遗传基因与环境对青少年早期抑郁的影响及其作用机制：一项追踪研究

Depression is among the top five leading causes of disability and disease burden throughout the world (Caspi et al., 2003). It is well established that depression often has its origins in childhood, and early adolescence is associated with a significant increase in the prevalence (Compas, Ey & Grant, 1993). The recognition that both genes and environments are important for understanding the etiology of depression has led to a rapid growth in research about gene-environment interactions. To date, the strongest support for a specific genetic risk factor for depression has been obtained for 5-HTTLPR polymorphism (Caspi et al., 2003), and MAOA-uVNTR is also considered as a key candidate gene polymorphism associated with depression (Beach et al., 2010). .However, most existing studies were based on the "diathesis-stress model", and have emphasized the cumulative negative effects of "risk genes" and adverse environments, whereas the effects of the same risk genes interacting with positive environments remains unclear. In addition, numerous studies were obtained on adults or adolescents maltreated in early childhood, and measured depression in the sense of major depression, however, few adolescents in the general population meet the diagnostic criteria for clinical depression (Steinberg, 1999). Whether previous findings are available for normal adolescent remains unclear. Literature shows that female adolescents are affected about twice as often as male adolescents (Feng, 2002). This well-documented gender differences may be explained by G×E interaction. However, whether there is a significant moderating effect of gender on G×E interaction, or whether this moderating effect varies with different genes or environments leave open. Existing G×E interaction research in adolescent depression ofen collected data cross-sectionally(Dunn et al., 2011), although few studies examined the longitudinal association among gene, environment and adolescent depression, their findings were limited by two-wave tracking. .To sum up, the present study aims to extend the previous research by a 4-year longitudinal design to explore the effect of 5-HTTLPR and MAOA-Uvntr polymorphisms and environment on early adolescent depression and the underlying mechanism among 2000 early adolescents (grade 6-9)in the general population.The specific research questions are as follows: (1) the developmental characteristics of early adolescent depression (i.e. average level, average developmental trajectory, group-based developmental trajectory); (2) the concurrent and longitudinal effects of genes and environments on early adolescent depression; (3) the effects of genes and environments on the average developmental trajectory of early adolescent depression; (4) the association among genes, environments and group-based developmental trajectories; (5) the gender differences in the above aspects; (6) the age differences in the effects of genes and environments on early adolescent depression.

遗传基因与环境因素如何相互作用影响青少年的抑郁是当前抑郁研究中的重要前沿课题之一。本项目以"不同易感性模型"为理论基础，采用基因-环境设计，选取5-HTTLPR和MAOA-uVNTR基因多态性作为遗传指标，负性生活事件、父母教养行为和家庭功能为环境指标，通过对2000名正常青少年4年的追踪研究，综合运用变量中心和个体中心的方法，考察基因与环境因素对青少年早期（6-9年级）抑郁的动态影响及其作用机制。具体研究问题包括：（1）青少年早期抑郁的发生发展特点（基本水平、平均和典型发展轨迹）；（2）基因与环境对该时期抑郁的即时和纵向影响；（3）基因与环境对该时期抑郁发展变化趋势的影响；（4）基因、环境与抑郁不同发展轨迹的关系；（5）上述方面的性别差异；（6）基因与环境对该时期抑郁影响的年龄差异。本项目能够系统、深入地阐明青少年早期抑郁的遗传与环境作用机制，对青少年抑郁的科学诊断与干预具有重要意义。

本项目以“不同易感性模型”为理论基础，通过为期4年的大样本追踪，考察了遗传基因与环境因素对青少年早期抑郁的动态影响及其作用机制。在研究周期内，本项目完成了既定研究内容，实现了预期研究目标，所取得的主要科学发现和研究成果具体如下：.1、全面梳理和分析总结了既有关于抑郁的遗传基础研究文献，厘清了抑郁的遗传基础研究现状，分析了既有相关研究的不足，展望了未来研究方向，如青少年抑郁的神经生物机制和多基因遗传机制等问题。2、本项目首次揭示了我国城市青少年早期抑郁的基本特征和纵向发展模式，包括抑郁的一般（平均）发展趋势、典型的亚组发展轨迹及其性别差异。3、系统分析了遗传基因与环境对青少年早期抑郁的即时与纵向影响，发现基因与环境因素的交互作用存在年龄差异，且青少年早期是考察基因—环境交互作用发展动态性的关键时期。4、首次调查了基因与环境因素在青少年早期抑郁轨迹中的作用，发现DRD2基因A241G多态性与母亲教养、MAOA基因T941G多态性与同伴侵害交互作用于抑郁的异质性轨迹。5、深入考察了遗传基因与环境因素对青少年早期抑郁的作用机制及其性别差异，发现5-HTR1A基因rs6295多态性、MAOA基因rs6323多态性与母亲教养、同伴接纳与拒绝的交互作用模式符合“不同易感性模型”理论假设，并且G×E交互作用存在性别差异。此外，MAOA基因rs6323多态性与同伴侵害对男青少年抑郁交互作用模式受到COMT基因的调节，支持抑郁的产生与个体差异存在多基因与环境间的复杂交互机制。.基于上述研究内容，项目组成员在《Journal of Youth and Adolescence》、《Journal of Research on Adolescence》、《心理学报》等高水平学术期刊正式发表22篇学术论文。本项目不仅能够系统而深入地阐明青少年早期抑郁的遗传与环境作用机制，同时对青少年早期抑郁的科学诊断与有效干预具有重要现实意义。