Approach to depressogenic genes from QTL analysis

人类抑郁或情绪障碍被定义为一种复杂的疾病，这使得位置克隆易感基因成为一项艰巨的任务。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QTL分析，并检测到控制不动时间的多个染色体位点。在小鼠11号染色体上检测到的一个QTL含有GAAA受体亚单位基因，候选基因为α1和α6。α1和α6的序列和表达分析显示，两个品系的父母鼠额叶皮质中存在显著差异。2.我们测试了这两个基因在人类情绪障碍患者中的相关性。一项连锁研究发现，定位GABA A型受体亚单位基因的染色体区域5q34是情绪障碍的易感区域，使这些基因成为此类疾病的候选基因。我们在5q34上获得了α1和α6亚单位基因与疾病的显著关联，特别是在女性。这一结果是惊人的，因为我们之前检测到小鼠11号染色体和X之间的上位性相互作用，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学支持。

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.