QTL ANALYSIS OF DEPRESSIVE, STRESS HYPERREACTIVE BEHAVIO

抑郁症是最常见的疾病之一，在美国有8- 16%的人口在一生中受到折磨。 这种疾病的病因尚不清楚，但压力性生活事件和遗传易感性显然是重要的风险因素。 抑郁症的家庭、双胞胎和收养研究表明多基因遗传传递，使得在异质人群中进行遗传研究变得相当困难。 复杂的疾病已接近遗传使用啮齿动物模型，开辟了可能性的多基因性状的遗传分析。 到目前为止，还没有动物模型被用于研究抑郁症的遗传基础。 我们认为，近交系Wistar京都（WKY）大鼠是一个很好的模型，以追求抑郁症的潜在遗传原因，因为他们的一些行为和激素特征模仿人类抑郁症的症状，他们是表型非常不同于其他近交系，包括费舍尔344（F344）。 血压正常的WKY大鼠在公认的行为模式中表现出抑郁样行为，通过抗抑郁药长期治疗使其正常化。 WKY大鼠也表现出应激反应过度的行为和过度分泌应激激素。 在这里，我们建议进行一个数量性状基因座（QTL）的研究抑郁和应激反应过度的行为在WKY大鼠作为第一步，以了解可能的遗传机制，在人类。 我们的具体目标是首先构建WKY和F344之间的两代互交。 我们将分析WKY/F344杂交的亲本和F2后代的行为和激素表型。 这些系列研究将描述WKY大鼠抑郁和应激反应过度行为之间的关系。 然后，我们将映射，与QTL分析，遗传标记的遗传相关的行为和激素表型在F2代。 通过证明这些表型的极端表达与其遗传图谱位置已知的标记等位基因之间的关联，我们将推定的基因座映射到个体染色体的特定区域。一旦确定了QTL，就需要对它们进行精细定位和确认。 通过标记辅助选择，基因座将被基因渗入到单独的同类菌株中。 这将在表型上验证基因座，并允许其与可能改变其表达的其他分离基因座隔离进行进一步的遗传、生理和生化分析。 最后，我们将在确定的染色体区域中寻找推定的候选基因。 利用小鼠和人类基因组的比较信息，我们将研究可能参与WKY大鼠抑郁和应激反应过度行为的候选基因。 我们假设，在这个动物模型中的QTL和候选基因的特性将有助于识别人类抑郁症相关基因。

Depressive disorders are among the most common diseases with 8-16 percent of the population in the United States afflicted during their lifetime. The etiology of this illness is unknown, but stressful life events and genetic predisposition are clearly important risk factors. Family, twin and adoption studies of depressive disorders suggest a multigenic genetic transmission, making genetic studies in the heterogeneous human population quite difficult. Complex diseases have been approached genetically by using rodent models, opening up possibilities for genetic analysis of polygenic traits. No animal models, to date, have been used to study the genetic basis of depressive disorders. We believe that the inbred Wistar Kyoto (WKY) rat is an excellent model to pursue underlying genetic causes of depressive disorder, because some of their behavior and hormonal characteristics mimic symptoms of depression in humans and they are phenotypically very different from other inbred strains, including Fisher 344 (F344). The normotensive WKY rat exhibits depressive-like behavior in accepted behavioral paradigms that is normalized by chronic treatment with antidepressants. WKY rats also show stress-hyperreactivity both behaviorally and by hypersecreting stress hormones. Here, we propose to conduct a quantitative trait loci (QTL) study of depressive and stress hyperreactive behavior in the WKY rats as a first step to understanding possible genetic mechanisms in humans. We specifically aim first to construct a two-generation intercross between WKY and F344. We will analyze the behavioral and hormonal phenotypes of the parents and the F2 progeny of the WKY/F344 cross. These series of studies will characterize the relationship between depressive and stress-hyperreactive behavior in the WKY rat. Then we will map, with a QTL analysis, genetic markers whose inheritance correlate with the behavioral and hormonal phenotypes in the F2 generation. By demonstrating an association between an extreme expression of these phenotypes and marker alleles whose genetic map position is known, we will map putative loci to specific regions of individual chromosomes. Once the QTL are identified, they will need to be fine-mapped and confirmed. Loci will be introgressed, with marker-assisted selection, into separate congenic strains. This will both validate the locus phenotypically and permit its further genetic, physiological, and biochemical analysis in isolation from other segregating loci that may modify its expression. Finally, we will conduct a search for putative candidate genes in the chromosomal regions identified. Using comparative information from mouse and human genomes, we will investigate candidate genes that may be involved in the depressive and stress-hyperreactive behavior of the WKY rat. We hypothesize that the characterization of QTL and candidate genes in this animal model will facilitate the identification of depression-related genes in humans.