STUDY FOR MOLECLULAR PATHOPHYSIOLOGY OF MENTAL DISORDERS AND SEROTONIN RECEPTOR POLYMORPHISMS

• Project/Area Number: 15591245
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: FUJITA HEALTH UNIVERSITY
• Principal Investigator: IWATA Nakao FUJITA HEALTH UNIVERSITY, SCHOOL OF MEDICINE, PROFESSOR, 医学部, 教授 (60312112)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000); Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: Schizophrenia / Association analysis / Serotonin receptors / GABA receptors / Linkage disequiblium

Research Abstract

I. Sample collection: 800 schizophrenia and 200 bipolar disorder patients samples were collected. Combined with corroboratory groups samples, total sample numbers account more than 1 000 for schizophrenia and 800 for bipolar disorder, respectively. For pharmacogenomics analysis, 120 schizophrenics who were evaluated the efficacy and adverse effect for treatment of atypical antipsychotics risperidone were collected. Also 100 major depressive disorder patients who were evaluated the efficacy for serotonin reuptake inhibitor Fluvoxamine and personality traits were. collected.
II. All subtypes of serotonin receptor genes and chromosome 5q GABAA receptor cluster genes were examined for polymorphisms search and evaluated for linkage disequibrium mapping for Japanese population.
III. For linkage disequibrium association study, we find an association between schizophrenia and GABAA receptor alphal subunit gene. However, we could not confirm which SNPs or variants is a real predisposal genetic factor for vulnerability for schizophrenia. Furtherer investigation needed to confirm our preliminary results.
IV. Association analysis were performed for the following candidate genes : SLCIA2, TNF-alpha, AIM, NRG1, BDNF, Dysbindin, chimerin2, and ZDHHC8. Among them, we find positive associations schizophrenia and AKT1 and chimerin2 gene.

Research Products

• [Journal Article] Haplotype-based localization of an alcohol dependence gene to the 5q34 ・-aminobutyric acid type A gene cluste (2005)
  • Author(s): Radel M, Vallejo RL, Iwata N, et al.
  • Journal Title: Arch Gen Psychiatry 62(1) Pages: 47-55
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] No association was found between a functional SNP in ZDHHC8 and schizophrenia in a Japanese case-control population (2005)
  • Author(s): Saito S, Ikeda M, Iwata N, et al.
  • Journal Title: Neurosci Lett 374(1) Pages: 21-24
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A nonsynonymous polymorphism in the human fatty acid amide hydrolase gene did not associate with either methamphetamine dependence or schizophrenia (2005)
  • Author(s): Morita Y, Ujike H, Tanaka Y, et al.
  • Journal Title: Neurosci Lett 376(3) Pages: 182-187
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] No association of GSK3beta gene (GSK3B) with Japanese schizophrenia (2005)
  • Author(s): Ikeda M, Iwata N, et al.
  • Journal Title: Am J Med Genet B Neuropsychiatr Genet 134(1) Pages: 90-92
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Haplotype association between GABA(A) receptor gamma2 subunit gene (GABRG2) and methamphetamine use disorder (2005)
  • Author(s): Nishiyama T, Ikeda M, Iwata N, et al.
  • Journal Title: Pharmacogenomics J 5(2) Pages: 89-95
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A missense polymorphism (H204R) of a Rho GTPase-activating protein, the chimerin 2 gene, is associated with schizophrenia in men. (2005)
  • Author(s): Hashimoto R, Yoshida M, et al.
  • Journal Title: Schizophrenia Research 73(2-3) Pages: 383-385
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Haplotype-based localization of an alcohol dependence gene to the 5q34 γ-aminobutyric acid type A gene cluster. (2005)
  • Author(s): Radel M, Vallejo RL, Iwata N, Aragon R, Long JC, Virkkunen M, Goldman D
  • Journal Title: Arch Gen Psychiatry. 62(1) Pages: 47-55
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] No association was found between a functional SNP in ZDHHC8 and schizophrenia in a Japanese case-control population. (2005)
  • Author(s): Saito S, Ikeda M, Iwata N, Suzuki T, Kitajima T, Yamanouchi Y, Kinoshita Y, Takahashi N, Inada T, Ozaki N
  • Journal Title: Neurosci Lett 374(1) Pages: 21-24
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A non synonymous polymorphism in the human fatty acid amide hydrolase gene did not associate with either methamphetamine dependence or schizophrenia. (2005)
  • Author(s): Morita Y, Ujike H, Tanaka Y, Uchida N, Nomura A, Ohtani K, Kishimoto M, Morio A, Imamura T, Sakai A, Inada T, Harano M, Komiyamma T, Yamada M, Sekine Y, Iwata N, Iyo M, Sora I, Ozaki N, Kuroda S
  • Journal Title: Neurosci Lett 376(3) Pages: 182-187
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] No association of GSK3beta gene (GSK3B) with Japanese schizophrenia. (2005)
  • Author(s): Ikeda M, Iwata N, Suzuki T, Kitajima T, Yamanouchi Y, Kinoshita Y, Ozaki N
  • Journal Title: Am J Med Genet B Neuropsychiatr Genet
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A functional glutathione S-transferase P1 gene polymorphism is associated with methamphetamine -induced psychosis in Japanese population. (2005)
  • Author(s): Hashimoto T, Hashimoto K, Matsuzawa D, Shimizu E, Sekine Y, Inada T, Ozaki N, Iwata N, Harano M, Komiyama T, Yamada M, Sora I, Ujike H, Iyo M
  • Journal Title: Am J Med Genet ; B Neuropsychiatr Genet
  • NAID: 120002311901
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association study of the frizzled-3 (FZD3) gene with schizophrenia and mood disorders. (2005)
  • Author(s): Hashimoto R, Suzuki T, Iwata N, Yamanouchi Y, Kitajima T, Kosuga A, Tatsumi M, Ozaki N, Kamijima K, Kunugi H
  • Journal Title: J Neural Transm 112(2) Pages: 303-307
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A missense polymorphism (H204R) of a Rho GTPase-activating protein, the chimerin 2 gene, is associated with schizophrenia in men (2005)
  • Author(s): Iashimoto R, Yoshida M, Ozaki N, Yamanouchi Y, Iwata N, Suzuki T, Kitajima T, Tatsumi M, Kamijima K, Kunugi H
  • Journal Title: chizophr Res 73(2-3) Pages: 383-385
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Haplotype-based localization of an alcohol dependence gene to the 5q34 γ-aminobutyric acid type A gene cluster (2005)
  • Author(s): Radel M, Vallejo RL, Iwata N et al.
  • Journal Title: Arch Gen Psychiatry 62(1) Pages: 47-55
• [Journal Article] A nonsynonymous polymorphism in the human fatty acid amide hydrolase gene did not associate with either methamphetamine dependence or schizophrenia (2005)
  • Author(s): Morita Y, Ujike H, Tanaka Y et al.
  • Journal Title: Neurosci Lett 376(3) Pages: 182-187
• [Journal Article] Association of AKT1 with schizophrenia confirmed in a Japanese population (2004)
  • Author(s): Ikeda M, Iwata N, et al.
  • Journal Title: Biol Psychiatry 56(9) Pages: 698-700
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] No Association Is Found between the Candidate Genes of t-PA/Plasminogen System and Japanese Methamphetamine-Related Disorder (2004)
  • Author(s): Iwata N, Inada T, et al.
  • Journal Title: Ann N Y Acad Sci 1025 Pages: 34-38
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] No association with the neuregulin 1 haplotype to Japanese schizophrenia (2004)
  • Author(s): Iwata N, Suzuki T et al.
  • Journal Title: Mol Psychiatry 9 Pages: 126-127
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Association analysis of the -308G > A promoter polymorphism of the tumor necrosis factor alpha (TNF-alpha) gene in Japanese patients with schizophrenia (2004)
  • Author(s): Hashimoto R, Yoshida M, et al.
  • Journal Title: J Neural Transm 111 Pages: 217-221
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Comparison of G-Protein Selectivity of Human 5-HT2C and 5-HT1A Receptors. (2004)
  • Author(s): Okada M, Goldman D, Linnoila M, Iwata N, Ozaki N, Northup JK
  • Journal Title: Ann N Y Acad Sci 1025 Pages: 570-577
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Evidence of novel neuronal functions of dysbindin, a susceptibility gone for schizophrenia. (2004)
  • Author(s): Numakawa T, Yagasaki Y, Ishimoto T, Okada T, Suzuki T, Iwata N, Ozaki N, Taguchi T, Tatsuini M, Kamijima K, Straub RE, Weinberger DR, Kunugi H, Hashimoto R
  • Journal Title: Hum Mol Genet 13(21) Pages: 2699-2708
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mitochondrial DNA 3644T-->C mutation associated with bipolar disorder (2004)
  • Author(s): Munakata K, Tanaka M, Mori.K, Washizuka S, Yoneda M Tajima O, Akiyama T, Nanko S, Kunugi H, Tadokoro K, Ozaki.N, Inada T, Sakamoto K, Fukunaga T, Iijima Y, Iwata N, Tatsumi M, Yamada K, Yoshikawa T, Kat
  • Journal Title: Genomics 84(6) Pages: 1041-1050
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] No association between the Va166Met polymorphism of the brain-derived no urotrophie factor gene and bipolar disorder in a Japanese population : a multicenter study. (2004)
  • Author(s): Kunugi H, Iijima Y, Tatsumi M, Yoshida M, Hashimoto R, Kato T, Sakamoto K, Fukunaga T, Inada T, Suzuki T, Iwata N, Ozaki N, Yamada K, Yoshikawa T
  • Journal Title: Biol Psychiatry 56(5) Pages: 376-378
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] No Association Is Found between the Candidate Genes of t-PA/Plasminogen System and Japanese Methamphetamine-Related Disorder : A Collaborative Study by the Japanese Genetics Initiative for Drug Abuse. (2004)
  • Author(s): Iwata N, Inada T, Harano M, Komiyama T, Yamada M, Sekine Y, Iyo M, Sora I, Ujike H, Ozaki N
  • Journal Title: Ann NY Acad Sci 1025 Pages: 34-38
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] No Association With the Neuregulin 1 Haplotype to Japanese Schizophrenia. (2004)
  • Author(s): Iwata N, Suzuki T, Ikeda M, Kitajima T, Yamanouchi Y, Inada T, Ozaki N
  • Journal Title: Mol Psychiatry 9(2) Pages: 126-127
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association study between brain-derived neurotrophic factor gene polymorphisms and methamphetamine abusers in Japan. (2004)
  • Author(s): Itoh K, Hashimoto K, Shimizu E, Sekine Y, Ozaki N, Inada T, Harano M, Iwata N, Komiyama T, Yamada M, Sora I, Nakata K, Ujike H, Iyo M
  • Journal Title: Am J Med Genet B Neuropsychiatr Genet 132B(1) Pages: 70-73
  • NAID: 120002311760
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association of AKT1 with schizophrenia confirmed in a Japanese population. (2004)
  • Author(s): Ikeda M, Iwata N, Suzuki T, Kitajima T, Yamanouchi Y, Kinoshita Y, Inada T, Ozaki N
  • Journal Title: Biol Psychiatry 56(9) Pages: 698-700
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association analysis of the G308A promoter polymorphism of the tumor necrosis factor alpha (TNF-α) gene in Japanese patients with schizophrenia. (2004)
  • Author(s): Hashimoto R, Yoshida M, Ozaki N, Yamanouchi Y, Iwata N, Suzuki T, Kitajima T, Tatsumi M, Kamijima K, Kunugi H
  • Journal Title: Journal of Neural Transmission 111(2) Pages: 217-222
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] No Association Is Found between the Candidate Genes of t-PA/Plasminogen System and Japanese Methamphetamine-d Related Disorder (2004)
  • Author(s): Iwata N, Inada T, et al.
  • Journal Title: Ann N Y Acad Sci 1025 Pages: 34-38
• [Patent(Industrial Property Rights)] 双極性感情障害、統合失調症等の精神病性障害の予防・治療剤、そのスクリーニング方法、及び該疾患の発症リスクの判定方法 (2005)
  • Inventor(s): 宮川 剛, 山崎 信幸, 遠山 桂子, 尾崎 紀夫, 岩田 仲生, 池田 匡志
  • Industrial Property Rights Holder: 宮川 剛, 山崎 信幸, 遠山 桂子, 尾崎 紀夫, 岩田 仲生, 池田 匡志, 京都大学, 名古屋大学, 藤田保健衛生大学
  • Industrial Property Number: 2005-150215
  • Filing Date: 2005-05-23
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Iwata N, Suzuki T et al.: "No association with the neuregulin 1 haplotype to Japanese schizophrenia"Mol Psychiatry. 9. 126-127 (2004)
• [Publications] Hashimoto R, Yoshida M, et al.: "Association analysis of the -308G > A promoter polymorphism of the tumor necrosis factor alpha (TNF-alpha) gene in Japanese patients with schizophrenia"J Neural Transm. 111. 217-221 (2004)
• [Publications] Hashimoto R, Yoshida M, et al.: "A missense polymorphism (H204R) of a Rho GTPase-activating protein, the chimerin 2 gene, is associated with schizophrenia in men"Schizophrenia Research. in press.