Mobile Technology to Identify Behavorial Mechanisms Linking Genetic Variation and Depression

大规模的全基因组关联研究首次明确确定了遗传变异 与重度抑郁症有关为了将这一进步转化为更好的诊断、监测和 治疗，关键的下一步是阐明行为机制连接牵连遗传变异 抑郁症不幸的是，已经确定相关变异的大规模研究通常 采用不适合研究机制的单时间点和有限表型评估 将基因与抑郁症联系起来，抑郁症是一种慢性多模式疾病。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。 我们在本申请中的目标是了解遗传变异如何与 抑郁症发挥其作用。医学实习，专业医师培训的第一年，提出了一个 在这种独特的情况下，我们可以前瞻性地预测一个统一的，慢性应激源的发作，并遵循 抑郁症状的发展。我们发现抑郁症的发病率从4% 实习年期间，实习前的比例降至26%。目前，这项研究每年招收3 000至3 500名实习生。我们 实习生队列是密切监测最近移动的健康抑郁症发展的理想人群 技术作为一种工具，以客观的措施实时跟踪这些人。在拟议的研究中， 我们将结合联合收割机、尖端基因组学、移动的医疗技术和未来的实习生压力设计， 确定抑郁症相关的遗传变异导致抑郁症的机制。我们 假设抑郁症相关的遗传变异通过以下方式增加抑郁症的风险： 特定的移动的测量行为表型。为了验证这一假设，我们提出以下三点： 具体目标：1）识别数据驱动的行为表型，其来源于移动的数据元素， 预测情绪变化和抑郁发作的短期风险; 2）识别遗传变异 与压力下的抑郁症有关; 3）阐明行为表型， 遗传变异可能会增加患抑郁症的风险。我们的方法是创新的，因为它 结合自然发生的压力范例和新的实时客观评估工具， 阐明基因，客观，实时标记和抑郁症之间的关系， 迄今为止，还没有尝试过。这个项目意义重大，因为它有可能确定关键的 压力下抑郁症的遗传相关机制，这一进展 在预测治疗反应和确定抗抑郁药开发的新靶点方面有希望。

Large scale genome-wide association studies, for the first time, have identified genetic variation definitively associated with major depression. To translate this advancement into improved diagnosis, monitoring, and treatment, a critical next step is to elucidate the behavioral mechanisms linking the implicated genetic variation with depression. Unfortunately, the large-scale studies that have identified associated variants have typically employed single-time point and limited phenotypic assessments that are not suited to study mechanisms linking genes and depression, a chronic multi-modal disease. 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 understand how genetic variants associated with the development of depression exert their effect. 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 follow the development of depressive symptoms. We have found that rates of depression increase dramatically, from 4% prior to internship to 26% during internship year. Currently, the study enrolls 3,000-3,500 interns annually. Our intern cohort is an ideal population to closely monitor the development of depression with recent mobile health technology as a tool to follow these individuals in real-time, with objective measures. In the proposed study, we will combine, cutting edge-genomics, mobile health technology, and the prospective intern stress design to identify the mechanisms through which depression-related genetic variation lead to depression. We hypothesize that depression-associated genetic variation acts to increase the risk of depression through specific mobile measured behavioral phenotypes. To test this hypothesis, we propose the following three specific aims: 1) Identify data driven behavioral phenotypes, derived from mobile data elements, that predict short-term risk for mood changes and depressive episodes; 2) Identify genetic variants associated with depression under stress; and 3) Elucidate behavioral phenotypes through which genetic variants may act to increase the risk of depression. Our approach is innovative because it combines a naturally occurring stress paradigm and new real-time objective assessment tools in order to elucidate the relationship between genes, objective, real-time markers and depression with an approach that, to date, has not been attempted. This project is significant because it has the potential to identify key mechanisms underlying genetic associations involved in depression under stress, an advancement that holds promises in predicting treatment response and identifying novel targets for antidepressant development.