Genes, Stress and Psychopathology

基因、压力和精神病理学

• 批准号: 7211002
• 负责人: GARY S WAND
• 金额: $ 45.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-25 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211002
• 关键词: Affective; Anxiety; Anxiety Disorders; Bioinformatics; Biological Assay; COMT gene; Candidate Disease Gene; Catchment Area; Catechol O-Methyltransferase; Catechols; DNA; Data; Development; Dimensions; Discipline; Disease; Disease remission; Dopamine-beta-monooxygenase; European; Follow-Up Studies; Gene Frequency; General Population; Genes; Genetic; Genetic Polymorphism; Goals; Haplotypes; Hormonal; Hydrocortisone; Individual; International; Investigation; Major Depressive Disorder; Measures; Mental Depression; Mental Health; Mental disorders; Metabolism; Methyltransferase; Minor; Mood Disorders; Neurosciences; Neurotic Disorders; Personality; Personality Traits; Personality inventories; Phenotype; Population; Prevalence; Psychological Stress; Psychopathology; Research Personnel; Risk; Risk Factors; Sampling; Score; Single Nucleotide Polymorphism; Stress; Stress Tests; Testing; Trier Social Stress Test; Variant; Woman; base; biological adaptation to stress; disability; genetic epidemiology; genetic variant; interest; men; mu opioid receptors; psychologic; response; serotonin transporter; trait

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.

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。导致间歇性异常皮质醇暴露的应激反应改变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。有人提出，异常的皮质醇动力学是一种中间表型，使个体患某些精神疾病的风险增加。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。我们在每个基因中选择了约20个小等位基因频率为10%的snp，并基于HAPMAP （International HAPMAP consortium, 2003）的数据，捕获了每个基因的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人格特征的关系，假设那些与抑郁和焦虑障碍最密切相关的人格将与高度的压力反应最相关。我们的初步数据显示，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著的相关性，这一假设得到了支持。人们对神经质作为抑郁症的风险因素的兴趣越来越大。在目标3中，将采用目标1中发现的相关遗传变异，并使用特定目标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，即流行病学集水区人格遗传学样本，包含350名女性，她们之前获得了NEO和TCI分数，并提供了DNA样本。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。