QTL ANALYSIS OF DEPRESSIVE, STRESS HYPERREACTIVE BEHAVIO

抑郁、应激反应过度行为的QTL分析

• 批准号: 6032673
• 负责人: Eva E Redei
• 金额: $ 26.21万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6032673
• 关键词: attention deficit disorder; autoradiography; behavior test; behavioral genetics; blood tests; computer assisted sequence analysis; depression; gene expression; genetic disorder; genetic mapping; genetic markers; genetic susceptibility; genotype; hypothalamic pituitary adrenal axis; laboratory rat; linkage mapping; open field behavior; phenotype; pituitary hormones; psychological stressor; quantitative trait loci; statistics /biometry

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.

抑郁症是最常见的疾病之一，美国8%-16%的人口在有生之年患有抑郁症。这种疾病的病因尚不清楚，但应激性生活事件和遗传易感性显然是重要的风险因素。对抑郁障碍的家庭、双胞胎和收养研究表明，这是一种多基因遗传传播，使得在不同人类群体中进行遗传研究变得非常困难。利用啮齿动物模型对复杂疾病进行了遗传学研究，为多基因性状的遗传分析打开了可能性。到目前为止，还没有动物模型被用来研究抑郁症的遗传基础。我们认为近交系Wistar京都(WKY)大鼠是探索抑郁症潜在遗传原因的优秀模型，因为它们的一些行为和激素特征模仿人类的抑郁症症状，并且它们的表型与其他近交系大鼠非常不同，包括Fisher 344(F344)。血压正常的WKY大鼠在公认的行为范式中表现出抑郁样行为，这是通过抗抑郁药物的长期治疗而正常化的。WKY大鼠在行为上和通过过度分泌应激激素也表现出应激-高反应。在这里，我们建议对WKY大鼠的抑郁和应激高反应行为进行数量性状基因座(QTL)研究，作为了解人类可能的遗传机制的第一步。我们的具体目标是首先构建WKY和F344的两代杂交组合。我们将对WKY/F344杂交亲本和F2代的行为和激素表型进行分析。这一系列研究将描述WKY大鼠抑郁和应激-高反应行为之间的关系。然后，我们将用QTL分析来定位遗传标记，这些遗传标记的遗传与F2代的行为和激素表型相关。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，我们将把可能的基因座定位到单个染色体的特定区域。一旦确定了QTL，就需要对它们进行精细定位和确认。在标记辅助选择的情况下，基因座将被导入到不同的同源菌株中。这将验证该基因座的表型，并允许在与其他可能改变其表达的分离基因座隔离的情况下，进行进一步的遗传、生理和生化分析。最后，我们将在已确定的染色体区域中搜索假定的候选基因。利用来自小鼠和人类基因组的比较信息，我们将研究可能与WKY大鼠抑郁和应激-高反应行为有关的候选基因。我们假设，在这个动物模型中QTL和候选基因的特征将有助于在人类中识别抑郁症相关基因。