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An investigation of the involvement of methylation in the parhogenesis of mental diseases by differential genomic analyses of monozygotic twins discordant for the diseases.

Research Project

Project/Area Number 13307027
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Psychiatric science
Research InstitutionMie University

Principal Investigator

OKAZAKI Yuji  Mie University, Faculty of Medicine, Professor, 医学部, 教授 (40010318)

Co-Investigator(Kenkyū-buntansha) YAMASHITA Hideji  Kyushu Tokai University, School of Agriculture, Assistant Professor, 農学部, 講師 (20289630)
IMAMURA Akira  Nagasaki University, Graduate School of Medicine, Dentist & Pharmacy, Assistant Professor, 大学院・医歯薬学総合研究科, 講師 (40325642)
JINNO Yoshihiro  Ryuukyu University, Graduate School of Medicine, Professor, 大学院・医学研究科, 教授 (20179097)
KATO Tadafumi  RIKEN Brain Science Institute, Laboratory for Molecular Dynamics of Mental Disorders, Team leader, 精神疾患動態研究チーム, チームリーダー (30214381)
SASAKI Tsukasa  University of Tokyo, Health Service Center, Associate Professor, 保健管理センター, 助教授 (50235256)
辻田 高宏  長崎大学, 医学部, 講師 (40304919)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥52,000,000 (Direct Cost: ¥40,000,000、Indirect Cost: ¥12,000,000)
Fiscal Year 2003: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2002: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
Fiscal Year 2001: ¥26,650,000 (Direct Cost: ¥20,500,000、Indirect Cost: ¥6,150,000)
KeywordsMental Diseases / Methylation / Monozygotic twin discordant for a disease / Scizophrenia / Bipolar disorder / XBP1 / Autism / Methylated cytosine / メチル化 / 組織特異性 / FRGP / ゲノム差異 / 遺伝子発現 / 一卵性双生児 / 成因 / エピジェネティックス / メチレーション / ゲノム解析
Research Abstract

(1) Methylation and schizophrenia
Total me ethylated cytosine volumes in leucocytes were measured using HPLC and compared between patients with schizophrenia and age and sex matched normal controls. Leucocytes from male patients with schizophrenia contained significantly less total me ethylated cytosine than those from normal controls. The difference was observed especially in the young patients (<35 years old). There was no significant difference for female patients. Two Human endogenous retrovirus (HERV) that retain the transcriptional activity which is inhibited by methylation were located on chromosome 1q21-q22 and 22q12 which were susceptible loci repeatedly observed in the linkage study of schizophrenia. These suggest the involvement of methylation in the pathogenesis of schizophrenia
(2) Differential genomic scans of discordant monozygotic twins
Fluorescent representational genomic profiling (FRGP) was applied to DNAs from monozygotic twins discordant for schizophrenia, bipolar disorder, autism and narcolepsy. Discordant spots containing discordant DNA fragments between affected and non-affected twins from the monozygotic twins from autism, schizophrenia and bipolar disorder. Two candidate genes (4p14, 12q24.11) for autism, 1gnee (6q13) and 1 gene (7q31) were implicated by the direct cloning of the spots. Furthermore, the difference of an autism gene was revealed due to its different methylation status in the promoter region.
(3) The discovery of bipolar disorder susceptibility gene, XBP1
DNA Microarray analysis of lymphoblasted cells from two monozygotic twins discordant for bipolar disorder revealed lower expression of XBP1 and GRP78 genes that involved in the lowered endoplasmic reticulum (ER) stress. A polymorphism (-116 G/C) in the promoter region of XBP1 was responsible for lowered expression. The involvement of methylation in the expression of XBP1 is a next focus

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (29 results)

All Other

All Publications (29 results)

  • [Publications] Kakiuchi C, Iwamoto K, Ishiwata M, Bundo M, Kasahara T, Kusumi I, Tsujita T, Okazaki Y, Nanko S, Kunugi H, Sasaki T.Kato T: "Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder"Nature Genetics. 35. 171-175 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakamura A, Okazaki Y, Sugimoto J, Oda T, Jinno Y: "Human endogenous retroviruses with transcriptional potential in the brain."Journal of Human Genetics. 48. 575-581 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fuke C, Shimabukuro M, Petronis A, Sugimoto J, Oda T, Miura K, Miyazaki T, Ogura C, Okazaki Y, Jinno Y: "Age related changes of the 5-methylcytosine content in human peripheral leukocytes and placentas : an HPLC-based study."Annals of Human Genetics. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 山下秀次, 芝田 猛: "簡易DNAメチル化検定法としてのHpa II-PCR法"九州東海大学農学部紀要. 23. 37-42 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 栃木衛, 日比野浩之, 佐々木司: "統合失調症とエピジェネティックス"実験医学. 21. 1571-1575 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 岡崎祐士: "脳を知る・創る・守る・育む(「脳の世紀」推進会議編)"クバプロ. 143 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kato c, Petronis A, Okazaki Y, Tochigi M, Sasaki T: "Molecular Genetics of schizophrenia : challenges and insights."Neuroscience Research. 43. 295-304 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Tochigi M, Okazaki Y, Kato N, Sasaki T: "What causes seasonality of birth in schizophrenia?"Neuroscience Research. 48. 1571-1575 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakamura A, Okazaki Y, Sugimoto J, Oda T, Jinno Y.: "Human endogenous retroviruses with transcriptional potential in the brain."Journal of Human Genetics. 48(11). 575-581 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fuke C, Shimabukuro M, Petronis A, Sugimoto J, Oda T, Miura K, Miyazaki T, Ogura C, Okazaki Y, Jinno Y: "Age related changes of the 5-methylcytosine content in human peripheral leukocytes and placentas: an HPLC-based study."Annals of Human Genetics. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kakiuchi C, Iwamoto K, Ishiwata M, Bundo M, Kasahara T, Kusumi I, Tsujita T, Okazaki Y, Nanko S, Kunugi H, SasakiT, Kato T: "Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder."Nature Genetics. 35. 171-175 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yokota H, Tsujita T, Okazaki Y, Kikuya E, Oishi M: "Polymorphic 33-bp Repeats with Promoter-like Activity in Synaptotagmin 11 Gene."DNA RESEARCH. 10(6). 263-275 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kakiuchi C, Iwamoto K, Ishiwata M, Bundo M, Kasahara T, Kusumi I, Tsujita T, Okazaki Y, Nanko S, Kunugi H, Sasaki T, Kato T: "Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder"Nature Genetics. 35(10). 171-175 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakamura A, Okazaki Y, Sugimoto J, Oda T, Jinno Y: "Human endogenous retroviruses with transcriptional potential in the brain."J Hum Genet. 48(5). 575-581 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] C.Fuke, M.Shimabukuro, A.Petronis, J.Sugimoto, T.Oda, K.Miura, T.Miyazaki, C.Ogura, Y.Okazaki, Y.Jinno: "Age related changes of the 5-methylcytosine content in human peripheral leukocytes and placentas : an HPLC-based study."Annals of Human Genetics. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 岡崎祐士, 辻田高宏, 加藤忠史: "双生児・同胞研究が明らかにした統合失調症の成因"臨床精神医学. 32(11). 1315-21 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 山下秀次: "簡易DNAメチル化検定法としてのHpa II-PCR法"九州東海大学農学部紀要. 21(in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 栃木衛, 日比野浩之, 佐々木司: "統合失調症とエピジェネティックス"実験医学. 21(12). 1571-75 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 岡崎祐士, 三好修, 佐々木司: "精神病(統合失調症、躁うつ病)"図説 分子病態学(一瀬白帝・鈴木宏治 編). 501 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kato C, Petronis A, Okazaki Y, Tochigi M, Umekage T, Sasaki T.: "Molecular genetic studies of schizophrenia : challenges and insights"Neurosci Res. 43・4. 295-304 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 加藤忠史: "DNAマイクロアレイの精神疾患の臨床検査法への応用可能性"精神科. 1:5. 424-426 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Matsumoto S, Sasaki T, Imamura A et al.: "HLA classl distribution in Japanese patients with schizophrenia"Am J Med Genet. 114・1. 42-45 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fujimaru K, Imamura A, Tsujita T et al.: "Minor Physical Aomalies in Japanese Patients with Schizophrenia"Acta Med. Nagasaki. 47・1. 133-137 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 藤丸浩輔, 辻田高宏: "一卵性双生児のゲノムの不一致について"分子精神医学. 2・3. 260-261 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 加藤忠史, 岡崎祐士: "統合失調症(精神分裂病)へのポストゲノム的アプローチ"実験医学. 21・1. 42-46 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 佐々木司, 岡崎祐士: "新世紀の精神科治療第1巻「統合失調症の診療学」(岡崎祐士編)"統合失調症成因の多様性と疾患過程のダイナミズム pp. 17-29. 357 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Petronis A: "Major psychosis and chromosome 22:Genetics meets epigenetics"CNS spectrum. (印刷中). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] 岡崎祐士: "精神分裂病の発達的脆弱性形成とエピジェネティックス"脳と精神の医学. 12・4. 293-302 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Imamura A: "Lack of association between the hKCa3 gene and Japanese schizophrenia patients"Psychiatric Genetics. 11・4. 227-229 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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