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

描述（由申请人提供）：尽管有数百项连锁和关联研究，包括最近的8项病例对照全基因组关联研究（GWAS），但在识别与抑郁症相关的特定基因方面进展有限。流行病学证据表明，生活压力是抑郁症的一个重要病因。确实有 越来越多的人认识到，对压力的解释有助于识别基因， 抑郁症的发展。然而，由于方法上的限制，基因X应激研究受到限制，无法利用广泛的基因组方法，这些方法在识别其他复杂疾病中的基因方面取得了成功。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。本申请的目的是通过利用医学实习作为模型来识别与压力下抑郁症发展相关的遗传变异。传统基因x压力相互作用研究的功效和有效性受到以下研究设计限制的影响：1）受试者之间压力类型和强度的实质性变化2）回顾性设计和3）由于统计相互作用检验而丧失功效。设计克服这些限制的方法一直很困难，因为慢性压力的发作很难事先预测，个人遇到的压力类型差异很大。医学实习，专业医师培训的第一年，呈现出一种独特的情况，在这种情况下，我们可以前瞻性地预测统一的慢性应激源的发作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罕见的SNP将与实习压力相互作用，影响抑郁症状表型。为了验证这一假设，我们提出了以下三个具体目标：1）确定实习压力下抑郁症状的纵向模式以及与抑郁症状模式相关的因素，2）确定常见和罕见，使用最先进的GWAS和外显子组芯片分析与实习压力期间抑郁症状和抑郁症状轨迹相关的功能性遗传变异，以及3）评估实习生样本中与抑郁症状的显著关联是否在其他抑郁症样本中复制。我们的方法是创新的，因为它利用了自然发生的压力，以克服现有研究的局限性，并允许我们进行大规模的，纵向队列基因x压力研究。该项目意义重大，因为它有可能确定压力下抑郁症的关键遗传因素，这一进展有望预测治疗反应和确定抗抑郁药开发的新靶点。

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.