Molecular analysis of bipolar disorder based on copy number variation

• Project/Area Number: 17H05090
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Psychiatric science
• Research Institution: Nagoya University
• Principal Investigator: Kushima Itaru 名古屋大学, 医学部附属病院, 病院講師 (00732645)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥25,480,000 (Direct Cost: ¥19,600,000、Indirect Cost: ¥5,880,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2017: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000)
• Keywords: 双極性障害 / ゲノムコピー数変異 / CNV

Outline of Final Research Achievements

Genetic factors have an important role for the risk of bipolar disorder (BD), but the details remained unclear. In this study, we performed a genome-wide analysis of copy number variations (CNVs), which have been implicated in other psychiatric disorders. We found that CNVs previously associated with psychiatric disorders may increase the risk for BD. Further analysis of CNV data revealed the involvement of lipid metabolism in the pathogenesis of BD. We analyzed iPS cells derived from BD patients with specific BD-associated CNVs and observed morphological abnormalities of dendrites and synapses in neurons.

Academic Significance and Societal Importance of the Research Achievements

双極性障害の発症には遺伝要因が強く関与するが、その詳細や発症メカニズムは不明であった。本研究結果から、精神疾患との関連が既に知られている様々なCNVが本疾患の発症に関与することが示唆され、双極性障害の遺伝要因の解明に繋がる成果といえる。また双極性障害の発症メカニズムとして脂質代謝異常の関与や、患者iPS細胞由来神経細胞において形態学的な異常も見出した。以上の知見は、双極性障害の病態の理解や治療法の開発に繋がる成果である。

Research Products

• [Journal Article] Comprehensive analysis of a novel mouse model of the 22q11.2 deletion syndrome: a model with the most common 3.0-Mb deletion at the human 22q11.2 locus (2020)
  • Author(s): Saito Ryo、Koebis Michinori、Nagai Taku、Shimizu Kimiko、Liao Jingzhu、Wulaer Bolati、Sugaya Yuki、Nagahama Kenichiro、Uesaka Naofumi、Kushima Itaru、Mori Daisuke、Maruyama Kazuaki、Nakao Kazuki、Kurihara Hiroki、Yamada Kiyofumi、Kano Masanobu、Fukada Yoshitaka、Ozaki Norio、Aiba Atsu
  • Journal Title: Translational Psychiatry Volume: 10 Issue: 1 Pages: 35-35
  • DOI: 10.1038/s41398-020-0723-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation and analysis of novel Reln-deleted mouse model corresponding to exonic Reln deletion in schizophrenia (2020)
  • Author(s): 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
  • Journal Title: Psychiatry and clinical neurosciences Volume: 1 Issue: 5 Pages: 1-10
  • DOI: 10.1111/pcn.12993
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2020)
  • Author(s): Satterstrom F. Kyle、Kosmicki Jack A.、Wang Jiebiao et al.
  • Journal Title: Cell Volume: 180 Issue: 3 Pages: 568-584.e23
  • DOI: 10.1016/j.cell.2019.12.036
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] In Vitro Modeling of the Bipolar Disorder and Schizophrenia Using Patient-Derived Induced Pluripotent Stem Cells with Copy Number Variations of PCDH15 and RELN (2019)
  • Author(s): Ishii Takaya、Ishikawa Mitsuru、Fujimori Koki、Maeda Takuji、Kushima Itaru、Arioka Yuko、Mori Daisuke、Nakatake Yuhki、Yamagata Bun、Nio Shintaro、Kato Takahiro A.、Yang Nan、Wernig Marius、Kanba Shigenobu、Mimura Masaru、Ozaki Norio、Okano Hideyuki
  • Journal Title: eNEURO Volume: 6 Issue: 5 Pages: 0403-18
  • DOI: 10.1523/eneuro.0403-18.2019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rare loss of function mutations in N-methyl-d-aspartate glutamate receptors and their contributions to schizophrenia susceptibility (2018)
  • Author(s): Yu Yanjie、Lin Yingni、Takasaki Yuto、Wang Chenyao、Kimura Hiroki、Xing Jingrui、Ishizuka Kanako、Toyama Miho、Kushima Itaru、Mori Daisuke、Arioka Yuko、Uno Yota、Shiino Tomoko、Nakamura Yukako、Okada Takashi、Morikawa Mako、Ikeda Masashi、Iwata Nakao、Okahisa Yuko、Takaki Manabu、Sakamoto Shinji、et al.
  • Journal Title: Translational Psychiatry Volume: 8 Issue: 1 Pages: 12-20
  • DOI: 10.1038/s41398-017-0061-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability (2018)
  • Author(s): Kunisawa Kazuo、Shimizu Takeshi、Kushima Itaru、Aleksic Branko、Mori Daisuke、Osanai Yasuyuki、Kobayashi Kenta、Taylor Anna M.、Bhat Manzoor A.、Hayashi Akiko、Baba Hiroko、Ozaki Norio、Ikenaka Kazuhiro
  • Journal Title: Journal of Neurochemistry Volume: 147 Issue: 3 Pages: 395-408
  • DOI: 10.1111/jnc.14553
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. (2018)
  • Author(s): Kushima I, (27名中略）, Hashimoto R,(80名中29番目) , et al.
  • Journal Title: Cell Rep Volume: 24(11) Issue: 11 Pages: 2838-2856
  • DOI: 10.1016/j.celrep.2018.08.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Possible involvement of a cell adhesion molecule, Migfilin, in brain development and pathogenesis of autism spectrum disorders (2017)
  • Author(s): Ishizuka Kanako、Tabata Hidenori、Ito Hidenori、Kushima Itaru、Noda Mariko、Yoshimi Akira、Usami Masahide、Watanabe Kyota、Morikawa Mako、Uno Yota、Okada Takashi、Mori Daisuke、Aleksic Branko、Ozaki Norio、Nagata Koh-ichi
  • Journal Title: Journal of Neuroscience Research Volume: 96 Issue: 5 Pages: 789-802
  • DOI: 10.1002/jnr.24194
  • Peer Reviewed / Open Access
• [Journal Article] Copy Number Variant in the Region of Adenosine Kinase (ADK) and Its Possible Contribution to Schizophrenia Susceptibility (2017)
  • Author(s): Kimura Hiroki、Kushima Itaru、Yohimi Akira、Aleksic Branko、Ozaki Norio
  • Journal Title: Int J Neuropsychopharmacol Volume: - Issue: 5 Pages: 1-5
  • DOI: 10.1093/ijnp/pyx103
  • Peer Reviewed
• [Presentation] A prospective cohort study of patients with 22q11.2 deletion syndrome aiming at early detection and treatment of psychiatric disorders. (2019)
  • Author(s): Kushima I
  • Organizer: CLEFT2019
  • Int'l Joint Research / Invited
• [Presentation] 精神疾患のゲノム解析に基づいた病態研究 (2019)
  • Author(s): 久島周
  • Organizer: 第115回日本精神神経学会学術総会
• [Presentation] 統合失調症と自閉スペクトラム症のゲノムコピー数変異解析と分子病態研究 (2019)
  • Author(s): 久島周
  • Organizer: 第115回日本精神神経学会学術総会
• [Book] 精神医学の科学的基盤 (2020)
  • Author(s): 加藤忠史
  • Total Pages: 192
  • Publisher: 学樹書院
  • ISBN: 9784906502530