Abstract: It has been well documented that both gene and environment contribute to and usually interact to affect the development of depression. Despite the fast accumulating evidence for G × E on depression, there are some important issues are less well understood. First, the majority of studies on the G × E have focused on genes of serotonergic and dopaminergic systems which were guided by the monoamine-deficiency hypothesis. However, genes involved in the function of hypothalamic–pituitary–cortisol (HPA) also may underlie depression. Second, compared with identifying genetic variations, the measurement of SLE is readily overshadowed by molecular genetic techniques. Researchers have measured participants’ life stress across varying time periods. As a consequence of these inadequacies, mixed findings regarding G × E were obtained. Third, the observed G × E effects could possibly be an artifact of gene–environment correlation (rGE), but fewer studies sought to control for it. In this study, one of the most widely studied functional polymorphism (Bcl1) in the glucocorticoid receptor gene (NR3C1) was used to test G × E effects. To our knowledge, a few studies investigated the interaction between Bcl1 polymorphism and adversities, however, mixed findings were obtained. Besides, the rGE effects should be ruled out before solid conclusions can be drawn. Therefore, SLEs were differentiated as independent SLEs if they had a nonsignificant genetic underlying as prior study. In addition, we also hypothesized that, if the measure of SLEs represents genetic risk, then SLEs would interact with gene even if they occurred after the depression. One thousand and eighty one adolescents (mean age 15.23 years at T3) were assessed three times with an interval of three years. During each assessment, the participants completed self-reported questionnaire on depressive symptoms. At the second assessment, a self-reported SLE questionnaire was completed. All measures showed good reliability. DNA was extracted from saliva. Genotyping at Bcl1 polymorphism was performed for each participant in real time with MassARRAY RT software version 3.0.0.4 and analyzed using the MassARRAY Typer software version 3.4 (Sequenom). To examine whether Bcl1 polymorphism interacts with SLE in predicting depression and whether it is a true G × E effect after controlling for rGE, hierarchical regression analyses were conducted. The findings indicated that no main effect of Bcl1 polymorphism on depression was found. SLE was associated with an increase in depressive symptoms. Both total SLEs by Bcl1 polymorphism interaction and independent SLEs by Bcl1 polymorphism interaction were significantly predicted T3 depression. C allele carriers were more susceptible to the detrimental effects of SLEs. However, such an interactive effect was not observed when predicting T1 depression. These findings highlight there is a true G × E effect underlying the observed interaction between Bcl1 polymorphism and SLEs on depression rather than an artifact of rGE. Besides, it’s important to test and report rGE in G × E studies in future.

Key words: adolescent depression, NR3C1 gene Bcl1 polymorphism, stressful life events, gene × environment

摘要： 迄今，有关抑郁的基因×环境交互研究多数基于“单胺缺陷假说”，相对较少有研究以“HPA轴假说”为框架考察抑郁的遗传机制，且忽视了基因-环境相关的影响。本研究对1081名青少年进行追踪研究，考察NR3C1基因Bcl1多态性与压力性生活事件对抑郁的影响。结果发现，经历较多压力性事件时，C等位基因携带者的抑郁水平显著高于GG纯合子携带者；经历较少压力性事件时，不同基因型携带者的抑郁水平无差异。此外，通过区分独立性压力性事件和预测早期抑郁进一步排除了基因-环境相关的影响，在一定程度上验证了结果的可靠性。

关键词: 青少年抑郁, NR3C1基因Bcl1多态性, 压力性生活事件, 基因×环境