Association analysis of schizophrenomimetic- and D-serine-inducible genes in bipolar disorder and schizophrenia.

双相情感障碍和精神分裂症中精神分裂拟态基因和 D-丝氨酸诱导基因的关联分析。

• 批准号: 17591197
• 负责人: ISHII Sumikazu
• 金额: $ 2.11万
• 依托单位: Tokyo Medical and Dental Unversity
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591197/
• 关键词: Bipolar disorder; D-serine; D-serine modulator-1 gene (dsm-1); NMDA receptor; PAPS; PAPST1; Schizophrenia; SNP; 脳神経疾患; ゲノム; フェンサイクリジン; メタンフェタミン; 連鎖不平衡

Hypofunction of the N-methyl-D-aspartate (NMDA) type glutamate receptor-mediated neurotransmission has been hypothesized to underlie the pathophysiology of schizophrenia. In the presence of glutamte, NMDA receptor activity is modulated by glycine and D-serine. In this study, we examined the association of PAPST1 (3'-Phosphoadenosine 5'-Phosphosulfate Transporter 1) in schizophrenia and bipolar disorder, (1) because PAPST1 is the human ortholog of the rat dsm-1, D-serine modulator-1, which modulate the D-serine transport, and (2) because of the suggestion of a genetic overlap between affective disorders and schizophrenia. In the case-control study, three polymorphisms, rs 575034, rs 1875324 and rs 3832441, showed a significant association with bipolar disorder (allelic associations, p=.0074, p=.0075 and p=.0451, respectively). The test of genotype frequency of the SNP (rs3832441) remained significant even after Bonferroni correction (alpha=0.0071) for multiple testing. The haplotypes constructed from these three SNPs were also associated with the bipolar disorder. However, no association was found in family-based association analysis in Caucasian bipolar disorder trios. The present study suggests that SNPs in the PAPST1 may confer the genetic risk for bipolar disorder.

N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体介导的神经传递功能减退已被假设为精神分裂症的病理生理基础。在谷氨酸存在下，NMDA受体活性受甘氨酸和D-丝氨酸调节。在这项研究中，我们研究了PAPST 1（3 '-磷酸腺苷5'-磷酸硫酸转运蛋白1）在精神分裂症和双相情感障碍中的相关性，（1）因为PAPST 1是大鼠dsm-1的人类直系同源物，D-serine modulator-1调节D-丝氨酸转运，（2）因为情感障碍和精神分裂症之间存在遗传重叠。在病例对照研究中，三个多态性，rs 575034，rs 1875324和rs 3832441，显示与双相情感障碍显著相关（等位基因相关性，分别为p=.0074，p=.0075和p=.0451）。SNP（rs3832441）的基因型频率的检验即使在多重检验的Bonferroni校正（α =0.0071）之后仍然是显著的。从这三个SNPs构建的单倍型也与双相情感障碍相关。然而，在以家族为基础的关联分析中，未发现与白人双相情感障碍三人组的关联。本研究提示PAPST 1基因的SNPs可能与双相情感障碍的遗传风险有关。

项目成果

脳のD-セリンシステムを標的とした統合失調症の新規薬物療法開発に関する研究

针对脑部D-丝氨酸系统的精神分裂症新药开发研究

• 发表时间: 2005
• 期刊: 精神科薬療研究年報 37
• 作者: Nakano N;et al;Tochigi M;山本直樹 他
• 通讯作者: 山本直樹 他

Evidenci for involvement of glial cell activity in the control of extracellular D-serine contents in the rat brain.

神经胶质细胞活性参与控制大鼠脑细胞外 D-丝氨酸含量的证据。

• 发表时间: 2006
• 期刊: J Neural Transm 113
• 作者: Koizumi Y;Awata S;Seki T;et al.;光定博生 他;Kanematsu S
• 通讯作者: Kanematsu S

Study on the D-serine system in the brain and its application for the development of novel anti-schizophrenic drugs.

脑内D-丝氨酸系统研究及其在新型抗精神分裂药物开发中的应用

• 发表时间: 2005
• 期刊: Ann Rep Mitsubishi Pharma Res Found 37
• 作者: Kitaichi Y;Inoue T;Nakagawa S;Izumi T;Koyama T;Yamamoto N et al.
• 通讯作者: Yamamoto N et al.

Selective serotonin reuptake inhibitors, fluoxetine and paroxetine, attenuate the expression of the established behavioral sensitization induced by methamphetamine

• DOI: 10.1038/sj.npp.1301111
• 发表时间: 2007-03-01
• 期刊: NEUROPSYCHOPHARMACOLOGY
• 影响因子: 7.6
• 作者: Kaneko, Yujiro;Kashiwa, Atsushi;Nishikawa, Toru
• 通讯作者: Nishikawa, Toru

Inhibition of D-serine accumulation in the Xenopus oocyte by expression of the rat ortholog of human 3'-phosphoadenosine 5'-phsphosulfate transporter gene isolated from the neocortex as D-serine modulator-1.

通过表达从新皮质分离的人 3-磷酸腺苷 5-磷酸硫酸盐转运蛋白基因的大鼠直系同源物作为 D-丝氨酸调节剂-1，抑制非洲爪蟾卵母细胞中的 D-丝氨酸积累。

• 发表时间: 2006
• 期刊: J Neurochem 96
• 作者: Kikuchi Y;et al;Sakai T etc.;Casadesus G et al.;Inoue T;Kaneko Y et al.;Shimazu D et al.
• 通讯作者: Shimazu D et al.