Examining several possible causes of GxE non-replications in depression

严重抑郁障碍(MDD)是公共卫生中的一个严重问题，并已成为大规模基因-环境相互作用(GxE)的主题(即当应激源“触发”先前存在的遗传脆弱性以增加风险时)，目的是揭示MDD治疗或预防的新进展。然而，正如最近的一项荟萃分析所强调的那样，GxE领域的进展一直受到极其不一致的发现的阻碍(Risch等人，2009年)。这项提案审查了导致这些不一致结论的几个可能原因。正如这一研究领域的一篇里程碑式的评论(Monroe&Reid，2008)所强调的那样，GxE关于MDD的报告以高度不一致的方式将生活压力具体化(例如，关注经历的压力源总数或最糟糕事件的严重程度评级)-以至于没有两份报告以完全相同的方式审查生活压力。这可能是因为还没有人系统地研究生活压力的可操作性最能预测MDD的发病。此外，GxE测试中是否应该包括慢性压力或童年逆境尚不清楚，因为几乎没有研究直接将它们的预测能力与传统研究的环境病原体应激生活事件的预测能力进行比较。第二个问题是，没有关于MDD的GxE报告来检查正在研究的MDD病例是MDD的首发还是复发。这一点很重要，因为众所周知，严重应激源与MDD发作的关系随着连续的复发而退化；一种假设是MDD使个体对应激的影响敏感，而较晚的发作可以由逐渐较温和的应激源“触发”。报告中MDD复发的比例越大，发现真正的GxE相互作用的可能性就越低。第三，也是最后一点，性别和种族/民族可能调节生活压力和MDD发病之间的关系。考虑到这样的主持人可以进一步减少统计误差方差，提高发现GxE交互作用的概率。这些问题将被检查并将结果应用于GxE测试(在先前研究的和新的多态中)，使用来自中等规模、种族多样化的前瞻性纵向调查的现有数据，对青春期晚期到成年早期的情绪障碍的风险进行调查。将采用比例风险回归(生存)分析和多水平建模。根据赞助机构的使命，这样的研究计划可以：1)消除障碍，进一步确定与MDD相关的遗传和环境因素；2)告知不同类型的生活压力对增加MDD风险的相对重要性；3)加强关于性别和种族/民族如何通过对生活压力的不同敏感度影响MDD的发生和复发的知识。

Major depressive disorder (MDD) is a serious problem in public health and has been the subject of a massive to identify gene-environment interactions (GxE) (i.e., when stressors "trigger" pre-existing genetic vulnerabilities to increase risk), with a goal of shedding light on new inroads for treatment or prevention of MDD. However, progress in the GxE field has been stymied by extremely inconsistent findings, as highlighted by a recent meta-analysis (Risch et al., 2009). This proposal examines several possible causes for these inconsistent findings. One issue, as highlighted by a landmark critique of this research area (Monroe & Reid, 2008), is that GxE reports on MDD have operationalized life stress in highly inconsistent ways (e.g., focusing on the total number of stressors experienced or the severity rating of the worst event)-to the extent that no two reports examine life stress in precisely the same manner. This may have occurred because no one has yet examined in a systematic fashion what operationalization of life stress best predicts MDD onset. Further, whether chronic stress or childhood adversity should be included in GxE tests is not known, as almost no research directly compares their predictive power with that of the traditionally studied environmental pathogen-stressful life events. A second issue is that no GxE reports on MDD examine whether the MDD cases under study are first lifetime onsets of MDD or recurrences. This is important because it is well- established that the relationship of severe stressors to MDD episode onset degrades with successive recurrences; one hypothesis is that MDD sensitizes individuals to the effects of stress, and later episodes can be "triggered" by progressively milder stressors. The larger the proportion of recurrences of MDD in a report, the lower the probability of finding a genuine GxE interaction would be. Third and finally, gender and race/ethnicity may moderate the relationship between life stress and MDD onset. Accounting for such a moderator may further reduce statistical error variance, improving the probability of findings GxE interactions. These issues will be examined and the results applied in GxE testing (in previously studied and novel polymorphisms) using existing data from a moderately large, racially diverse, prospective longitudinal investigation of risk for emotional disorders in late adolescence to early adulthood. Proportional hazards regression (survival) analysis and multilevel modeling will be employed. In keeping with the mission of the sponsoring agency, such a plan of research may: 1) remove barriers to further identifying the genetic and environmental factors associated with MDD, 2) inform the relative importance of different types of life stress for increasing risk for MDD, and 3) enhance knowledge of how gender and race/ethnicity may influence the onset and recurrence of MDD through differences in sensitivity to life stress.