Genes, Stress and Psychopathology

描述（由申请人提供）：抑郁症是女性疾病相关残疾的主要原因。研究表明，女性重度抑郁症的终生患病率（21.3%）几乎是男性（12.7%）的两倍。压力反应的改变导致间歇性异常的皮质醇暴露，通常伴有抑郁症和焦虑症。越来越多的证据表明，这种表型可能先于情感性疾病的表现，即使精神障碍已经长期缓解，这种表型也会持续存在。已经提出，异常的皮质醇动力学是一种中间表型，使个体处于发展某些精神障碍的增加的风险中。在目标1中，我们建议在健康女性人群中进行一项数量性状研究，以检测特定表型与一组15个候选基因和功能多态性之间的关联。我们将确定哪些功能多态性和基因单倍型预测皮质醇对心理压力的反应程度。我们选择了每个基因约20个具有> 10%的次要等位基因频率的SNP，并且基于来自HAPMAP（International HAPMAP consortium，2003）的数据，捕获了每个基因的单倍型块内的常见变异。在目标2中，我们建议检查皮质醇反应与人格特质的关系，假设那些与抑郁症和焦虑症最密切相关的人格与应激反应的增强最相关。这一假设得到了我们的初步数据的支持，这些数据显示，皮质醇对心理压力测试的反应与神经质的人格维度之间存在显着的相关性。人们越来越关注神经质作为抑郁症的一个危险因素。在目标3中，将采用目标1中发现的相关遗传变异，并使用目标2中与皮质醇相关的人格特征，在一个单独的、已经存在的样本上进行测试。现有的样本，流行病学集水区人格遗传学样本包含350名妇女谁拥有NEO和TCI分数以前获得，和DNA样本可用。这些研究的结果将为心理健康领域以及更广泛的神经科学和代谢学科提供信息。

DESCRIPTION (provided by applicant): Depression is the leading cause of disease-related disability in women. Studies have shown that the lifetime prevalence of a major depressive disorder in women (21,3%) is almost twice that in men (12.7%). An altered stress response resulting in intermittent aberrant cortisol exposure often accompanies depression and anxiety disorders. Growing evidence indicates that this phenotype may precede the manifestations of affective illness and persist even when the mental disorder has been in long term remission. It has been proposed that aberrant cortisol dynamics is an intermediate phenotype placing individuals at increased risk for the development of certain psychiatric disorders. In aim 1, we are proposing to perform a quantitative trait study testing for an association of a specific phenotype with a set of 15 candidate genes and functional polymorphisms in a population of healthy women. We will determine Which functional polymorphisms and gene haplotypes predict the magnitude of cortisol responses to psychological stress. We selected ~20 SNPs per gene that had minor allelic frequencies of >10%, and based on data from HAPMAP (International HAPMAP consortium, 2003), captured the common variation within the haplotype blocks across each gene. In aim 2, we propose to examine the relationship of cortisol responses to personality traits, with the hypothesis that those personalities most closely related to depression and anxiety disorders will be most correlated with heightened stress response. This hypothesis is supported by our preliminary data showing a significant correlation between cortisol responses to the psychological stress test and the personality dimensions of Neuroticism. There is growing interest in neuroticism as a risk factor for depression. In aim 3, will take the associated genetic variants discovered in aim 1 and test them on a separate, already existing sample, using the cortisol-correlated personality traits from specific aim 2. The existing sample, the Epidemiologic Catchment Area Genetics of Personality Sample contains 350 women who have NEO and TCI scores previously obtained, and DNA samples available. Results from these studies will inform the mental health field as well as the broader disciplines of neuroscience and metabolism.