Examining several possible causes of GxE non-replications in depression

重度抑郁症（MDD）是公共卫生中的一个严重问题，一直是大量确定基因-环境相互作用（GxE）的主题（即，当压力源“触发”预先存在的遗传脆弱性以增加风险时），其目标是揭示治疗或预防重度抑郁症的新进展。然而，正如最近的一项荟萃分析所强调的那样，GxE领域的进展受到了极不一致的发现的阻碍（Risch et al., 2009）。本提案探讨了这些不一致发现的几个可能原因。一个问题，正如该研究领域的里程碑式批判（Monroe & Reid, 2008）所强调的那样，是关于重度抑郁症的GxE报告以高度不一致的方式操作生活压力（例如，关注所经历的压力源的总数或最坏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检查生活压力。这可能是因为还没有人以一种系统的方式研究生活压力的操作化最能预测重度抑郁症的发作。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它们的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的首次发病还是复发。这一点很重要，因为已经明确的是，重度应激源与重度抑郁症发作的关系随着连续复发而减弱；一种假设是，重度抑郁症使个体对压力的影响变得敏感，随后的发作可以由逐渐减轻的压力源“触发”。报告中MDD的复发比例越大，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/民族可能会缓和生活压力和重度抑郁症发病之间的关系。考虑到这样一个调节因素可以进一步减少统计误差方差，提高GxE相互作用的发现概率。这些问题将被检查，结果将应用于GxE测试（在先前研究和新的多态性中），使用现有的数据，这些数据来自一个中等规模的、种族多样化的、对青春期晚期到成年早期情绪障碍风险的前瞻性纵向调查。比例风险回归（生存）分析和多水平建模将被采用。为了与赞助机构的使命保持一致，这样的研究计划可能：1)消除进一步确定与重度抑郁症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增加重度抑郁症风险的相对重要性，以及3)增强对性别和种族/民族如何通过对生活压力的敏感性差异影响重度抑郁症的发病和复发的认识。

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.