精神分裂病感受性遺伝子としてのグルタミン酸受容体遺伝子群の包括的研究

• Project/Area Number: 14704056
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Human genetics
• Research Institution: Kyushu University
• Principal Investigator: 柴田 弘紀 九州大学, 生体防御医学研究所, 助手 (80315093)
• Project Period (FY): 2002 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥29,380,000 (Direct Cost: ¥22,600,000、Indirect Cost: ¥6,780,000); Fiscal Year 2004: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2003: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2002: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000)
• Keywords: 多因子疾患 / 統合失調症 / 関連解析 / グルタミン酸受容体 / SNP / 連鎖不平平衡 / ハプロタイプ解析 / ノックアウトマウス / 多因子病 / 連鎖不平衡

Research Abstract

1)前年度に引き続き5個のグルタミン酸受容体(GluR)遺伝子GRIN2D、GRIN3A、GRIN3B、GRIK3、GRIK4の5遺伝子座の解析を完了した。各遺伝子から複数個のSNPを選択し(合計70SNPs)、個別に、またはハプロタイプを構築して統合失調症との関連を検討したところ、GRIN2Dにおいて疾患と有意な関連を示す多型を同定し、論文として発表した(Makino et al.(印刷中))。またGRIK3、GRIK4、GRIK5の結果もあわせて現在論文投稿中である。本研究計画全体としては17個のGluR遺伝子の解析が完了し、以前に解析が完了していた2個とあわせて予定通りGluR遺伝子族のほぼ全てのメンバーを網羅することができた。さらに本年度はSLC1A1、SLC1A2、SLC1A3、SLC1A6の4個のグルタミン酸トランスポーター遺伝子についても同様の関連解析を行った。その結果SLC1A2とSLC1A6について疾患と有意な関連を示す多型を同定し、SLC1A2の結果を論文として発表した(Deng et al.2004)。
2)疾患との有意な関連が確認されたGRM3とGRIA4については、統合失調症マウスモデルの確立をめざしてノックアウトマウスの作製を進めた。GRM3のノックアウトは、キメラマウスまでは作製が完了したが、次代が生まれてこないことからヘテロ接合でも致死であることが強く示唆された。現在はこの致死機構の解明を進めるとともに、ダブルノックアウトの培養細胞を作成しGRM3の機能解析を行っている。GRIA4についてはノックアウトマウスの作出に成功した。ヘテロ、ホモ接合体ともに外見的な異状はなく、妊性も正常であったため系統として確立できた。

Research Products

• [Journal Article] Identification of single-nucleotide polymorphisms in the human N-methyl-D-aspartate receptor subunit NR2D gene, GRIN2D, and association study with schizophrenia. (2005)
  • Author(s): Makino C, Shibata H, Ninomiya H, Tashiro N. Fukumaki Y.
  • Journal Title: Psychiatric Genetics (印刷中)
• [Journal Article] Association study of polymorphisms in the excitatory amino acid transporter 2 gene (SLC1A2) with schizophrenia. (2004)
  • Author(s): Deng X, Shibata H, Ninomiya H, Tashiro N, Iwata N, Ozaki N, Fukumaki Y.
  • Journal Title: BMC Psychiatry. 4(1) Pages: 21-21
• [Journal Article] Positive associations of polymorphisms in the metabotropic glutamate receptor type 8 gene (GRM8) with schizophrenia. (2004)
  • Author(s): Takaki H, Kikuta R, Shibata H, Ninomiya H, Tashiro N, Fukumaki Y
  • Journal Title: American Journal of Medical Genetics 128B Pages: 6-14
• [Journal Article] Glutamate receptor genes as candidates for schizophrenia susceptibility (Review). (2003)
  • Author(s): Fukumaki Y, Shibata H.
  • Journal Title: Drug Development Research 60 Pages: 137-151
• [Journal Article] Association and linkage disequilibrium between synapsin 2 and complexin2 gene and Korean schizophrenia. (2003)
  • Author(s): Lee HJ, Kim JW, Kim MK, Kim SJ, Jin SY, Hong MS, Park HJ, Shin DH, Chung J, Shibata H, Fukumaki Y.
  • Journal Title: American Journal of Human Genetics 73 Pages: 1850-1850
• [Journal Article] Association study of polymorphisms in two metabotropic glutamate receptor genes, GRM3 and GRM8 with schizophrenia. (2003)
  • Author(s): Shibata H, Fujii Y, Takaji M, Takaki H, Kikuta R, Makino C, Tani A, Hirata N, Shibata A, Ninomiya H, Tashiro N, Fukumaki Y.
  • Journal Title: American Journal of Human Genetics 73 Pages: 2144-2144
• [Journal Article] Association studies of schizophrenia with the metabotropic glutamate receptor genes, GRM1,GRM5 regions (2003)
  • Author(s): Kikuta R, Ayako T, Takaki, H, Takaji M, Shibata H, Ninomiya H, Tashiro N, Fukumaki Y.
  • Journal Title: American Journal of Medical Genetics 122B Pages: 336-336
• [Journal Article] Initial genome-wide scan for linkage with schizophrenia in the Japanese Schizophrenia Sib-pair Linkage Group (JSSLG) families. (2003)
  • Author(s): The Japanese Schizophrenia Sib-pair Linkage Group.
  • Journal Title: American Journal of Medical Genetics 120B Pages: 22-28
• [Journal Article] Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRAB) with schizophrenia. (2003)
  • Author(s): Fujii Y, Shibata H, Kikuta R, Makino C, Tani A, Hirata N, Shibata A, Ninomiya H, Tashiro N, Fukumaki Y.
  • Journal Title: Psychiatric Genetics 13(2) Pages: 71-76
• [Journal Article] Positive association of the AMPA receptor subunit GluR4 gene (GRIA4) haplotype with schizophrenia : linkage disequilibrium mapping using SNPs evenly distributed across the gene region. (2003)
  • Author(s): Makino C, Fujii Y, Kikuta R, Hirata N, Tani A, Shibata A, Ninomiya H, Tashiro N, Shibata H, Fukumaki Y
  • Journal Title: American Journal of Medical Genetics 116B(1) Pages: 17-22
• [Journal Article] Association study of polymorphisms in the GluR6 kainate receptor gene (GRIK2) with schizophrenia. (2002)
  • Author(s): Shibata H, Shibata A, Ninomiya H, Tashiro N, Fukumaki Y.
  • Journal Title: Psychiatry Research 113(1-2) Pages: 59-67
• [Journal Article] Polymorphism analysis of upstream regions of the human N-methyl-D-aspartate receptor subunit NR1 gene (GRIN1): implications for schizophrenia. (2002)
  • Author(s): Tani A, Kikuta R, Itoh K, Joo A, Shibata H, Ninomiya H, Tashiro N, Fukumaki Y.
  • Journal Title: Schizophrenia Research 58(1) Pages: 83-86
• [Journal Article] Association studies of the metabotropic glutamate receptor genes, GRM3 and GRM4, with schizophrenia. (2002)
  • Author(s): Tani A, Fujii Y, Shibata H, Kikuta R, Makino C, Hirata N, Shibata A, Ninomiya T, Tashiro N, Fukumaki Y.
  • Journal Title: American Journal of Medical Genetics 114(7) Pages: 875-875
• [Patent(Industrial Property Rights)] 統合失調症関連代謝型グルタミン酸受容体遺伝子内一塩基多型およびその同定方法 (2002)
  • Inventor(s): 服巻 保幸, 柴田 弘紀, 築原 智之
  • Industrial Property Rights Holder: 服巻 保幸, 柴田 弘紀, 築原 智之
  • Industrial Property Number: 2002-337434
  • Filing Date: 2002-11-21
• [Patent(Industrial Property Rights)] 疾患感受性遺伝子座の同定法および精神分裂病疾患感受性遺伝子としてのグルタミン酸受容体遺伝子 (2002)
  • Inventor(s): 服巻 保幸, 柴田 弘紀, 田代 信維, 二宮 英彰, 藤井 洋, 牧野 千絵子
  • Industrial Property Rights Holder: 服巻 保幸, 柴田 弘紀, 田代 信維, 二宮 英彰, 藤井 洋, 牧野 千絵子
  • Industrial Property Number: 2002-000964
  • Filing Date: 2002-01-08
• [Publications] Takaki H, Kikuta R, Shibata H, Ninomiya H, Tashiro N, Fukumaki Y.: "Positive associations of polymorphisms in the metabotropic glutamate receptor type 8 gene (GRM8) with schizophrenia."Neuropsychiatric Genetics. 印刷中.
• [Publications] Fukumaki Y, Shibata H.: "Glutamate receptor genes as candidates for schizophrenia susceptibility."Drug Development Research. 60. 137-151 (2003)
• [Publications] Lee HJ, Kim JW, Kim MK, Kim SJ, Jin SY, Hong MS, Park HJ, Shin DH, Chung J, Shibata H, Fukumaki Y.: "Association and linkage disequilibrium between synapsin 2 and complexin2 gene and Korean schizophrenia."American Journal of Human Genetics. 73. 1850 (2003)
• [Publications] Shibata H, Fujii Y, Takaji M, Takaki H, Kikuta R, Makino C, Tani A, Hirata N, Shibata A, Ninomiya H, Tashiro N, Fukumaki Y.: "Association study of polymorphisms in two metabotropic glutamate receptor genes, GRM3 and GRM8 with schizophrenia."American Journal of Human Genetics. 73. 2144 (2003)
• [Publications] Kikuta R, Ayako T, Takaki, H, Takaji M, Shibata H, Ninomiya H, Tashiro N, Fukumaki Y.: "Association studies of schizophrenia with the metabotropic glutamate receptor genes, GRM1, GRM5 regions."American Journal of Medical Genetics. 122. 336 (2003)
• [Publications] The Japanese Schizophrenia Sib-pair Linkage Group.: "Initial genome-wide scan for linkage with schizophrenia in the Japanese Schizophrenia Sib-pair Linkage Group (JSSLG) families."American Journal of Medical Genetics. 120. 22-28 (2003)
• [Publications] Fujii Y, Shibata H, Kikuta R, Makino C, Tani A, Hirata N, Shibata A, Ninomiya H, Tashiro N, Fukumaki Y.: "Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia."Psychiatric Genetics. 13. 71-76 (2003)
• [Publications] Makino C, Fujii Y, Kikuta R, Hirata N, Tani A, Shibata A, Ninomiya H, Tashiro N, Shibata H, Fukumaki Y.: "Positive association of the AMPA receptor subunit GluR4 gene (GRIA4) haplotype with schizophrenia : linkage disequilibrium mapping using SNPs evenly distributed across the region."American Journal of Medical Genetics. 116. 17-22 (2002)
• [Publications] Shibata H, Shibata A, Ninomiya H, Tashiro N, Fukumaki Y.: "Association study of polymorphisms in the GluR6 kainate receptor gene (GRIK2) with schizophrenia."Psychiatry Research. 113. 59-67 (2002)
• [Publications] Tani A, Kikuta R, Itoh K, Joo A, Shibata H, Ninomiya H, Tashiro N, Fukumaki Y.: "Polymorphism analysis of upstream regions of the human N-methyl-D-aspartate receptor subunit NR1 gene (GRIN1) : implications for schizophrenia."Schizophrenia Research. 58. 83-86 (2002)
• [Publications] Tani A, Fujii Y, Shibata H, Kikuta R, Makino C, Hirata N, Shibata A, Ninomiya T, Tashiro N, Fukumaki Y.: "Association studies of the metabotropic glutamate receptor genes, GRM3 and GRM4, with schizophrenia"American Journal of Medical Genetics. 114. 335 (2002)
• [Publications] Fujii Y, Shibata H, Kikuta R, Makino C, Tani A, Hirata N, Shibata A, Ninomiya H, Tashiro N, Fukumaki Y: "Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia"Psychiatric Genetics. (印刷中).
• [Publications] The Japanese Schizophrenia Sib-pair Linkage Group: "Initial genome-wide scan for linkage with schizophrenia in the Japanese Schizophrenia Sib-pair Linkage Group (JSSLG) families"American Journal of Medical Genetics. (印刷中).
• [Publications] Makino C, Fujii Y, Kikuta R, Hirata N, Tani A, Shibata A, Ninomiya H, Tashiro N, Shibata H, Fukumaki Y: "Positive association of the AMPA receptor subunit GluR4 gene (GRIA4) haplotype with schizophrenia : linkage disequilibrium mapping using SNPs evenly distributed across the gene region"American Journal of Medical Genetics. 116. 17-22 (2002)
• [Publications] Shibata H, Shibata A, Ninomiya H, Tashiro N, Fukumaki Y: "Association study of polymorphisms in the GluR6 kainate receptor gene (GRIK2) with schizophrenia"Psychiatry Research. 113. 59-67 (2002)
• [Publications] Tani A, Kikuta R, Itoh K, Joo A, Shibata H, Ninomiya H, Tashiro N, Fukumaki Y: "Polymorphism analysis of upstream regions of the human N-methyl-D-asparate receptor subunit NR1 gene (GRIN1) : implications for schizophernia"Schizophrenia Research. 58. 83-86 (2002)
• [Publications] Tani A, Fujii Y, Shibata H, Kikuta R, Makino C, Hirata N, Shibata A, Ninomiya T, Tashiro N, Fukumaki Y: "Association studies of the metabotropic glutamate receptor genes, GRM3 and GRM4, with schizophrenia"American Journal of Medical Genetics. 114. 335 (2002)