Medical Internship as a Model to Find Gene x Stress Interactions in Depression

描述（由申请人提供）：该导师职业发展奖旨在将重点研究、个性化指导和教学相结合，为候选人提供先进基因组学和纵向研究设计方面的培训。申请人已完成精神病学住院医师培训和博士学位，主要研究涉及横断面数据的单变异遗传关联研究。他的职业目标是成为一名独立的研究者，开展研究，进一步了解严重抑郁症的遗传和环境因素，从而改善患有这种疾病的个体的生活。申请人建议建立在他的背景和发展一套新的必要的技能，以实现这一职业目标。该奖项的重点研究部分将建立在流行病学研究的基础上，这些研究表明，基因和生活压力是抑郁症病因学中最重要的两个因素。在过去的十年里，人们对确定特定基因和压力在抑郁症发展过程中的相互作用越来越感兴趣。尽管最初的研究令人兴奋，但我们得出明确结论的能力受到重大研究设计限制的影响：1)受试者之间的压力特征和强度存在实质性差异；2)回顾性设计；3)由于统计相互作用的测试而丧失能力。不幸的是，由于慢性压力的发作很难预先预测，而且每个人所遇到的压力类型差异很大，所以设计克服这些限制的方法一直很困难。医学实习是专业医师培训的第一年，它提供了一种独特的情况，在这种情况下，可以前瞻性地预测统一的慢性压力源的发作。本研究的第一个研究目的是：确定实习压力发生后，实习医师抑郁症状的纵向轨迹。这将使候选人达到研究的第一个培训目标：在纵向设计和分析技术方面打下坚实的基础。本研究的第二个研究目的是：评估抑郁候选通路遗传变异（单核苷酸多态性和拷贝数变异）与实习压力在实习压力下抑郁症状水平和轨迹上的相互作用。这将使候选人能够实现该研究的第二个培训目标：发展先进基因组工具的专业知识。

DESCRIPTION (provided by applicant): This Mentored Career Development Award seeks to combine a program of focused research, individualized mentorship and didactics to provide the candidate with the training in advanced genomics and longitudinal study design. The applicant has already completed psychiatry residency training and PhD centered around single variant genetic association studies involving cross-sectional data. His career goal is to become an independent investigator, conducting studies that further our understanding of the genetic and environmental factors underlying major depression in a manner that improves the lives of individuals suffering from this disorder. The applicant proposes to build on his background and develop a new set of skills necessary to achieve this career goal. The focused research part in the award will build on epidemiological studies that indicate that genes and life stress are two of the most important factors in the etiology of depression. Over the past decade, there has been growing interest in identifying interactions between specific genes and stress in the development of depression. Despite the excitement surrounding the initial studies, our ability to draw definitive conclusions is compromised by significant study design limitations: 1) substantial variation in the character and intensity of stress between subjects 2) retrospective design 3) loss of power due to tests of statistical interaction. Unfortunately, because the onset of chronic stress is so difficult to predict beforehand and because the type of stress encountered varies widely between individuals, designing methods to overcome these limitations has been difficult. Medical internship, the first year of professional physician training, presents a unique situation where the onset of a uniform, chronic stressor can be prospectively predicted. The first research aim of this study is: to identify longitudinal trajectories of depressive symptoms among medical interns after the onset of internship stress. This will allow the candidate to achieve the first training aim of the study: to develop a strong foundation in longitudinal design and analytic techniques. The second research aim of this study is: to evaluate the interaction between genetic variation (single nucleotide polymorphisms and copy number variants) in depression candidate pathways and internship stress on both the level and trajectory of depressive symptoms under the stress of internship. This will allow the candidate to achieve the second training aim of the study: to develop expertise in advanced genomic tools.