Examining several possible causes of GxE non-replications in depression

重度抑郁症（MDD）是公共卫生中的严重问题，并且已经成为大规模鉴定基因-环境相互作用（GxE）（即，当压力源“触发”预先存在的遗传脆弱性以增加风险时），目的是揭示治疗或预防MDD的新进展。然而，GxE领域的进展已经被极其不一致的发现所阻碍，如最近的荟萃分析所强调的（Risch等人，2009年）。本提案审查了这些不一致调查结果的几个可能原因。一个问题，正如对这一研究领域的一个里程碑式的批评所强调的那样（门罗和里德，2008年），是关于MDD的GxE报告以高度不一致的方式操作了生活压力（例如，侧重于经历的压力源总数或最严重事件的严重程度），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以系统的方式研究生活压力的操作化最能预测MDD的发作。此外，慢性压力或童年逆境是否应该包括在GxE测试中尚不清楚，因为几乎没有研究直接将其预测能力与传统研究的环境病原体压力生活事件进行比较。第二个问题是，没有关于MDD的GxE报告检查所研究的MDD病例是MDD的首次终生发作还是复发。这一点很重要，因为已经明确的是，重度压力源与MDD发作的关系随着连续复发而降低;一种假设是MDD使个体对压力的影响敏感，并且以后的发作可以由逐渐温和的压力源“触发”。报告中MDD复发的比例越大，发现真正GxE相互作用的概率就越低。第三，性别和种族/民族可能会缓和生活压力和MDD发作之间的关系。考虑到这种调节剂可以进一步减少统计误差方差，提高发现GxE相互作用的概率。这些问题将被检查，并将结果应用于GxE测试（在以前研究和新的多态性），使用现有的数据从一个中等规模的，种族多样的，前瞻性的纵向调查的风险情绪障碍在青春期后期到成年早期。将采用比例风险回归（生存）分析和多水平建模。为了与申办机构的使命保持一致，这样的研究计划可能：1）消除进一步识别与MDD相关的遗传和环境因素的障碍，2）告知不同类型的生活压力对MDD风险增加的相对重要性，3）增强性别和种族/民族如何通过对生活压力敏感性的差异影响MDD的发作和复发的知识。

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.