Copy number variation analysis of schizophrenia and elucidation of molecular pathogenesis using bioinformatic approach

• Project/Area Number: 15K19720
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Psychiatric science
• Research Institution: Nagoya University
• Principal Investigator: Kushima Itaru 名古屋大学, 高等研究院(医), 特任助教 (00732645)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 統合失調症 / ゲノムコピー数変異 / シナプス

Outline of Final Research Achievements

Using array comparative genomic hybridization, we performed a genome-wide CNV analysis (1699 SCZ cases and 824 controls). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10－9). 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). Gene set analysis replicated previous findings (e.g., synapse) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling.

Research Products

• [Int'l Joint Research] Chang Gung University(Taiwan)
• [Int'l Joint Research] Cardiff University(United Kingdom)
• [Int'l Joint Research] University of Toronto(Canada)
• [Int'l Joint Research] University of Wurzburg(Germany)
• [Int'l Joint Research] Stanford University(米国)
• [Int'l Joint Research]
• [Int'l Joint Research] Yuli Mental Health Research Center/Chang Gung Memorial Hospital-Linkou(Taiwan)
• [Journal Article] High-resolution copy number variation analysis of schizophrenia in Japan. (2017)
  • Author(s): Kushima I, Aleksic B, Nakatochi M, Shimamura T, Shiino T, Yoshimi A, Kimura H, Takasaki Y, Wang C, Xing J, Ishizuka K, Oya-Ito T, Nakamura Y, Arioka Y, Maeda T, Yamamoto M, Yoshida M, Noma H, Hamada S, Morikawa M, Uno Y, Okada T, Iidaka T, Iritani S, Yamamoto T,
  • Journal Title: Molecular Psychiatry Volume: 22 Issue: 3 Pages: 430-440
  • DOI: 10.1038/mp.2016.88
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population. (2016)
  • Author(s): Takasaki Y, Koide T, Wang C, Kimura H, Xing J, Kushima I, Ishizuka K, Mori D, Sekiguchi M, Ikeda M, Aizawa M, Tsurumaru N, Iwayama Y, Yoshimi A, Arioka Y, Yoshida M, Noma H, Oya-Ito T, Nakamura Y, Kunimoto S, Aleksic B, Uno Y, Okada T, Ujike H, Egawa J, Kuwabara H, Someya T, Yoshikawa T, Iwata N, Ozaki N
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 33311-33311
  • DOI: 10.1038/srep33311
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a rare variant in CHD8 that contributes to schizophrenia and autism spectrum disorder susceptibility (2016)
  • Author(s): Kimura H, Wang C, Ishizuka K, Xing J, Takasaki Y, Kushima I, Aleksic B, Uno Y, Okada T, Ikeda M, Mori D, Inada T, Iwata N, Ozaki N.
  • Journal Title: Schizophr Res Volume: 178 Issue: 1-3 Pages: 104-106
  • DOI: 10.1016/j.schres.2016.08.023
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Resequencing and Association Analysis of Six PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism Spectrum Disorders (2016)
  • Author(s): Xing J, Kimura H, Wang C, Ishizuka K, Kushima I, Arioka Y, Yoshimi A, Nakamura Y, Shiino T, Oya-Ito T, Takasaki Y, Uno Y, Okada T, Iidaka T, Aleksic B, Mori D, Ozaki N.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 27491-27491
  • DOI: 10.1038/srep27491
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders. (2016)
  • Author(s): Isles AR, Ozaki N, Aleksic B, Kushima I,
  • Journal Title: PLoS Genet. Volume: 12 Issue: 5 Pages: e1005993-e1005993
  • DOI: 10.1371/journal.pgen.1005993
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Identification of Rare, Single-Nucleotide Mutations in NDE1 and Their Contributions to Schizophrenia Susceptibility. (2015)
  • Author(s): Kimura H, Tsuboi D, Wang C, Kushima I, Koide T, Ikeda M, Iwayama Y, Toyota T, Yamamoto N, Kunimoto S, Nakamura Y, Yoshimi A, Banno M, Xing J, Takasaki Y, Yoshida M, Aleksic B, Uno Y, Okada T, Iidaka T, Inada T, Suzuki M, Ujike H, Kunugi H, Kato T, Yoshikawa T, Iwata N, Kaibuchi K
  • Journal Title: Schizophrenia Bulltein Volume: 41 Issue: 3 Pages: 744-753
  • DOI: 10.1093/schbul/sbu147
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Association study of BCL9 gene polymorphism rs583583 with schizophrenia and negative symptoms in Japanese population. (2015)
  • Author(s): Kimura H, Tanaka S, Kushima I, Koide T, Banno M, Kikuchi T, Nakamura Y, Shiino T, Yoshimi A, Oya-Ito T, Xing J, Wang C, Takasaki Y, Aleksic B, Okada T, Ikeda M, Inada T, Iidaka T, Iwata N, Ozaki N.
  • Journal Title: Scientific reports Volume: 5 Issue: 1 Pages: 15705-15705
  • DOI: 10.1038/srep15705
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 統合失調症の高解像度ゲノムコピー数変異解析 (2016)
  • Author(s): 久島周、アレクシッチ・ブランコ、中杤昌弘、島村徹平、尾崎紀夫
  • Organizer: 第38回日本生物学的精神医学会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
• [Presentation] Copy number variations in schizophrenia (2015)
  • Author(s): Itaru Kushima, Branko Aleksic, Daisuke Mori, Shohko Kunimoto, Tomoko Shiino, Akira Yoshimi, Hiroki Kimura, Chenyao Wang, Jingrui Xing, Yuto Takasaki, Kanako Ishizuka, Tomoko Oya-Ito, Yuko Arioka, Takuji Maeda, Norio Ozaki
  • Organizer: 4th Asian Congress of Schizophrenia Research
  • Place of Presentation: Taipei (Taiwan)
  • Year and Date: 2015-11-18
  • Int'l Joint Research / Invited
• [Book] 臨床精神医学 (2015)
  • Author(s): 有岡 祐子、久島 周、尾崎 紀夫
  • Total Pages: 104
  • Publisher: アークメディア
• [Book] 分子精神医学 (2015)
  • Author(s): 久島 周、アレクシッチ・ブランコ
  • Total Pages: 100
  • Publisher: 先端医学社