Approach to depressogenic genes from QTL analysis

从QTL分析中寻找抑郁基因

• 批准号: 15591250
• 负责人: WATANABE Akiko
• 金额: $ 2.05万
• 依托单位: RIKEN
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591250/
• 关键词: mood disorder; mouse model; QTL Analysis; Forced swimming test; Tail suspension test; GABA-A Receptor; α1 and α6 subunit; 気分障害; ケースコントロール研究; GABA-A レセプターサブユニット; α1; α6; QTL; うつ病モデル; QTL解析; DNAマイクロアレイ

Human depression or mood disorder is defined as acomplex disease, making positional cloning of susceptibility genes a formidable task. We have undertaken genetic analyses of animal models for depression, comparing our results with advanced database resources.1.We performed quantitative trait loci(QTL) analysis on two mouse models of "despair", namely the forced swim test(FST) and tail suspension test(TST), and detected multiple chromosomal loci that control immobility time in these test. One QTL detected on mouse chromosome 11 harbors the GABAA receptor subunit genes, α1 and α6 as candidates genes. Sequence and expression analyses of α1 and α6 revealed significantly difference in the frontal cortex of two strains parents mice.2.We tested these genes for association in human mood disorder patients. A linkage study has detected chromosomal area 5q34,where GABA type A receptor subunit genes are mapped, as a susceptibility region for mood disorders, making these genes compelling candidates for such diseases. We obtained significant associations of the α1 and α6 subunit genes with the disease on 5q34,particularly in females. This result was striking, because we had previously detected an epistatic interaction between mouse chromosome 11 and X that regulates immobility time in these animals.3.These data offer genetic support for a role of GABA-A receptor genes in susceptibility to mood disorders.

人类抑郁症或情绪障碍被定义为复杂疾病，使得易感基因的定位克隆成为一项艰巨的任务。本研究对抑郁症动物模型进行了遗传学分析，并与先进的数据库资源进行了比较。1.对强迫游泳试验（FST）和悬尾试验（TST）两种“绝望”小鼠模型进行了数量性状基因座（QTL）分析，检测到多个控制不动时间的染色体基因座。在小鼠11号染色体上检测到一个QTL，该QTL携带GABAA受体亚基基因α1和α6作为候选基因。α1和α6基因的序列和表达分析显示，两品系小鼠的额叶皮层存在显著差异。2.我们检测了这些基因在人类情绪障碍患者中的关联性。一项连锁研究发现，GABA A型受体亚单位基因所在的染色体区域5 q34是情绪障碍的易感区域，使这些基因成为此类疾病的有力候选者。我们获得了α1和α6亚基基因与5 q34上的疾病的显著关联，特别是在女性中。这一结果是惊人的，因为我们之前已经检测到小鼠11号染色体和X染色体之间的上位相互作用，调节这些动物的不动时间。3.这些数据为GABA-A受体基因在情绪障碍易感性中的作用提供了遗传支持。

项目成果

Comprehensive expression analysis of a rat depression model

• DOI: 10.1038/sj.tpj.6500234
• 发表时间: 2004-04
• 期刊: The Pharmacogenomics Journal
• 作者: Noriaki Nakatani;Hiroyuki Aburatani;Hiroyuki Aburatani;Kunihiro Nishimura;Jun'ichi Semba;Takeo Yoshikawa

Approach to Depressogenic Genes from Genetic Analyses of Animal Models.

从动物模型的遗传分析中寻找致抑郁基因的方法。

• 发表时间: 2004
• 期刊: Psychiatria et Neurologia Japonica 106, 8
• 作者: Yoshikawa;T.et al.;Takeo Yoshikawa
• 通讯作者: Takeo Yoshikawa

Kazuo Yamada, Akiko Watanabe, Yoshimi Iwayama-Shigeno, Takeo Yoshikawa: "Evidence of association between gamma-aminobutyric acid type A receptor genes located on 5q34 and female patients with mood disorders."Neuroscience Letter. 349. 9-12 (2003)

Kazuo Yamada、Akiko Watanabe、Yoshimi Iwayama-Shigeno、Takeo Yoshikawa：“位于 5q34 的 γ-氨基丁酸 A 型受体基因与女性情绪障碍患者之间存在关联的证据。”《神经科学快报》。

渡辺明子, 豊田倫子, 石塚祐一, 吉川武男: "Prepulse inhibitionの量的遺伝子座(QTL)解析-マウス系統差の検討-"Jap.J.Neuropsychopharmacol.. 23. 295 (2003)

Akiko Watanabe、Michiko Toyota、Yuichi Ishizuka、Takeo Yoshikawa：“前脉冲抑制的定量基因座 (QTL) 分析 - 小鼠品系差异的检查 -”Jap.J.Neuropsychopharmacol.. 23. 295 (2003)

Evidence of association between gamma-aminobutyric acid type A receptor genes located on 5q34 and female patients with mood disorder

位于 5q34 的 γ-氨基丁酸 A 型受体基因与女性情绪障碍患者相关的证据

• 发表时间: 2003
• 期刊: Neuroscience Letter 349
• 作者: Kazuo Yamada;Akiko Watanabe et al.
• 通讯作者: Akiko Watanabe et al.