Broad Scale Genomic Analysis to Find Genes Associated with Depression Under Stres

大规模基因组分析寻找与压力下抑郁症相关的基因

基本信息

批准号：
9317292
负责人：
SRIJAN SEN
金额：
$ 28.84万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9317292
关键词：
Accounting Affect American Antidepressive Agents Architecture Awareness Biological Candidate Disease Gene Chronic Chronic stress Code Complex Data Data Set Depressed mood Development Disease Effectiveness Environmental Risk Factor Epidemiology Etiology Frequencies Genes Genetic Genetic Polymorphism Genome Genomic approach Genomics Goals Health and Retirement Study Heart Diseases Individual Inherited Internships Investigation Life Stress Longitudinal cohort Major Depressive Disorder Medical Mental Depression Mental disorders Methodology Methods Modeling Pathway interactions Patients Pattern Phenotype Physicians Public Health Research Design Retrospective Studies Risk Sampling Stress Study Subject Testing Time Training Untranslated RNA Variant Work World Health Organization base case control cohort depressive symptoms design disability disorder risk epidemiology study exome experience falls genetic variant genome wide association study genome-wide improved innovation novel predictive of treatment response prospective public health relevance stressor

项目摘要

DESCRIPTION (provided by applicant): Despite hundreds of linkage and association studies, including eight recent case-control genome-wide association studies (GWAS), there has been limited progress in identifying specific genes associated with depression. Epidemiological evidence indicates that life stress is a key factor in the etiology of depression. Indeed, there is growing recognition that accounting for stress facilitates the identification of genes important in the development of depression. Because of methodological limitations however, gene x stress studies have been limited from utilizing the broad-scale genomic approaches that have been successful in identifying genes in other complex disorders. Our long-term goal is to elucidate the pathophysiological architecture underlying depression to facilitate the development of improved treatments. Our objective in this application is to identify genetic variants associated with the development of depression under stress by utilizing medical internship as a model. The power and effectiveness of traditional gene x stress interaction studies have been compromised by the following study design limitations: 1) substantial variation in the type and intensity of stress between subjects 2) retrospective design and 3) loss of power due to tests of statistical interaction. Designing methods to overcome these limitations has been difficult because the onset of chronic stress is difficult to predict beforehand and the type of stress encountered by individuals varies greatly. Medical internship, the first year of professional physician training, presents a unique situation in which we can prospectively predict the onset of a uniform, chronic stressor and a dramatic increase in depressive symptoms. We hypothesize that both common and rare SNPs from across the genome will interact with internship stress to impact depressive symptom phenotypes. To test this hypothesis, we propose the following three specific aims: 1) identify longitudinal patterns of depressive symptoms under internship stress and factors associated with the depressive symptom patterns, 2) identify common and rare, functional genetic variants associated with depressive symptoms and depressive symptom trajectories during internship stress using cutting edge GWAS and Exome chip analysis and 3) assess whether significant associations with depressive symptoms in the intern sample replicate in other depression samples. Our approach is innovative because it takes advantage of a naturally occurring stress to overcome limitations of existing studies and allows us to perform a broad-scale, longitudinal cohort gene x stress study. This project is significant because it has the potential to identify key genetic factors involved in depression under stress, an advance that holds promises in predicting treatment response and identifying novel targets for antidepressant development.

描述（由申请人提供）：尽管有数百个连锁和关联研究，包括八项最近的病例对照基因组关联研究（GWAS），但在识别与抑郁症相关的特定基因方面的进展有限。流行病学证据表明，生命压力是抑郁症病因的关键因素。确实，有越来越认识到应对压力会有助于识别重要的基因抑郁症的发展。然而，由于使用方法上的局限性，基因X胁迫研究受到了利用在其他复杂疾病中成功鉴定基因的广泛基因组方法的限制。我们的长期目标是阐明抑郁症的病理生理结构，以促进改善治疗的发展。我们在本应用中的目标是通过利用医疗实习作为模型来确定与压力下抑郁症的发展相关的遗传变异。传统基因X压力相互作用研究的功率和有效性已因以下研究设计局限性而损害：1）受试者之间应力类型和强度的实质性变化2）回顾性设计和3）由于统计相互作用的测试而导致的功率损失。设计克服这些局限性的方法非常困难，因为很难事先预测慢性压力的发作，并且个人遇到的压力类型差异很大。医疗实习是专业医师培训的第一年，它提出了一种独特的情况，我们可以预测统一，慢性压力源和抑郁症状的急剧增加。我们假设来自整个基因组的常见和稀有SNP都会与实习压力相互作用，以影响抑郁症状表型。为了检验这一假设，我们提出以下三个具体目的：1）在实习压力和与抑郁症状模式相关的因素下确定抑郁症状的纵向模式，2）确定常见且罕见的功能性，功能性遗传变异，与抑郁症状的抑郁症状和抑郁症状相关的抑郁症状轨迹和在实习期间使用降低型GWAS和Exeme Shimations进行抑郁症状的抑郁症状以及其他相关性的抑制作用3）在其他抑郁症状中是否相关性。我们的方法具有创新性，因为它利用了自然发生的压力来克服现有研究的局限性，并使我们能够进行广泛的，纵向的队列基因X压力研究。该项目之所以重要，是因为它具有识别压力下抑郁症涉及的关键遗传因素，这一前进有望预测治疗反应并确定抗抑郁药发育的新目标。