAM92B</jats:italic>. 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, <jats:italic>P</jats:italic> = 0.0254).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our study provides the first preliminary evidence that NDD‐CNVs may confer risk for severe EDs. The pathophysiology may involve synaptic dysfunction.</jats:p></jats:sec>

DOI： 10.1111/pcn.13430

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/pcn.13430

Exome sequencing analysis of Japanese autism spectrum disorder case-control sample supports an increased burden of synaptic function-related genes

Kimura, H; Nakatochi, M; Aleksic, B; Guevara, J; Toyama, M; Hayashi, Y; Kato, H; Kushima, I; Morikawa, M; Ishizuka, K; Okada, T; Tsurusaki, Y; Fujita, A; Miyake, N; Ogi, T; Takata, A; Matsumoto, N; Buxbaum, J; Ozaki, N; Sebat, J

TRANSLATIONAL PSYCHIATRY 12 巻 ( 1 ) 頁： 265 2022年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Translational Psychiatry

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

その他リンク： https://www.nature.com/articles/s41398-022-02033-6

Treatment-resistant schizophrenia in patients with 3q29 deletion: A case series of four patients 国際誌

Nawa, Y; Kushima, I; Aleksic, B; Yamamoto, M; Kimura, H; Banno, M; Hashimoto, R; Ozaki, N

PSYCHIATRY AND CLINICAL NEUROSCIENCES 76 巻 ( 7 ) 頁： 338 - 339 2022年7月

Psychiatric patients with a de novo 17q12 deletion: Two case reports 国際誌

Kushima, I; Uematsu, M; Ishizuka, K; Aleksic, B; Ozaki, N

PSYCHIATRY AND CLINICAL NEUROSCIENCES 76 巻 ( 7 ) 頁： 345 - 347 2022年7月

Exome sequencing of Japanese schizophrenia multiplex families supports the involvement of calcium ion channels.

Toyama M, Takasaki Y, Branko A, Kimura H, Kato H, Nawa Y, Kushima I, Ishizuka K, Shimamura T, Ogi T, Ozaki N

PloS one 17 巻 ( 5 ) 頁： e0268321 - e0268321 2022年5月

Investigation of OLIG2 as a candidate gene for schizophrenia and autism spectrum disorder

Furuta, S; Aleksic, B; Nawa, Y; Kimura, H; Kushima, I; Ishizuka, K; Kato, H; Toyama, M; Arioka, Y; Mori, D; Morikawa, M; Inada, T; Ozaki, N

NAGOYA JOURNAL OF MEDICAL SCIENCE 84 巻 ( 2 ) 頁： 260 - 268 2022年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nagoya Journal of Medical Science

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

Case report of a female with bipolar disorder and MBD5 deletion

Kushima, I; Lo, T; Aleksic, B; Ozaki, N

PSYCHIATRY AND CLINICAL NEUROSCIENCES 76 巻 ( 4 ) 頁： 127 - 128 2022年4月

Variable psychiatric manifestations in patients with 16p11.2 duplication: a case series of 4 patients

Hayashi, Y; Kushima, I; Aleksic, B; Senaha, T; Ozaki, N

PSYCHIATRY AND CLINICAL NEUROSCIENCES 76 巻 ( 3 ) 頁： 86 - 88 2022年3月

Identification of ultra-rare disruptive variants in voltage-gated calcium channel-encoding genes in Japanese samples of schizophrenia and autism spectrum disorder 国際誌

Wang, CY; Horigane, S; Wakamori, M; Ueda, S; Kawabata, T; Fujii, H; Kushima, I; Kimura, H; Ishizuka, K; Nakamura, Y; Iwayama, Y; Ikeda, M; Iwata, N; Okada, T; Aleksic, B; Mori, D; Yoshida, T; Bito, H; Yoshikawa, T; Takemoto-Kimura, S; Ozaki, N

TRANSLATIONAL PSYCHIATRY 12 巻 ( 1 ) 頁： 84 - 84 2022年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Translational Psychiatry

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

Sequencing of selected chromatin remodelling genes reveals increased burden of rare missense variants in ASD patients from the Japanese population

Lo, T; Kushima, I; Aleksic, B; Kato, H; Nawa, Y; Hayashi, Y; Otgonbayar, G; Kimura, H; Arioka, Y; Mori, D; Ozaki, N

INTERNATIONAL REVIEW OF PSYCHIATRY 34 巻 ( 2 ) 頁： 154 - 167 2022年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Informa UK Limited

Chromatin remodelling is an important process in neural development and is related to autism spectrum disorder (ASD) and schizophrenia (SCZ) aetiology. To further elucidate the involvement of chromatin remodelling genes in the genetic aetiology of ASD and SCZ in the Japanese population, we performed a case–control study. Targeted sequencing was conducted on coding regions of four BAF chromatin remodelling complex genes: SMARCA2, SMARCA4, SMARCC2, and ARID1B in 185 ASD, 432 SCZ patients, and 517 controls. 27 rare non-synonymous variants were identified in ASD and SCZ patients, including 25 missense, one in-frame deletion in SMRACA4, and one frame-shift variant in SMARCC2. Association analysis was conducted to investigate the burden of rare variants in BAF genes in ASD and SCZ patients. Significant enrichment of rare missense variants in BAF genes, but not synonymous variants, was found in ASD compared to controls. Rare pathogenic variants indicated by in silico tools were significantly enriched in ASD, but not statistically significant in SCZ. Pathogenic-predicted variants were located in disordered binding regions and may confer risk for ASD and SCZ by disrupting protein–protein interactions. Our study supports the involvement of rare missense variants of BAF genes in ASD and SCZ susceptibility.

DOI： 10.1080/09540261.2022.2072193

Autism spectrum disorder comorbid with obsessive compulsive disorder and eating disorder in a woman with NBEA deletion

Kato, H; Kushima, I; Yoshimi, A; Ishizuka, K; Kimura, H; Aleksic, B; Takahashi, N; Okada, T; Ozaki, N

PSYCHIATRY AND CLINICAL NEUROSCIENCES 76 巻 ( 1 ) 頁： 36 - 38 2022年1月

Elucidation of molecular pathogenesis and drug development for psychiatric disorders from rare disease-susceptibility variants

Kimura, H; Mori, D; Aleksic, B; Ozaki, N

NEUROSCIENCE RESEARCH 170 巻頁： 24 - 31 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Neuroscience Research

Recent rapid progress in genome analysis and large-scale consortia has made it possible to discover variants with a variety of allele frequencies and effect sizes associated with psychiatric disorders. Among psychiatric disorder-susceptibility variants, rare variants with large effect sizes detected by sequencing analysis or array comparative genomic hybridization would be particularly useful for elucidating pathophysiology by developing disease models, such as genome-edited mouse or induced pluripotent stem cells. In the last decade, investigations of rare variants with large effect size have revealed an important role of neurodevelopment in the pathogenesis of psychiatric disorders. In future research, integration of recent evidence concerning the contribution of the immune system or gut microbiota will enhance our understanding of psychiatric disorders and facilitate novel drug development.

DOI： 10.1016/j.neures.2020.11.008

Problem-Based Learning in Child and Adolescent Psychiatry: A Perspective from Japan

Iwatsuki, J; Kondo, T; Takahashi, N; Takami, H; Nishigori, H; Bustos-Villalobos, I; Aleksic, B; Kasuya, H; Ban, NO; Yagi, T; Skokauskas, N

ADVANCES IN MEDICAL EDUCATION AND PRACTICE 12 巻頁： 1329 - 1335 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Advances in Medical Education and Practice

Purpose: Japanese higher education institutions have long been striving for the globaliza-tion of medical education. Nagoya University (NU) adopted PBL as a means of enhancing intercultural awareness in globalizing medical education by working with the Norwegian University of Science and Technology (NTNU), Faculty of Medicine and Health Science, under the Trondheim NTNU-Nagoya (TroNa) partnership for mobility and internationaliza-tion of child and mental health studies. This study aims to assess students’ attitudes towards PBL and to suggest future developments in this form of education by introducing common PBL scenarios experienced at NTNU and NU. Methods: Two 90-minute PBL sessions were conducted at NU. Ten groups of medical students were formed, each consisting of up to 10 students, and students were asked to fill in a questionnaire developed to assess their understanding of, attitudes to and satisfaction with the classes. We investigated three different groups of questions on: NU medical students’ general impressions of PBL; their impressions of PBL in child and adolescent psychiatry (CAP); and their impressions of PBL in specific case scenarios. Correlations between each of the questions from the three groups were evaluated using multivariate analysis. Results: Overall, a majority of the NU medical students were satisfied with PBL, while a small number preferred traditional lecture-style learning (5%). More than half of the students agreed that PBL increased their understanding and interest in CAP (53%), although some male students felt that the amount of time spent was insufficient (20.3%). Correlations were seen for students who thought that PBL enhanced their understanding of and interest in CAP. Regarding case scenarios, most students (82.5%) agreed that PBL helped them to develop clinical problem-solving skills. Conclusion: The study found an overall positive attitude towards PBL, PBL in CAP and the specific PBL case scenario presented.

DOI： 10.2147/AMEP.S333958

Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder

Kato, H; Kushima, I; Mori, D; Yoshimi, A; Aleksic, B; Nawa, Y; Toyama, M; Furuta, S; Yu, YJ; Ishizuka, K; Kimura, H; Arioka, Y; Tsujimura, K; Morikawa, M; Okada, T; Inada, T; Nakatochi, M; Shinjo, K; Kondo, Y; Kaibuchi, K; Funabiki, Y; Kimura, R; Suzuki, T; Yamakawa, K; Ikeda, M; Iwata, N; Takahashi, T; Suzuki, M; Okahisa, Y; Takaki, M; Egawa, J; Someya, T; Ozaki, N

TRANSLATIONAL PSYCHIATRY 10 巻 ( 1 ) 頁： 421 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Translational Psychiatry

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

DOI： 10.1038/s41398-020-01107-7

その他リンク： http://www.nature.com/articles/s41398-020-01107-7

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論文 - アレクシッチ ブランコ

<アレクシッチ　ブランコ>

論文 - アレクシッチ　ブランコ