Genes, Stress and Psychopathology

描述(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，女性患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皮质醇暴露，通常伴随着抑郁症和焦虑症。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，甚至在精神障碍长期缓解时也会持续存在。已有研究提出，异常皮质醇动力学是一种中间表型，会增加个体患某些精神疾病的风险。在目标1中，我们建议在健康女性群体中进行一项数量性状研究，测试特定表型与一组15个候选基因和功能多态的相关性。我们将确定哪些功能多态和基因单倍型预测皮质醇对心理应激反应的大小。我们选择了大约20个等位基因频率为10%的SNPs，并基于HapMap(国际HapMap联合会，2003)的数据，捕捉到了每个基因单倍型块内的共同变异。在目标2中，我们建议研究皮质醇反应与个性特征的关系，假设那些与抑郁和焦虑症关系最密切的个性将与高度应激反应最相关。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个性维度之间存在显着相关性。神经质是抑郁症的一个风险因素，人们对此越来越感兴趣。在目标3中，将采用在目标1中发现的相关基因变异，并使用特定目标2中与皮质醇相关的人格特征，在单独的现有样本上对它们进行测试。现有样本--流行病学领域个性遗传学样本--包含350名以前获得过NEO和TCI评分的女性，以及可用的DNA样本。这些研究的结果将为精神健康领域以及神经科学和新陈代谢的更广泛学科提供信息。

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.