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大きな遺伝子効果を利用した統合失調症の病因研究

Research Project

Project/Area Number 20023039
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTokyo Metropolitan Organization for Medical Research

Principal Investigator

糸川 昌成  Tokyo Metropolitan Organization for Medical Research, 東京都精神医学総合研究所, 参事研究員 (40332324)

Co-Investigator(Kenkyū-buntansha) 吉川 武男  財団法人東京都医学研究機構, 理化学研究所・分子精神科学研究チーム, チームリーダー (30249958)
Project Period (FY) 2008 – 2009
Project Status Completed (Fiscal Year 2009)
Budget Amount *help
¥8,200,000 (Direct Cost: ¥8,200,000)
Fiscal Year 2009: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2008: ¥4,400,000 (Direct Cost: ¥4,400,000)
Keywordsカルボニルストレス / ビタミンB6 / common disease rare variant仮説 / 統合失調症 / フレームシフト変異
Research Abstract

統合失調症45例、対象61例を用いて検討した結果、症例の一部(ゲノム解析で同定される約1%、生化学解析検体の約47%:21例/45例中)にAGEが上昇し(カルボニルストレス)、ビタミンB6が低下している患者がいることを見出した。これらの患者の多くがAGEformationの掬制律速酵素であるglyoxalasel(GLO1)遺伝子にフレームシフト変異またはAla111Gluの低活性型(Ala)のホモ接合体だった。
ビタミンB6はカルボニルスカベンジャーとして作用するので、カルボニルストレス性統合失調症ではビタミンB6が動員され枯渇している可能性があり、B6の補充により症状改善の可能性が見込まれる。健常者でもGLO1にフレームシフト変異とAlaのホモ接合体は同定されたが、AGEもビタミンB6も正常だった。
予備的検討ではあるが、これら変異を持つ健常者ではグルタチオンや亜鉛などGLO1の補酵素が上昇しており、代償によってカルボニルストレスが回避されていた可能性が示唆された。さらに対象サンプルを統合失調症200例、健常者95例まで拡大して検討した結果、41.5%の症例でAFEsの蓄積を認め、結果が再現された。

Report

(2 results)
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (38 results)

All 2010 2009 2008 Other

All Journal Article (16 results) (of which Peer Reviewed: 14 results) Presentation (22 results)

  • [Journal Article] Association of the HSPG2 Gene with Neuroleptic-Induced Tardive Dyskinesia.2010

    • Author(s)
      Syu A, Ishiguro H, Inada T, Horiuchi Y, Tanaka S, Ishikawa M, Arai M, Itokawa M, Niizato K, Iritani S, Ozaki N, Takahashi M, Kakita A, Takahashi H, Nawa H, Keino-Masu K, Arikawa-Hirasawa E, Arinami T.
    • Journal Title

      Neuropsychopharmacology. 35(5)

      Pages: 1155-1164

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The dopamine D3 receptor (DRD3) gene and risk of schizophrenia : case-control studies and an updated meta-analysis.2010

    • Author(s)
      Nunokawa A, Watanabe Y, Kaneko N, Sugai T, Yazaki S, Arinami T, Ujike H, Inada T, Iwata N, Kunugi H, Sasaki T, Itokawa M, Ozaki N, Hashimoto R, Someya T.
    • Journal Title

      Schizoph Res 116(1)

      Pages: 61-67

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TDP-43 M337V Mutation in Familial Amyotrophic Lateral Sclerosis in Japan.2010

    • Author(s)
      Tamaoka A, Arai M, Itokawa M, Arai T, Hasegawa M, Tsuchiya K, Takuma H, Tsuji H, Ishii A, Watanabe M, Takahashi Y, Goto J, Tsuji S, Akiyama H.
    • Journal Title

      Int Medicine 49(4)

      Pages: 331-334

    • NAID

      130000152618

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 脳と心の分子メカニズム:大きな遺伝子効果を利用した統合失調症の病因研究2010

    • Author(s)
      新井誠, 市川智恵, 糸川昌成
    • Journal Title

      Biophilia 6

      Pages: 6-12

    • Related Report
      2009 Annual Research Report
  • [Journal Article] 気分障害の遺伝子研究2010

    • Author(s)
      糸川昌成, 吉川武男
    • Journal Title

      別冊・医学のあゆみ最新うつ病のすべて

      Pages: 166-171

    • Related Report
      2009 Annual Research Report
  • [Journal Article] Persistence criteria for susceptibility genes for schizophrenia : a discussion from an evolutionary viewpoint.2009

    • Author(s)
      Doi N, Hoshi Y, Itokawa M, Usui C, Yoshikawa T, Tachikawa H.
    • Journal Title

      PLoS One 4(11)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of SMARCA2/BRM in the SWIISNF chromatin-remodeling complex in schizophrenia.2009

    • Author(s)
      Koga M, Ishiguro_ H, Yazaki S, Horiuchi Y, Arai M, Niizato K, Iritani S, Itokawa M, Inada T, Iwata N, Ozaki. N, Ujike H, Kunugi H, Sasaki T, Takahashi M, Watanabe Y, Someya T, Kakita A, Takahashi H, Nawa H, Muchardt C, Yaniv M, Arinami T.
    • Journal Title

      Hum Mol Genet 13

      Pages: 2483-2494

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Preliminary Genome-wide Association Study of Bipolar Disorder in the Japanese Population.2009

    • Author(s)
      Hattori E, Toyota T, Ishitsuka Y, Iwayama Y, Yamada K, Ujike H, Morita Y, Kodama M, Nakata K, Minabe Y, Nakamura K, Iwata Y, Takei N, Mori N, Naitoh H, Yamanouchi Y, Iwata N, Ozaki N, Kato T, Nishikawa T, Kashiwa A, Suzuki M, Shioe K, Shinohara M, Hirano M, Nanko S, Akahane A, Ueno M, Kaneko N, Watanabe Y, Someya T, Hashimoto K, Iyo M, Itokawa M, Arai M, Nankai M, Inada T, Yoshida S, Kunugi H, Nakamura M, Iijima Y, Okazaki Y, Higuchi T, Yoshikawa T.
    • Journal Title

      Am J Med Genet 150B(8)

      Pages: 1110-1117

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Replication study for associations between polymorphisms in the CLDN5 and DGCR2 genes in the 22q11 deletion syndrome region and schizophrenia.2008

    • Author(s)
      Ishiguro H, Imai K, Koga M, HoriucM Y, Inada T, Iwata N, Ozaki N, Ujike H, Itokawa m, Kunugi H, Sasaki T, Watanabe Y, Someya T, Arinami T.
    • Journal Title

      Psychiatr Genet 18

      Pages: 255-256

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Large-scale case-control study of a functional polymorphism in the glutamate receptor, metabotropic 3 gene in patients with schizophrenia.2008

    • Author(s)
      Nunokawa A, Watanabe Y, Kitamura H, Kaneko N, Arinami T, Ujike H, Inada T, Iwata N, Kunugi H, Itokawa M, Ozaki N, Someya T.
    • Journal Title

      Psychiatry Clin Neurosci 62

      Pages: 239-240

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Brain Cannabinoid CB2 Receptor in Schizophrenia.

    • Author(s)
      Ishiguro H, Horiuchi Y, Ishikawa M, Koga M, Imai K, Suzuki Y, Morikawa M, Inada T, Watanabe Y, Takahashi M, Someya T, Ujike H, Iwata N, Ozaki N, Onatvi ES, Kunugi H, Sasaki T, Itokawa M, Arai M, Niizato K, Iritani S, Naka I, Ohashi J,_ Kakita A, Takahashi H, Nawa H, Arinami T.
    • Journal Title

      Biol Psychiatry (in press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Two-stage case-control association study of PADI2 with schizophrenia.

    • Author(s)
      Watanabe Y, Nunokawa A, Kaneko N, Arinami T, Ujike, Inada T, Iwata N, Kunugi H, Itokawa M, Otowa T, Ozaki N, Someya T.
    • Journal Title

      J Hum Genet (in press)

    • NAID

      10030731190

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Failure to find an association between myosin heavy chain 9, non-muscle (MYH9) and schizophrenia : a three-stage case-control association study

    • Author(s)
      Amagane H, Watanabe Y, Kaneko N, Nunokawa A, Muratake T, Ishiguro H, Arinami T, Ujike H, Inada T, Iwata N, Kunugi H, Sasaki T, Hashimoto R, Itokawa M, Ozaki N, Someya T.
    • Journal Title

      Schizoph Res (in press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Supportive evidence for reduced expression of GNB1L in schizophrenia.

    • Author(s)
      Ishiguro H, Koga M, Horiuchi Y, Noguchi E, Morikawa M, Suzuki Y, Arai M, Niizato K, Iritani S, Itokawa M, Inada T, Iwata N, Ozaki N, Ujike H, Kunugi H, Sasaki T, Takahashi M, Watanabe Y, Someya T, Kakita A, Takahashi H, Nawa H, Arinami T.
    • Journal Title

      Schizophr Bull (in press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Preliminary Genome-wide Association Study of Bipolar Disorder in the Japanese Population.

    • Author(s)
      Hattori E, Toyota T, Ishitsuka Y, Iwayama Y, Yamada K, Ujike H, Morita Y, Kodama M, Nakata K, Minabe Y, Nakamura K, Iwata Y, Takei N, Mori N, Naitoh H, Yamanouchi Y, Iwata N, Ozaki N, Kato T, Nishikawa T, Kashiwa A, Suzuki M, Shioe K, Shinohara M, Hirano M, Nanko S, Akahane A, Ueno M, Kaneko N, Watanabe Y, Someya T, Hashimoto K, Iyo M, Itokawa M, Arai M, Nankai M, Inada T, Yoshida S, Kunugi H, Nakamura M, Iijima Y, Okazaki Y, Higuchi T, Yoshikawa T.
    • Journal Title

      Am J Med Genet (in press)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Supportive evidence for reduced expression of GNB1L in schizophrenia.

    • Author(s)
      Ishiguro H, Koga M, Horiuchi Y, Noguchi E, Morikawa M, Suzuki Y, Arai M, Niizato K, Iritani S, Itokawa M, Inada T, Iwata N, Ozaki N, Ujike H, Kunugi H, Sasaki T, Takahashi M, Watanabe Y, Someya T, Kakita A, Takahashi H, Nawa H, Arinami T.
    • Journal Title

      Schizophr Bull (in press)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Presentation] 染色体均衡転座を持つ男性統合失調症患者から同定されたDISC-Mのresequence解析.2010

    • Author(s)
      前田直彦, 羽賀誠一, 小幡菜々子, 野原泉, 新井麻友美, 大出智美, 田中陽子, 市川智恵, 新井誠, 高橋哲夫, 岡崎祐士, 吉川武男, 糸川昌成
    • Organizer
      第5回日本統合失調症学会
    • Place of Presentation
      福岡
    • Year and Date
      2010-03-27
    • Related Report
      2009 Annual Research Report
  • [Presentation] 染色体異常をともなった統合失調症を利用した病態解明の研究.2009

    • Author(s)
      市川智恵, 新井誠, 羽賀誠一,数藤由美子, 前田直彦, 小幡菜々子, 野原泉, 新井麻友美, 田中陽子, 大西哲生, 松下正明, 岡崎祐士, 渡辺明子, 吉川武男, 糸川昌成
    • Organizer
      第42回精神神経系薬物治療研究報告会
    • Place of Presentation
      豊中
    • Year and Date
      2009-12-04
    • Related Report
      2009 Annual Research Report
  • [Presentation] 脳と心の分子メカニズム:統合失調症の病態解明2009

    • Author(s)
      新井誠, 市川智恵, 西田淳志, 新井麻友美, 小幡菜々子, 野原泉, 前田直彦, 大出智美, 吉田有希, 田中陽子, 糸川昌成
    • Organizer
      首都大バイオコンファレンス2009
    • Place of Presentation
      東京
    • Year and Date
      2009-11-06
    • Related Report
      2009 Annual Research Report
  • [Presentation] TDP-43 M337V mutation in familial amyotrophlc lateral sclerosls in Japan.2009

    • Author(s)
      Tamaoka A, Arai M, Itokawa M, Arai T, Hasegawa M, Tsuchiya K, Takuma H, Tsuji H, Ishii A, Watanabe M, Takahashi Y, Goto J, Tsuji S, Akiyama H.
    • Organizer
      Society for Neuroscience 39th Annual Meeting
    • Place of Presentation
      Chicago,USA
    • Year and Date
      2009-10-18
    • Related Report
      2009 Annual Research Report
  • [Presentation] 大きな遺伝子効果を利用した統合失調症の病因研究2009

    • Author(s)
      糸川昌成,吉川武男
    • Organizer
      平成21年度特定領域研究「統合脳」夏のワークショップ,合同班会議
    • Place of Presentation
      札幌
    • Year and Date
      2009-08-10
    • Related Report
      2009 Annual Research Report
  • [Presentation] 染色体均衡転座を持つ男性統合失調症から同定されたDISC-Mのresequence解析2009

    • Author(s)
      前田直彦, 羽賀誠一, 小幡菜々子, 野原泉, 田中陽子, 新井麻友美, 新井誠, 市川智恵, 高橋哲夫, 糸川昌成
    • Organizer
      第31回日本生物学的精神医学会
    • Place of Presentation
      京都
    • Year and Date
      2009-04-24
    • Related Report
      2009 Annual Research Report
  • [Presentation] 統合失調症のde novo均衡転座を伴う1症例から見出したDISC-Mのbinding partnersの単離.2009

    • Author(s)
      糸川昌成, 羽賀誠一, 前田直彦, 小幡菜々子, 野原泉, 新井麻友美, 市川智恵, 田中陽子, 大西哲生, 豊田倫子, 氏家寛, 曽良一郎, 岡崎祐士, 吉川武男
    • Organizer
      第31回日本生物学的精神医学会
    • Place of Presentation
      京都
    • Year and Date
      2009-04-24
    • Related Report
      2009 Annual Research Report
  • [Presentation] ドパミン受容体遺伝子多型と精神疾患.2009

    • Author(s)
      糸川昌成.
    • Organizer
      第82回日本薬理学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2009-03-17
    • Related Report
      2008 Annual Research Report
  • [Presentation] 稀少変異アプローチによる統合失調症の病態解析.2009

    • Author(s)
      新井誠, 野原泉, 小幡菜々子, 新井麻友美, 羽賀誠一, 大西哲生, 豊田倫子, 田中陽子, 氏家寛, 岡崎祐士, 吉川武男, 宮田敏男, 糸川昌成.
    • Organizer
      第4回日本統合失調症学会
    • Place of Presentation
      吹田
    • Year and Date
      2009-01-31
    • Related Report
      2008 Annual Research Report
  • [Presentation] 統合失調症におけるMethylenetetrahydrofolatereductase(MTHFR)の遺伝子解析.2009

    • Author(s)
      田中陽子, 新井誠, 小幡菜々子, 野原泉, 新井麻友美, 前田直彦, 羽賀誠一, 糸川昌成.
    • Organizer
      第4回日本統合失調症学会
    • Place of Presentation
      吹田
    • Year and Date
      2009-01-31
    • Related Report
      2008 Annual Research Report
  • [Presentation] PLEと遺伝的検索.2009

    • Author(s)
      糸川昌成.
    • Organizer
      平成20年度厚生労働省科学研究費補助金こころの健康科学研究事業「思春期精神病理の疫学と精神疾患の早期介入方策に関する研究」第2回班会議
    • Place of Presentation
      東京
    • Year and Date
      2009-01-25
    • Related Report
      2008 Annual Research Report
  • [Presentation] 大きな遺伝子効果を利用した統合失調症の原因研究.2008

    • Author(s)
      糸川昌成, 新井誠, 小幡菜々子, 野原泉, 新井麻友美, 羽賀誠一, 吉川武男.
    • Organizer
      平成20年度文部科学省特定領域研究「統合脳」第5領域班会議
    • Place of Presentation
      東京
    • Year and Date
      2008-12-14
    • Related Report
      2008 Annual Research Report
  • [Presentation] 統合失調症死後脳における海馬の細胞構築異常を遺伝子変異との関連研究.2008

    • Author(s)
      新里和弘, 岡崎祐士, 中村亮介, 大島健一, 東儀瑞穂, 野中俊宏, 新井誠, 糸川昌成.
    • Organizer
      第41回精神神経系薬物治療研究報告会
    • Place of Presentation
      豊中
    • Year and Date
      2008-12-05
    • Related Report
      2008 Annual Research Report
  • [Presentation] Detection of a vulnerable gene for schizophrenia by investigating a case carrying a rare mutation.2008

    • Author(s)
      Arai M, Nohara I, Obata N, Haga S, Yuzawa H, Ohnishi T, Toyota T, Sora I, Okazaki Y, Ujike H, Yoshikawa T, Miyata T, Itokawa M.
    • Organizer
      Society for Neuroscience 38th Annual Meeting
    • Place of Presentation
      Washington DC, USA
    • Year and Date
      2008-11-18
    • Related Report
      2008 Annual Research Report
  • [Presentation] Hypoglutamatergic hypothesis : a genetic study on schizophrenia.2008

    • Author(s)
      Itokawa M.
    • Organizer
      13th Pacific Rim College of Psychiatrists Scientific Meeting
    • Place of Presentation
      Tokyo
    • Year and Date
      2008-11-01
    • Related Report
      2008 Annual Research Report
  • [Presentation] Molecular mechanism of brain and mind : investigation regarding pathophysiology of schizophrenia.2008

    • Author(s)
      Itokawa M, Arai M, Obata N, Nohara I, Arai M, Haga S, Maeda N, Tanaka Y.
    • Organizer
      首都大バイオコンファレンス2008
    • Place of Presentation
      八王子
    • Year and Date
      2008-10-23
    • Related Report
      2008 Annual Research Report
  • [Presentation] Supportive evidence for reduced expression of GNB1L in schizophrenia.2008

    • Author(s)
      Ishiguro H, Koga M, Horiuchi Y, Noguchi E, Arai M, Niizato K, Iritani S, Itokawa M, Kakita A, Takahashi H, Nawa H, Arinami T.
    • Organizer
      XVIth World Congress on Psychiatric Genetics
    • Place of Presentation
      Osaka
    • Year and Date
      2008-10-14
    • Related Report
      2008 Annual Research Report
  • [Presentation] Mitochondrial DNA hypothesis of schizophrenia : an integration of epidemiological and pathophysiological aspects.2008

    • Author(s)
      Doi N, Hoshi Y, Itokawa M, Usui C, Yoshikawa T, Utena H.
    • Organizer
      XVIth World Congress on Psychiatric Genetics
    • Place of Presentation
      Osaka
    • Year and Date
      2008-10-14
    • Related Report
      2008 Annual Research Report
  • [Presentation] 都精神研における統合失調症研究.2008

    • Author(s)
      糸川昌成.
    • Organizer
      精神疾患の分子神経生物学的研究のためのワークショップ-米国・日本の研究教育機関における研究の取り組み-
    • Place of Presentation
      東京
    • Year and Date
      2008-10-10
    • Related Report
      2008 Annual Research Report
  • [Presentation] 統合失調症におけるMethylenetetrahydrofolatereductase(MTHFR)の遺伝子解析.2008

    • Author(s)
      田中陽子, 新井誠, 羽賀誠一, 小幡菜々子, 野原泉, 前田直彦, ロバート・ランベルト, 糸川昌成.
    • Organizer
      第30回日本生物学的精神医学会
    • Place of Presentation
      富山
    • Year and Date
      2008-09-12
    • Related Report
      2008 Annual Research Report
  • [Presentation] 染色体均衡転座を持つ男性統合失調症から同定されたDISC-Mのresequence解析.2008

    • Author(s)
      前田直彦, 新井誠, 小幡菜々子, 野原泉, 羽賀誠一, 田中陽子, 糸川昌成.
    • Organizer
      第30回日本生物学的精神医学会
    • Place of Presentation
      富山
    • Year and Date
      2008-09-12
    • Related Report
      2008 Annual Research Report
  • [Presentation] 稀な症例を出発点とした統合失調症の遺伝子研究.2008

    • Author(s)
      糸川昌成.
    • Organizer
      第51回日本神経化学会大会
    • Place of Presentation
      富山
    • Year and Date
      2008-09-12
    • Related Report
      2008 Annual Research Report

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Published: 2008-04-01   Modified: 2018-03-28  

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