論文 - 石塚 佳奈子
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Prescription patterns for attention−deficit hyperactivity disorder (ADHD) medications in Japan: A retrospective claims analysis 査読あり
Kanako Ishizuka
Asian Journal of Psychiatry 94 103961 - 103961 2024年04月
担当区分：筆頭著者, 責任著者 掲載種別：研究論文（学術雑誌） 出版者・発行元：Elsevier BV
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Machine learning algorithm‐based estimation model for the severity of depression assessed using Montgomery‐Asberg depression rating scale 査読あり
Masanori Shimamoto, Kanako Ishizuka, Kento Ohtani, Toshiya Inada, Maeri Yamamoto, Masako Tachibana, Hiroki Kimura, Yusuke Sakai, Kazuhiro Kobayashi, Norio Ozaki, Masashi Ikeda
Neuropsychopharmacology Reports 2023年12月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Wiley
Abstract
Aim
Depressive disorder is often evaluated using established rating scales. However, consistent data collection with these scales requires trained professionals. In the present study, the “rater & estimation‐system” reliability was assessed between consensus evaluation by trained psychiatrists and the estimation by 2 models of the AI‐MADRS (Montgomery‐Asberg Depression Rating Scale) estimation system, a machine learning algorithm‐based model developed to assess the severity of depression.
Methods
During interviews with trained psychiatrists and the AI‐MADRS estimation system, patients responded orally to machine‐generated voice prompts from the AI‐MADRS structured interview questions. The severity scores estimated from two models of the AI‐MADRS estimation system, the max estimation model and the average estimation model, were compared with those by trained psychiatrists.
Results
A total of 51 evaluation interviews conducted on 30 patients were analyzed. Pearson's correlation coefficient with the scores evaluated by trained psychiatrists was 0.76 (95% confidence interval 0.62–0.86) for the max estimation model, and 0.86 (0.76–0.92) for the average estimation model. The ANOVA ICC rater & estimation‐system reliability with the evaluation scores by trained psychiatrists was 0.51 (−0.09 to 0.79) for the max estimation model, and 0.75 (0.55–0.86) for the average estimation model.
Conclusion
The average estimation model of AI‐MADRS demonstrated substantially acceptable rater & estimation‐system reliability with trained psychiatrists. Accumulating a broader training dataset and the refinement of AI‐MADRS interviews are expected to improve the performance of AI‐MADRS. Our findings suggest that AI technologies can significantly modernize and potentially revolutionize the realm of depression assessments.DOI： 10.1002/npr2.12404
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Kanako Ishizuka
Psychiatry and Clinical Neurosciences Reports 2 ( 3 ) 2023年09月
担当区分：筆頭著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌）
DOI： 10.1002/pcn5.147
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Factors predicting early treatment discontinuation among depressed patients of working age in a psychiatric outpatient practice 査読あり
Kanako Ishizuka, Tomomi Ishiguro, Daisuke Kawaguchi, Norio Nomura, Toshiya Inada
Psychiatry Research Communications 3 ( 3 ) 100128 - 100128 2023年09月
担当区分：筆頭著者 掲載種別：研究論文（学術雑誌） 出版者・発行元：Elsevier BV
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「発達障害は遺伝しますか？」という質問にどのようにアドバイスすべきでしょうか？ 招待あり
石塚 佳奈子
精神医学増大号 65 ( 5 ) 558 - 560 2023年05月
担当区分：筆頭著者, 最終著者, 責任著者 記述言語：日本語
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抗うつ薬服薬中にみられる躁転 招待あり
松岡崇史, 石塚佳奈子, 稲田俊也
臨床精神薬理 26 ( 4 ) 417 - 424 2023年04月
記述言語：日本語
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Molecular diagnosis of 405 individuals with autism spectrum disorder. 査読あり 国際誌
Noriko Miyake, Yoshinori Tsurusaki, Ryoko Fukai, Itaru Kushima, Nobuhiko Okamoto, Kei Ohashi, Kazuhiko Nakamura, Ryota Hashimoto, Yoko Hiraki, Shuraku Son, Mitsuhiro Kato, Yasunari Sakai, Hitoshi Osaka, Kimiko Deguchi, Toyojiro Matsuishi, Saoko Takeshita, Aviva Fattal-Valevski, Nina Ekhilevitch, Jun Tohyama, Patrick Yap, Wee Teik Keng, Hiroshi Kobayashi, Keiyo Takubo, Takashi Okada, Shinji Saitoh, Yuka Yasuda, Toshiya Murai, Kazuyuki Nakamura, Shouichi Ohga, Ayumi Matsumoto, Ken Inoue, Tomoko Saikusa, Tova Hershkovitz, Yu Kobayashi, Mako Morikawa, Aiko Ito, Toshiro Hara, Yota Uno, Chizuru Seiwa, Kanako Ishizuka, Emi Shirahata, Atsushi Fujita, Eriko Koshimizu, Satoko Miyatake, Atsushi Takata, Takeshi Mizuguchi, Norio Ozaki, Naomichi Matsumoto
European journal of human genetics : EJHG 2023年03月
記述言語：英語 掲載種別：研究論文（学術雑誌）
Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses. All candidate variants were validated by Sanger sequencing or quantitative polymerase chain reaction and were evaluated using the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines for molecular diagnosis. We identified 55 disease-causing SNVs/indels in 53 affected individuals and 13 disease-causing CNVs in 13 affected individuals, achieving a molecular diagnosis in 66 of 405 affected individuals (16.3%). Among the 55 disease-causing SNVs/indels, 51 occurred de novo, 2 were compound heterozygous (in one patient), and 2 were X-linked hemizygous variants inherited from unaffected mothers. The molecular diagnosis rate in females was significantly higher than that in males. We analyzed affected sibling cases of 24 quads and 2 quintets, but only one pair of siblings shared an identical pathogenic variant. Notably, there was a higher molecular diagnostic rate in simplex cases than in multiplex families. Our simulation indicated that the diagnostic yield is increasing by 0.63% (range 0-2.5%) per year. Based on our simple simulation, diagnostic yield is improving over time. Thus, periodical reevaluation of ES data should be strongly encouraged in undiagnosed ASD patients.
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Exome sequencing analysis of Japanese autism spectrum disorder case-control sample supports an increased burden of synaptic function-related genes 査読あり
Hiroki Kimura, Masahiro Nakatochi, Branko Aleksic, James Guevara, Miho Toyama, Yu Hayashi, Hidekazu Kato, Itaru Kushima, Mako Morikawa, Kanako Ishizuka, Takashi Okada, Yoshinori Tsurusaki, Atsushi Fujita, Noriko Miyake, Tomoo Ogi, Atsushi Takata, Naomichi Matsumoto, Joseph Buxbaum, Norio Ozaki, Jonathan Sebat
Translational Psychiatry 12 ( 1 ) 2022年12月
掲載種別：研究論文（学術雑誌） 出版者・発行元：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<sup>−4</sup>, 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. -
A systematic review and network meta‐analysis of antimanic drugs for the treatment of acute mania used in Japan 査読あり
Kanako Ishizuka, Toshiya Inada
Psychiatry and Clinical Neurosciences Reports 1 ( 4 ) 2022年11月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌）
DOI： 10.1002/pcn5.60
その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/pcn5.60
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日常臨床で家族の精神疾患発症リスクが話題になった時どう応じるか，患者の母親に遺伝カウンセリングを行った一例を通じて考える 査読あり
石塚 佳奈子
児童青年精神医学とその近接領域 63 ( 4 ) 546 - 553 2022年08月
担当区分：筆頭著者, 責任著者 記述言語：日本語 掲載種別：研究論文（学術雑誌）
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Exome sequencing of Japanese schizophrenia multiplex families supports the involvement of calcium ion channels 査読あり
Miho Toyama, Yuto Takasaki, Aleksic Branko, Hiroki Kimura, Hidekazu Kato, Yoshihiro Nawa, Itaru Kushima, Kanako Ishizuka, Teppei Shimamura, Tomoo Ogi, Norio Ozaki
PLOS ONE 17 ( 5 ) e0268321 - e0268321 2022年05月
掲載種別：研究論文（学術雑誌） 出版者・発行元：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. -
Investigation of OLIG2 as a candidate gene for schizophrenia and autism spectrum disorder. 査読あり
Sho Furuta, Branko Aleksic, Yoshihiro Nawa, Hiroki Kimura, Itaru Kushima, Kanako Ishizuka, Hidekazu Kato, Miho Toyama, Yuko Arioka, Daisuke Mori, Mako Morikawa, Toshiya Inada, Norio Ozaki
Nagoya journal of medical science 84 ( 2 ) 260 - 268 2022年05月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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.
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Psychiatric patients with a de novo 17q12 deletion: two case reports. 査読あり 国際誌
Itaru Kushima, Mariko Uematsu, Kanako Ishizuka, Branko Aleksic, Norio Ozaki
Psychiatry and clinical neurosciences 2022年04月
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Cross-disorder analysis of genic and regulatory copy number variations in bipolar disorder, schizophrenia, and autism spectrum disorder 査読あり
Itaru Kushima, Masahiro Nakatochi, Branko Aleksic, Takashi Okada, Hiroki Kimura, Hidekazu Kato, Mako Morikawa, Toshiya Inada, Kanako Ishizuka, Youta Torii, Yukako Nakamura, Satoshi Tanaka, Miho Imaeda, Nagahide Takahashi, Maeri Yamamoto, Kunihiro Iwamoto, Yoshihiro Nawa, Nanayo Ogawa, Shuji Iritani, Yu Hayashi, Tzuyao Lo, Gantsooj Otgonbayar, Sho Furuta, Nakao Iwata, Masashi Ikeda, Takeo Saito, Kohei Ninomiya, Tomo Okochi, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Kenichiro Miura, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Kazuya Toriumi, Kazutaka Ohi, Toshiki Shioiri, Kiyoyuki Kitaichi, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Tsutomu Takahashi, Michio Suzuki, Tsukasa Sasaki, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Hitoshi Kuwabara, Tomoyasu Wakuda, Takahiro A. Kato, Shigenobu Kanba, Hideki Horikawa, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Takeo Yoshikawa, Tomoko Toyota, Shigeru Yokoyama, Toshio Munesue, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Minyoung Jung, Kiyoto Kasai, Tempei Ikegame, Seiichiro Jinde, Shusuke Numata, Makoto Kinoshita, Tadafumi Kato, Chihiro Kakiuchi, Kazuhiro Yamakawa, Toshimitsu Suzuki, Naoki Hashimoto, Shuhei Ishikawa, Bun Yamagata, Shintaro Nio, Toshiya Murai, Shuraku Son, Yasuto Kunii, Hirooki Yabe, Masumi Inagaki, Yu-ichi Goto, Yuto Okumura, Tomoya Ito, Yuko Arioka, Daisuke Mori, Norio Ozaki
Biological Psychiatry 92 ( 5 ) 362 - 374 2022年04月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Elsevier BV
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Autistic traits as predictors of persistent depression. 査読あり 国際誌
Kanako Ishizuka, Tomomi Ishiguro, Norio Nomura, Toshiya Inada
European archives of psychiatry and clinical neuroscience 272 ( 2 ) 211 - 216 2022年03月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌）
Persistent depression has been suggested to be associated with autistic traits in people of working age. This study aimed to clarify which autistic characteristics at the initial visit were associated with persistent depression at the 12 week follow-up in a primary care setting. Newly depressed outpatients aged 24-59 years with no history of autism were asked to complete the 50-item autism spectrum quotient (AQ) and the Beck depression inventory (BDI) at baseline and 12 week follow-up (N = 123, males: 48%, age: 37.7 ± 9.15 years). Nearly 40% of participants had an AQ score ≥ 26. Significant differences were observed between the group with remitted depression (N = 43) and those with persistent depression (N = 80) in educational years and AQ "attention switching" and "attention to detail" subscale scores. In addition, a statistically significant decrease in the total AQ and the "communication" and "imagination" scores were observed in the remitted group, while no such change was observed in the group with persistent depression. It remains unclear whether the self-perceived severity of communication and imagination traits in persistent depression was due to the state of persistent depression or a kind of premorbid autistic trait. The results suggest that high levels of autistic traits are frequently present in adults with depression. High "attention switching" and "attention to detail" scores in AQ screening at the first visit might predict the persistence of depressive symptoms after 12 weeks in adults with depression, while total AQ scores, especially for "communication" and "imagination" items, might be state-dependent.
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Identification of ultra-rare disruptive variants in voltage-gated calcium channel-encoding genes in Japanese samples of schizophrenia and autism spectrum disorder. 査読あり 国際誌
Chenyao Wang, Shin-Ichiro Horigane, Minoru Wakamori, Shuhei Ueda, Takeshi Kawabata, Hajime Fujii, Itaru Kushima, Hiroki Kimura, Kanako Ishizuka, Yukako Nakamura, Yoshimi Iwayama, Masashi Ikeda, Nakao Iwata, Takashi Okada, Branko Aleksic, Daisuke Mori, Takashi Yoshida, Haruhiko Bito, Takeo Yoshikawa, Sayaka Takemoto-Kimura, Norio Ozaki
Translational psychiatry 12 ( 1 ) 84 - 84 2022年02月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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.
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Autism spectrum disorder comorbid with obsessive compulsive disorder and eating disorder in a woman with NBEA deletion. 査読あり 国際誌
Hidekazu Kato, Itaru Kushima, Akira Yoshimi, Kanako Ishizuka, Hiroki Kimura, Branko Aleksic, Nagahide Takahashi, Takashi Okada, Norio Ozaki
Psychiatry and clinical neurosciences 76 ( 1 ) 36 - 38 2022年01月
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Catatonia and Delirium: Similarity and Overlap of Acute Brain Dysfunction. 招待あり 査読あり 国際誌
Masako Tachibana, Kanako Ishizuka, Toshiya Inada
Frontiers in psychiatry 13 876727 - 876727 2022年
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Possible Commonalities of Clinical Manifestations Between Dystonia and Catatonia. 招待あり 査読あり 国際誌
Kanako Ishizuka, Masako Tachibana, Toshiya Inada
Frontiers in psychiatry 13 876678 - 876678 2022年
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Psychosocial characteristics of alcoholic and non-alcoholic liver disease recipient candidates in liver transplantation: a prospective observational study. 国際誌
Masato Shizuku, Hiroyuki Kimura, Hideya Kamei, Shinichi Kishi, Tatsuya Tokura, Nobuhiko Kurata, Kanta Jobara, Atsushi Yoshizawa, Chisato Tsuboi, Naoko Yamaguchi, Midori Kato, Keita Kawai, Makoto Yamashiki, Emi Kanai, Kanako Ishizuka, Norio Ozaki, Yasuhiro Ogura
BMC gastroenterology 21 ( 1 ) 449 - 449 2021年11月
記述言語：英語 掲載種別：研究論文（学術雑誌）
BACKGROUND: There are long-standing controversies about the transplant indications for alcoholic liver disease (ALD), because of the recognition that ALD is fundamentally self-inflicted. However, it is unclear whether psychosocial characteristics of ALD are different from that of non-alcoholic liver disease (NALD) in the selection of liver transplantation (LT) recipients. We aimed to clarify the psychosocial characteristics of ALD recipients (ALD-R)/ALD recipient candidates (ALD-RC) and NALD recipients (NALD-R)/ NALD recipient candidates (NALD-RC). METHODS: From 2011 to 2019, 75 patients were enrolled in this prospective observational study (ALD-RC, n = 19; NALD-RC, n = 56), LT were carried out as follow; ALD-R, n = 6; NALD-R, n = 52. We evaluated psychosocial characteristics in the preoperative period and 3, 12 months after LT (ALD-R, n = 3/3; NALD-R, n = 28/25). The following scales were used to evaluate psychosocial characteristics: Visual Analogue Scale, Alcohol Use Disorders Identification Test, Hospital Anxiety and Depression Scale, Beck Depression Inventory, Brief Evaluation of Medication Influences and Beliefs, Social Support Questionnaire (SSQ), Temperament and Character Inventory, Parental Bonding Instrument (PBI), the Short Form Health Survey (SF-36). RESULTS: When evaluating on the basis of abstinence rule, a comparison of ALD-RC and NALD-RC in the preoperative period identified similar patterns of psychosocial characteristics, except that the NALD-RC scored higher on the PBI item "overprotection from mother" (P < 0.05). The only significant difference between ALD-R and NALD-R after liver transplantation was in SSQ scores at 3 months. CONCLUSION: The psychosocial characteristics of ALD-RC and NALD-RC may be similar when evaluated on the basis of Japan's abstinence rule. This result also imply that the psychosocial characteristics of ALD-RC may differ from the previously reported psychosocial characteristics of alcohol dependent patients. These findings have the potential to provide helpful information for the evaluation of ALD-RC.
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COVID-19が不安症・ストレス障害に及ぼす影響
石塚佳奈子
臨床精神薬理 24 ( 10 ) 1001 - 1009 2021年10月
担当区分：筆頭著者, 責任著者
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発達障害がある人の抑うつ症状に自己記入式評価尺度を用いる際の注意点
石塚佳奈子
臨床精神薬理 24 ( 8 ) 803 - 809 2021年08月
担当区分：筆頭著者, 責任著者
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Establishment of in-hospital clinical network for patients with neurofibromatosis type 1 in Nagoya University Hospital. 国際誌
Yoshihiro Nishida, Kunihiro Ikuta, Atsushi Natsume, Naoko Ishihara, Maki Morikawa, Hiroyuki Kidokoro, Yukako Muramatsu, Norie Nonobe, Kanako Ishizuka, Takuya Takeichi, Miki Kanbe, Seiji Mizuno, Shiro Imagama, Norio Ozaki
Scientific reports 11 ( 1 ) 11933 - 11933 2021年06月
記述言語：英語 掲載種別：研究論文（学術雑誌）
Neurofibromatosis type 1 (NF1) is a genetic multisystem disorder. Clinicians must be aware of the diverse clinical features of this disorder in order to provide optimal care for it. We have set up an NF1 in-hospital medical care network of specialists regardless of patient age, launching a multidisciplinary approach to the disease for the first time in Japan. From January 2014 to December 2020, 246 patients were enrolled in the NF1 patient list and medical records. Mean age was 26.0 years ranging from 3 months to 80 years. The number of patients was higher as age at first visit was lower. There were 107 males (41%) and 139 females. After 2011, the number of patients has increased since the year when the medical care network was started. Regarding orthopedic signs, scoliosis was present in 60 cases (26%), and bone abnormalities in the upper arm, forearm, and tibia in 8 cases (3.5%). Neurofibromas other than cutaneous neurofibromas were present in 90 cases (39%), and MPNST in 17 cases (7.4%). We launched a multidisciplinary NF1 clinic system for the first time in Japan. For patients with NF1, which is a hereditary and systemic disease associated with a high incidence of malignant tumors, it will be of great benefit when the number of such clinics in Japan and the rest of Asia is increased.
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Depressive mood changes are associated with self-perceptions of ADHD characteristics in adults. 査読あり 国際誌
Kanako Ishizuka, Tomomi Ishiguro, Norio Nomura, Toshiya Inada
Psychiatry research 300 113893 - 113893 2021年06月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌）
Subjective attention deficit/hyperactivity disorder (ADHD) symptoms seen in adult depressive patients have often become a pathophysiological topic in recent years. Screening questionnaires are widely used for detecting ADHD; however, the risk of misdiagnosis exists. The present study examined whether self-perceptions of ADHD-related characteristics were consistent regardless of changes in the severity of depressive symptoms. Between April to October 2018, newly diagnosed depressed outpatients aged 24-59 years with good social functioning and without a history of ADHD were asked to fill out the Adult ADHD Self-Report Scale version 1.1 (ASRS) and the Beck Depression Inventory (BDI) at baseline (n = 726) and 12-week follow-up (n = 202). A statistically significant correlation was found between a change in BDI and ASRS scores (score at baseline minus score at the endpoint; r = .57). In addition, the higher the rate of improvement in BDI, the lower the frequency of positive screening for ADHD by ASRS. This study showed that subjective ADHD symptoms were correlated with depressive states. Diagnostic evaluation of comorbid ADHD using self-report scales in a primary care setting should be made with caution.
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特集 同意取得が困難な事例を対象とした症例報告や研究における問題点と課題 「遺伝負因」の終焉から当事者・家族と進めるゲノム医療へ―ゲノム解析・遺伝カウンセリングに携わる臨床遺伝専門医の立場から― 査読あり
石塚 佳奈子
精神神経学雑誌 123 ( 6 ) 342 - 348 2021年06月
記述言語：日本語 出版者・発行元：(公社)日本精神神経学会
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Peripheral biomarkers of attention-deficit hyperactivity disorder: Current status and future perspective. 国際誌
Nagahide Takahashi, Kanako Ishizuka, Toshiya Inada
Journal of psychiatric research 137 465 - 470 2021年05月
記述言語：英語 掲載種別：研究論文（学術雑誌）
Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, characterized by a persistent pattern of inattention, hyperactivity, and impulsivity. Since the diagnosis of ADHD is defined by operational diagnostic criteria consisting of several clinical symptoms, a number of heterogeneous mechanisms have been considered to be implicated in its pathophysiology. Although no clinically reliable biomarkers are available for the diagnosis of ADHD, several plausible candidate biomarkers have been proposed based on recent advances in biochemistry and molecular biology. This review article summarizes potential peripheral biomarkers associated with ADHD, mainly from recently published case-control studies. These include 1) biochemical markers: neurotransmitters and their receptors, neurotrophic factors, serum electrolytes, and inflammation markers; 2) genetic and epigenetic markers: microRNA, mRNA expression, and peripheral DNA methylation; 3) physiological markers: eye movement and electroencephalography. It also discusses the limitations and future directions of these potential biomarkers for application in clinical practice.
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Preliminary investigation of public perspectives towards psychiatric genetics in Japan. 査読あり 国際誌
Kanako Ishizuka
Asian journal of psychiatry 55 102519 - 102519 2021年01月
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Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder. 国際誌
Hidekazu Kato, Itaru Kushima, Daisuke Mori, Akira Yoshimi, Branko Aleksic, Yoshihiro Nawa, Miho Toyama, Sho Furuta, Yanjie Yu, Kanako Ishizuka, Hiroki Kimura, Yuko Arioka, Keita Tsujimura, Mako Morikawa, Takashi Okada, Toshiya Inada, Masahiro Nakatochi, Keiko Shinjo, Yutaka Kondo, Kozo Kaibuchi, Yasuko Funabiki, Ryo Kimura, Toshimitsu Suzuki, Kazuhiro Yamakawa, Masashi Ikeda, Nakao Iwata, Tsutomu Takahashi, Michio Suzuki, Yuko Okahisa, Manabu Takaki, Jun Egawa, Toshiyuki Someya, Norio Ozaki
Translational psychiatry 10 ( 1 ) 421 - 421 2020年12月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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.
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Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility. 国際誌
Yoshihiro Nawa, Hiroki Kimura, Daisuke Mori, Hidekazu Kato, Miho Toyama, Sho Furuta, Yanjie Yu, Kanako Ishizuka, Itaru Kushima, Branko Aleksic, Yuko Arioka, Mako Morikawa, Takashi Okada, Toshiya Inada, Kozo Kaibuchi, Masashi Ikeda, Nakao Iwata, Michio Suzuki, Yuko Okahisa, Jun Egawa, Toshiyuki Someya, Fumichika Nishimura, Tsukasa Sasaki, Norio Ozaki
Human genome variation 7 ( 1 ) 37 - 37 2020年11月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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.
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Functional characterization of rare NRXN1 variants identified in autism spectrum disorders and schizophrenia. 査読あり 国際誌
Kanako Ishizuka, Tomoyuki Yoshida, Takeshi Kawabata, Ayako Imai, Hisashi Mori, Hiroki Kimura, Toshiya Inada, Yuko Okahisa, Jun Egawa, Masahide Usami, Itaru Kushima, Mako Morikawa, Takashi Okada, Masashi Ikeda, Aleksic Branko, Daisuke Mori, Toshiyuki Someya, Nakao Iwata, Norio Ozaki
Journal of neurodevelopmental disorders 12 ( 1 ) 25 - 25 2020年09月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Springer Science and Business Media LLC
<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
その他リンク： http://link.springer.com/article/10.1186/s11689-020-09325-2/fulltext.html
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ARHGAP10, which encodes Rho GTPase-activating protein 10, is a novel gene for schizophrenia risk. 査読あり 国際誌
Mariko Sekiguchi, Akira Sobue, Itaru Kushima, Chenyao Wang, Yuko Arioka, Hidekazu Kato, Akiko Kodama, Hisako Kubo, Norimichi Ito, Masahito Sawahata, Kazuhiro Hada, Ryosuke Ikeda, Mio Shinno, Chikara Mizukoshi, Keita Tsujimura, Akira Yoshimi, Kanako Ishizuka, Yuto Takasaki, Hiroki Kimura, Jingrui Xing, Yanjie Yu, Maeri Yamamoto, Takashi Okada, Emiko Shishido, Toshiya Inada, Masahiro Nakatochi, Tetsuya Takano, Keisuke Kuroda, Mutsuki Amano, Branko Aleksic, Takashi Yamomoto, Tetsushi Sakuma, Tomomi Aida, Kohichi Tanaka, Ryota Hashimoto, Makoto Arai, Masashi Ikeda, Nakao Iwata, Teppei Shimamura, Taku Nagai, Toshitaka Nabeshima, Kozo Kaibuchi, Kiyofumi Yamada, Daisuke Mori, Norio Ozaki
Translational psychiatry 10 ( 1 ) 247 - 247 2020年07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：Springer Science and Business Media LLC
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.
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【その定説は本当ですか?】注意欠如多動症の診断と薬物療法は過少か?過剰か? 招待あり
石塚 佳奈子
臨床精神薬理 23 ( 6 ) 633 - 641 2020年06月
担当区分：筆頭著者, 責任著者 記述言語：日本語 出版者・発行元：(株)星和書店
ADHDはDSM-5で神経発達症の1つに組み込まれ、成人期まで問題が続く慢性疾患と認識されるようになった。ADHDは生物学的基盤と環境が複雑かつ力動的に相互作用する多因子的な疾患概念である。生活している限り環境との齟齬は生じうるため、小児期の一時的な介入は必ずしも長期予後を改善しない。ライフコースに沿った継続的な患者-治療者関係が必要な疾患である。ADHDの疾患概念の拡がりや疾患啓発は、見過ごされてきた群への適切な診断や介入につながった一方で、鑑別を欠く過剰なADHD診断と薬物療法を引き起こした。本稿ではADHD概念を臨床でどのように活かすのか、診断や薬物療法の過剰、過少に影響しうる要因を通じて検討したい。(著者抄録)
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Generation and analysis of novel Reln-deleted mouse model corresponding to exonic Reln deletion in schizophrenia. 査読あり 国際誌
Masahito Sawahata, Daisuke Mori, Yuko Arioka, Hisako Kubo, Itaru Kushima, Kanako Kitagawa, Akira Sobue, Emiko Shishido, Mariko Sekiguchi, Akiko Kodama, Ryosuke Ikeda, Branko Aleksic, Hiroki Kimura, Kanako Ishizuka, Taku Nagai, Kozo Kaibuchi, Toshitaka Nabeshima, Kiyofumi Yamada, Norio Ozaki
Psychiatry and clinical neurosciences 74 ( 5 ) 318 - 327 2020年05月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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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児童思春期のうつ病に対する抗うつ薬療法の是非 招待あり
松川剛, 石塚佳奈子, 稲田俊也
臨床精神薬理 23 ( 6 ) 627 - 632 2020年05月
担当区分：責任著者
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Clinical Features and Long-Term Outcomes of Living Donors of Liver Transplantation Who Developed Psychiatric Disorders. 査読あり 国際誌
Masato Shizuku, Hideya Kamei, Hiroyuki Kimura, Nobuhiko Kurata, Kanta Jobara, Atsushi Yoshizawa, Kanako Ishizuka, Aoi Okada, Shinichi Kishi, Norio Ozaki, Yasuhiro Ogura
Annals of transplantation 25 e918500 - 7 2020年01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：International Scientific Information, Inc.
BACKGROUND In the field of living donor liver transplantation (LDLT), it is important to ensure donor's psychological well-being. We report on clinical features and long-term outcomes of LDLT donors who developed psychiatric disorders after their donor operations. Additionally, we compare patient backgrounds, as well as surgical and perioperative aspects between LDLT donors with and without postoperative psychiatric complications. MATERIAL AND METHODS Between November 1998 and March 2018, we identified 254 LDLT donors at our hospital. Among these, we investigated those who had newly developed psychiatric complications and required psychiatric treatment after donor operation. RESULTS The median duration of follow-up was 4 years. Sixty-five donors were lost to follow-up. Eight donors (3.1%) developed postoperative psychiatric complications, including major depressive disorder in 4, panic disorder in 2, conversion disorder and panic disorder in 1, and adjustment disorder in 1. The median duration from donor surgery to psychiatric diagnosis was 104.5 days (range, 12 to 657 days) and the median treatment duration was 18 months (range, 3 to 168 months). Of those, 3 donors required psychiatric treatment over 10 years, and 4 donors remained under treatment. The duration of hospital stay after donor operation was significantly longer and perioperative complications with Clavien classification greater than grade IIIa were more frequent in donors with psychiatric complications than in those without psychiatric complications (P=0.02 and P=0.006, respectively). CONCLUSIONS Accurate diagnosis and appropriate treatment for psychiatric disorders by psychiatrists and psychologists are important during LDLT donor follow-up. Minimization of physiological complications might be important to prevent postoperative psychiatric complications in LDLT donors.
DOI： 10.12659/AOT.918500
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分子精神医学の気になる進歩：ゲノム医学領域の進展を中心に 招待あり
瀬名波徹, 石塚佳奈子, 久島周, 尾崎紀夫
精神科 36 ( 1 ) 92 - 97 2020年01月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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「遺伝」を継承と多様性で語る精神科医療に―精神疾患の遺伝要因を当事者やその家族とどう話し合うか― 査読あり
石塚佳奈子, 尾崎紀夫
日本精神神経学会雑誌 121 ( 8 ) 602 - 611 2019年08月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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Assessment of a glyoxalase I frameshift variant, p.P122fs, in Japanese patients with schizophrenia. 国際誌
Kanako Ishizuka, Hiroki Kimura, Itaru Kushima, Toshiya Inada, Yuko Okahisa, Masashi Ikeda, Nakao Iwata, Daisuke Mori, Branko Aleksic, Norio Ozaki
Psychiatric genetics 28 ( 5 ) 90 - 93 2018年10月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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.
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Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. 査読あり 国際誌
Itaru Kushima, Branko Aleksic, Masahiro Nakatochi, Teppei Shimamura, Takashi Okada, Yota Uno, Mako Morikawa, Kanako Ishizuka, Tomoko Shiino, Hiroki Kimura, Yuko Arioka, Akira Yoshimi, Yuto Takasaki, Yanjie Yu, Yukako Nakamura, Maeri Yamamoto, Tetsuya Iidaka, Shuji Iritani, Toshiya Inada, Nanayo Ogawa, Emiko Shishido, Youta Torii, Naoko Kawano, Yutaka Omura, Toru Yoshikawa, Tokio Uchiyama, Toshimichi Yamamoto, Masashi Ikeda, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Ayako Nunokawa, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Akiko Kobori, Michio Suzuki, Tsutomu Takahashi, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Tsukasa Sasaki, Hitoshi Kuwabara, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Yosuke Eriguchi, Seico Benner, Masaki Kojima, Walid Yassin, Toshio Munesue, Shigeru Yokoyama, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Makoto Ishitobi, Tetsuro Ohmori, Shusuke Numata, Takeo Yoshikawa, Tomoko Toyota, Kazuhiro Yamakawa, Toshimitsu Suzuki, Yushi Inoue, Kentaro Nakaoka, Yu-Ichi Goto, Masumi Inagaki, Naoki Hashimoto, Ichiro Kusumi, Shuraku Son, Toshiya Murai, Tempei Ikegame, Naohiro Okada, Kiyoto Kasai, Shohko Kunimoto, Daisuke Mori, Nakao Iwata, Norio Ozaki
Cell reports 24 ( 11 ) 2838 - 2856 2018年09月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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.
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Single-cell trajectory analysis of human homogenous neurons carrying a rare RELN variant. 国際誌
Yuko Arioka, Emiko Shishido, Hisako Kubo, Itaru Kushima, Akira Yoshimi, Hiroki Kimura, Kanako Ishizuka, Branko Aleksic, Takuji Maeda, Mitsuru Ishikawa, Naoko Kuzumaki, Hideyuki Okano, Daisuke Mori, Norio Ozaki
Translational psychiatry 8 ( 1 ) 129 - 129 2018年07月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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.
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Possible involvement of a cell adhesion molecule, Migfilin, in brain development and pathogenesis of autism spectrum disorders. 査読あり 国際誌
Kanako Ishizuka, Hidenori Tabata, Hidenori Ito, Itaru Kushima, Mariko Noda, Akira Yoshimi, Masahide Usami, Kyota Watanabe, Mako Morikawa, Yota Uno, Takashi Okada, Daisuke Mori, Branko Aleksic, Norio Ozaki, Koh-Ichi Nagata
Journal of neuroscience research 96 ( 5 ) 789 - 802 2018年05月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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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精神疾患のジェネティクス・自閉スペクトラム症 招待あり
石塚佳奈子, 尾崎紀夫
Clinical Neuroscience 36 ( 2 ) 238-241 2018年02月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder. 国際誌
Atsushi Takata, Noriko Miyake, Yoshinori Tsurusaki, Ryoko Fukai, Satoko Miyatake, Eriko Koshimizu, Itaru Kushima, Takashi Okada, Mako Morikawa, Yota Uno, Kanako Ishizuka, Kazuhiko Nakamura, Masatsugu Tsujii, Takeo Yoshikawa, Tomoko Toyota, Nobuhiko Okamoto, Yoko Hiraki, Ryota Hashimoto, Yuka Yasuda, Shinji Saitoh, Kei Ohashi, Yasunari Sakai, Shouichi Ohga, Toshiro Hara, Mitsuhiro Kato, Kazuyuki Nakamura, Aiko Ito, Chizuru Seiwa, Emi Shirahata, Hitoshi Osaka, Ayumi Matsumoto, Saoko Takeshita, Jun Tohyama, Tomoko Saikusa, Toyojiro Matsuishi, Takumi Nakamura, Takashi Tsuboi, Tadafumi Kato, Toshifumi Suzuki, Hirotomo Saitsu, Mitsuko Nakashima, Takeshi Mizuguchi, Fumiaki Tanaka, Norio Mori, Norio Ozaki, Naomichi Matsumoto
Cell reports 22 ( 3 ) 734 - 747 2018年01月
記述言語：英語 掲載種別：研究論文（学術雑誌）
Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the "de novo paradigm" of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.
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Rare loss of function mutations in N-methyl-D-aspartate glutamate receptors and their contributions to schizophrenia susceptibility. 国際誌
Yanjie Yu, Yingni Lin, Yuto Takasaki, Chenyao Wang, Hiroki Kimura, Jingrui Xing, Kanako Ishizuka, Miho Toyama, Itaru Kushima, Daisuke Mori, Yuko Arioka, Yota Uno, Tomoko Shiino, Yukako Nakamura, Takashi Okada, Mako Morikawa, Masashi Ikeda, Nakao Iwata, Yuko Okahisa, Manabu Takaki, Shinji Sakamoto, Toshiyuki Someya, Jun Egawa, Masahide Usami, Masaki Kodaira, Akira Yoshimi, Tomoko Oya-Ito, Branko Aleksic, Kinji Ohno, Norio Ozaki
Translational psychiatry 8 ( 1 ) 12 - 12 2018年01月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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.
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乳幼児期の環境と発育発達〜精神医学の観点から〜 招待あり
石塚佳奈子
子どもと発育発達 15 ( 4 ) 271-277 2018年01月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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Successful post-transplant psychiatric interventions during long-term follow-up of patients receiving liver transplants for alcoholic liver disease 国際誌
Hiroyuki Kimura, Yasuharu Onishi, Shinichi Kishi, Nobuhiko Kurata, Satoshi Ogiso, Hideya Kamei, Chisato Tsuboi, Naoko Yamaguchi, Azusa Shiga, Mai Kondo, Yushun Yokoyama, Fumika Takasato, Hiroshige Fujishiro, Kanako Ishizuka, Takashi Okada, Yasuhiro Ogura, Norio Ozaki
American Journal of Case Reports 18 1215 - 1219 2017年11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：International Scientific Information, Inc.
Objective: Unusual setting of medical care Background: Around 20-30% of patients who undergo liver transplantation (LT) for alcoholic liver disease (ALD) will resume heavy drinking after LT. It is crucial to control post-transplant relapse of alcohol use, because alcoholic recidivism has been shown to have a negative impact on post-transplant compliance and long-term outcomes of LT recipients. However, there is currently no specific, effective psychiatric intervention for preventing additional alcohol consumption in clinical practice. Case Report: We present 3 patients who underwent LT for ALD at Nagoya University Hospital who were followed up for prolonged periods (7.2, 8.8, and 11.3 years, respectively), and review the psychiatric interventions employed to address critical situations. Additional alcohol consumption was noted in Case 1, but prompt collaborative care led to stable abstinence. In Case 2, marked anger and irritation were exacerbated as a result of work, but the anger was controlled by anger management. Case 3 abused a minor tranquilizer, but limit-setting resulted in adequate medical adherence. Conclusions: Transplant teams need to provide comprehensive treatment for alcoholic recidivism to improve long-term health after LT for ALD.
DOI： 10.12659/AJCR.906446
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MUTATION SCREENING OF THE PCDH15 GENE IN PATIENTS SUFFERING FROM AUTISM SPECTRUM DISORDERS AND SCHIZOPHRENIA 査読あり
Kanako Ishizuka, Chenyao Wang, Hiroki Kimura, Jingrui Xing, Itaru Kushima, Yuko Arioka, Akira Yoshimi, Yukako Nakamura, Tomoko Oya-Ito, Yuto Takasaki, Yota Uno, Takashi Okada, Daisuke Mori, Branko Aleksic, Norio Ozaki
EUROPEAN NEUROPSYCHOPHARMACOLOGY 27 S162 - S163 2017年10月
記述言語：英語 掲載種別：研究論文（国際会議プロシーディングス）
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統合失調症発症に強い影響を及ぼす、頻度の低い稀な遺伝子変異を22q11.2欠失領域に存在するミエリン関連遺伝子のRTN4Rに同定した
木村 大樹, 藤田 幸, 川端 猛, 石塚 佳奈子, Wang Chenyao, 岩山 佳美, 岡久 祐子, 久島 周, 宇野 洋太, 岡田 俊, 森川 真子, 森 大輔, 池田 匡志, 稲田 俊也, Aleksic Branko, 吉川 武男, 岩田 仲生, 中村 春木, 山下 俊英, 尾崎 紀夫
日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集 39回・47回 190 - 190 2017年09月
記述言語：日本語 出版者・発行元：日本生物学的精神医学会・日本神経精神薬理学会
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Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders 査読あり
K. Ishizuka, Y. Fujita, T. Kawabata, H. Kimura, Y. Iwayama, T. Inada, Y. Okahisa, J. Egawa, M. Usami, I. Kushima, Y. Uno, T. Okada, M. Ikeda, B. Aleksic, D. Mori, To Someya, T. Yoshikawa, N. Iwata, H. Nakamura, T. Yamashita, N. Ozaki
TRANSLATIONAL PSYCHIATRY 7 ( 8 ) e1184 2017年08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：NATURE PUBLISHING GROUP
CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To address the impacts of variants in CX3CR1 on neurodevelopmental disorders, we conducted coding exon-targeted resequencing of CX3CR1 in 370 Japanese SCZ and 192 ASD patients using next-generation sequencing technology, followed by a genetic association study in a sample comprising 7054 unrelated individuals (2653 SCZ, 574 ASD and 3827 controls). We then performed in silico three-dimensional (3D) structural modeling and in vivo disruption of Akt phosphorylation to determine the impact of the detected variant on CX3CR1-dependent signal transduction. We detected a statistically significant association between the variant Ala55Thr in CX3CR1 with SCZ and ASD phenotypes (odds ratio = 8.3, P = 0.020). A 3D structural model indicated that Ala55Thr could destabilize the conformation of the CX3CR1 helix 8 and affect its interaction with a heterotrimeric G protein. In vitro functional analysis showed that the CX3CR1-Ala55Thr mutation inhibited cell signaling induced by fractalkine, the ligand for CX3CR1. The combined data suggested that the variant Ala55Thr in CX3CR1 might result in the disruption of CX3CR1 signaling. Our results strengthen the association between microglia-specific genes and neurodevelopmental disorders.
DOI： 10.1038/tp.2017.173
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A novel rare variant R292H in RTN4R affects growth cone formation and possibly contributes to schizophrenia susceptibility
H. Kimura, Y. Fujita, T. Kawabata, K. Ishizuka, C. Wang, Y. Iwayama, Y. Okahisa, I. Kushima, M. Morikawa, Y. Uno, T. Okada, M. Ikeda, T. Inada, A. Branko, D. Mori, T. Yoshikawa, N. Iwata, H. Nakamura, T. Yamashita, N. Ozaki
TRANSLATIONAL PSYCHIATRY 7 2017年08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：NATURE PUBLISHING GROUP
Reticulon 4 receptor (RTN4R) plays an essential role in regulating axonal regeneration and plasticity in the central nervous system through the activation of rho kinase, and is located within chromosome 22q11.2, a region that is known to be a hotspot for schizophrenia (SCZ) and autism spectrum disorder (ASD). Recently, rare variants such as copy-number variants and single-nucleotide variants have been a focus of research because of their large effect size associated with increased susceptibility to SCZ and ASD and the possibility of elucidating the pathophysiology of mental disorder through functional analysis of the discovered rare variants. To discover rare variants with large effect size and to evaluate their role in the etiopathophysiology of SCZ and ASD, we sequenced the RTN4R coding exons with a sample comprising 370 SCZ and 192 ASD patients, and association analysis using a large number of unrelated individuals (1716 SCZ, 382 ASD and 4009 controls). Through this mutation screening, we discovered four rare (minor allele frequency <1%) missense mutations (R68H, D259N, R292H and V363M) of RTN4R. Among these discovered rare mutations, R292H was found to be significantly associated with SCZ (P = 0.048). Furthermore, in vitro functional assays showed that the R292H mutation affected the formation of growth cones. This study strengthens the evidence for association between rare variants within RTN4R and SCZ, and may shed light on the molecular mechanisms underlying the neurodevelopmental disorder.
DOI： 10.1038/tp.2017.170
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自閉スペクトラム症の診断と病態 招待あり
石塚佳奈子, 尾崎紀夫
日本生物学的精神医学会誌 28 ( 1 ) 11-17 2017年04月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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High-resolution copy number variation analysis of schizophrenia in Japan
I. Kushima, B. Aleksic, M. Nakatochi, T. Shimamura, T. Shiino, A. Yoshimi, H. Kimura, Y. Takasaki, C. Wang, J. Xing, K. Ishizuka, T. Oya-Ito, Y. Nakamura, Y. Arioka, T. Maeda, M. Yamamoto, M. Yoshida, H. Noma, S. Hamada, M. Morikawa, Y. Uno, T. Okada, T. Iidaka, S. Iritani, T. Yamamoto, M. Miyashita, A. Kobori, M. Arai, M. Itokawa, M-C Cheng, Y-A Chuang, C-H Chen, M. Suzuki, T. Takahashi, R. Hashimoto, H. Yamamori, Y. Yasuda, Y. Watanabe, A. Nunokawa, T. Someya, M. Ikeda, T. Toyota, T. Yoshikawa, S. Numata, T. Ohmori, S. Kunimoto, D. Mori, N. Iwata, N. Ozaki
MOLECULAR PSYCHIATRY 22 ( 3 ) 430 - 440 2017年03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：NATURE PUBLISHING GROUP
Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (< 100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio = 3.04, P = 9.3 x 10 (-9), 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e. g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio = 2.79, P = 0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e. g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.
DOI： 10.1038/mp.2016.88
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選択性緘黙 招待あり
石塚佳奈子, 本城秀次
臨床精神医学 45 216-219 2016年12月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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Investigation of single-nucleotide variants in MBD5 associated with autism spectrum disorders and schizophrenia phenotypes. 査読あり
Kanako Ishizuka, Hiroki Kimura, Akira Yoshimi, Masahiro Banno, Itaru Kushima, Yota Uno, Takashi Okada, Daisuke Mori, Branko Aleksic, Norio Ozaki
Nagoya journal of medical science 78 ( 4 ) 465 - 474 2016年12月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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.
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Identification of a rare variant in CHD8 that contributes to schizophrenia and autism spectrum disorder susceptibility 査読あり
Hiroki Kimura, Chenyao Wang, Kanako Ishizuka, Jingrui Xing, Yuto Takasaki, Itaru Kushima, Branko Aleksic, Yota Uno, Takashi Okada, Masashi Ikeda, Daisuke Mori, Toshiya Inada, Nakao Iwata, Norio Ozaki
SCHIZOPHRENIA RESEARCH 178 ( 1-3 ) 104 - 106 2016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：ELSEVIER SCIENCE BV
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Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population. 査読あり 国際誌
Yuto Takasaki, Takayoshi Koide, Chenyao Wang, Hiroki Kimura, Jingrui Xing, Itaru Kushima, Kanako Ishizuka, Daisuke Mori, Mariko Sekiguchi, Masashi Ikeda, Miki Aizawa, Naoko Tsurumaru, Yoshimi Iwayama, Akira Yoshimi, Yuko Arioka, Mami Yoshida, Hiromi Noma, Tomoko Oya-Ito, Yukako Nakamura, Shohko Kunimoto, Branko Aleksic, Yota Uno, Takashi Okada, Hiroshi Ujike, Jun Egawa, Hitoshi Kuwabara, Toshiyuki Someya, Takeo Yoshikawa, Nakao Iwata, Norio Ozaki
Scientific reports 6 33311 - 33311 2016年09月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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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乳幼児精神医学という視点 招待あり
石塚佳奈子, 本城秀次
精神科治療学 31 ( 7 ) 839-843 2016年07月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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Resequencing and Association Analysis of Six PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism Spectrum Disorders. 査読あり 国際誌
Jingrui Xing, Hiroki Kimura, Chenyao Wang, Kanako Ishizuka, Itaru Kushima, Yuko Arioka, Akira Yoshimi, Yukako Nakamura, Tomoko Shiino, Tomoko Oya-Ito, Yuto Takasaki, Yota Uno, Takashi Okada, Tetsuya Iidaka, Branko Aleksic, Daisuke Mori, Norio Ozaki
Scientific reports 6 27491 - 27491 2016年06月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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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PM338. Investigation of the association of rare single nucleotide variants in methyl-CpG-binding domain protein 5 (MBD5) with phenotypes of autism spectrum disorders and schizophrenia. 査読あり
Ishizuka K, Aleksic B, Chenyao W, Kimura H, Kushima I, Okada T, Ozaki N, Uno Y
The international journal of neuropsychopharmacology 2016年05月
掲載種別：研究論文（学術雑誌）
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Investigation of Rare Single-Nucleotide PCDH15 Variants in Schizophrenia and Autism Spectrum Disorders 査読あり
Kanako Ishizuka, Hiroki Kimura, Chenyao Wang, Jingrui Xing, Itaru Kushima, Yuko Arioka, Tomoko Oya-Ito, Yota Uno, Takashi Okada, Daisuke Mori, Branko Aleksic, Norio Ozaki
PLOS ONE 11 ( 4 ) e0153224 2016年04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：PUBLIC LIBRARY SCIENCE
Both schizophrenia (SCZ) and autism spectrum disorders (ASD) are neuropsychiatric disorders with overlapping genetic etiology. Protocadherin 15 (PCDH15), which encodes a member of the cadherin super family that contributes to neural development and function, has been cited as a risk gene for neuropsychiatric disorders. Recently, rare variants of large effect have been paid attention to understand the etiopathology of these complex disorders. Thus, we evaluated the impacts of rare, single-nucleotide variants (SNVs) in PCDH15 on SCZ or ASD. First, we conducted coding exon-targeted resequencing of PCDH15 with next-generation sequencing technology in 562 Japanese patients (370 SCZ and 192 ASD) and detected 16 heterozygous SNVs. We then performed association analyses on 2,096 cases (1,714 SCZ and 382 ASD) and 1,917 controls with six novel variants of these 16 SNVs. Of these six variants, four (p. R219K, p. T281A, p. D642N, c. 3010-1G> C) were ultra-rare variants (minor allele frequency < 0.0005) that may increase disease susceptibility. Finally, no statistically significant association between any of these rare, heterozygous PCDH15 point variants and SCZ or ASD was found. Our results suggest that a larger sample size of resequencing subjects is necessary to detect associations between rare PCDH15 variants and neuropsychiatric disorders.
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Resequencing and Association Analysis of CLN8 with Autism Spectrum Disorder in a Japanese Population 査読あり
Emiko Inoue, Yuichiro Watanabe, Jingrui Xing, Itaru Kushima, Jun Egawa, Shujiro Okuda, Satoshi Hoya, Takashi Okada, Yota Uno, Kanako Ishizuka, Atsunori Sugimoto, Hirofumi Igeta, Ayako Nunokawa, Toshiro Sugiyama, Norio Ozaki, Toshiyuki Someya
PLOS ONE 10 ( 12 ) e0144624 2015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：PUBLIC LIBRARY SCIENCE
Rare variations contribute substantially to autism spectrum disorder (ASD) liability. We recently performed whole-exome sequencing in two families with affected siblings and then carried out a follow-up study and identified ceroid-lipofuscinosis neuronal 8 (epilepsy, progressive with mental retardation) (CLN8) as a potential genetic risk factor for ASD. To further investigate the role of CLN8 in the genetic etiology of ASD, we performed resequencing and association analysis of CLN8 with ASD in a Japanese population. Resequencing the CLN8 coding region in 256 ASD patients identified five rare missense variations: g.1719291G>A (R24H), rs201670636 (F39L), rs116605307 (R97H), rs143701028 (T108M) and rs138581191 (N152S). These variations were genotyped in 568 patients (including the resequenced 256 patients) and 1017 controls. However, no significant association between these variations and ASD was identified. This study does not support a contribution of rare missense CLN8 variations to ASD susceptibility in the Japanese population.
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臨床知に根ざした神経科学を担う人材育成 統合失調症の発症に強い影響を与える稀なゲノムコピー数変異(CNV)の検討
久島 周, アレクシッチ・ブランコ, 椎野 智子, 吉見 陽, 大矢 友子, 木村 大樹, Wang Chenyao, 高崎 悠登, 石塚 佳奈子, 鈴木 道雄, 糸川 昌成, 大森 哲郎, 染矢 俊幸, 吉川 武男, Xing Jingrui, 武田 雅俊, 橋本 亮太, 岩田 仲生, 池田 匡志, 尾崎 紀夫
日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集 37回・45回 123 - 123 2015年09月
記述言語：日本語 出版者・発行元：日本生物学的精神医学会・日本神経精神薬理学会
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遺伝と遺伝子研究を正しく理解する 招待あり
石塚佳奈子, 木村大樹, 尾崎紀夫
こころの科学 180 87-90 2015年03月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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自閉スペクトラム症の児童に対する応用行動分析に基づく介入 招待あり
宍戸恵美子, 石塚佳奈子, 岡田俊, 尾崎紀夫
Clinical Neuroscience 33 ( 2 ) 206-210 2015年02月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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抜毛症の子の症状理解をめざして 招待あり
石塚佳奈子
発達 139 36-40 2014年07月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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新生児専門医の到達目標の評価法－専門医試験で求められるレベルは－ 招待あり
諌山哲哉, 石塚佳奈子, 井上真改, 今井香織, 後藤貴子, 鶴田志緒, 邊見勇人, 三木裕子
日本未熟児新生児学会雑誌 19 ( 1 ) 117-120 2007年01月
記述言語：日本語 掲載種別：研究論文（学術雑誌）
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