多基因与环境对青少年早期抑郁的动态影响及中介机制

Early adolescence is a crucial stage for the etiology of depression, with both the incidence rates of depression and levels of depressive symptoms increasing dramatically during this period. It has been well documented that both gene and environment contribute to and usually interact to affect the development of depression. However, despite the fast accumulating evidence for G × E interactions on depression, most of the extant studies have typically been conducted using a single polymorphism as the genetic risk index. The effect of any single polymorphism is always very modest (usually less than 2% of the variance), far below the heritability estimates (24%-55%) found in twin studies. .There is evidence that depression is highly polygenic, arising from the combined effects of many gene variants with small effect sizes. Therefore, research on G×E interaction should take polygenic information into account. Recently there is increasing appreciation for the need to employ a polygene-environment interaction design in exploring the underlying mechanisms of depression. .To our knowledge, only three studies on G×E interaction on adolescent depression have examined polygenic variation thus far. Two studies only examined the effect of two genetic loci, and another one focused on the candidate genes of only the serotonergic system. The environmental indices in those three studies were limited to negative stressful life experiences, because they were guided by a “diathesis-stress model”. As a result, it is not known how multiple environmental factors, and genes within and between multiple neurotransmitter systems, jointly impact the development of depression—or whether polygene×environment interaction effects change over development in adolescence. Moreover, to date no study has tested potential mediators of gene-environment interaction effects on depression..Based on the differential susceptibility model and gene-brain/endophenotype-behavior framework, the current study aims to extend previous studies by employing a polygene×environment design to examine the combined effect of multiple genes (16 loci) of serotonergic and dopaminergic systems and multiple environment factors, on early adolescent depression and its underlying mechanisms. A longitudinal design will be employed to examine potential age differences in polygene×environment effects and to test a proposed mediating effect of executive function. Participants are 1100 early adolescents and their mothers in a general population, who will be followed from grade 7 to 9. Environment indices include adolescent maternal parenting (both positive and negative) and peer relationships (peer acceptance, rejection and victimization). The specific research questions are: (1) how do polygene effects jointly impact the development of early adolescent depression (including analysis of haplotypes, multigene interactions, and polygenic scores); (2) what is the typical pattern of polygene×environment interaction on early adolescent depression; (3) does the effects of polygene and environments and their interaction on early adolescent depression change with age; and (4) does adolescents’ executive functioning statistically mediate the effect of polygene×environment interaction on early adolescent depression..This study is expected to shed light on the polygenic underpinnings of adolescent depression, and the complex interplay between polygene and environments, as well as the role of executive function as an underlying mechanism. In this way, the present study can make a novel contribution to the scientific literature on adolescent depression and also offer important implications for diagnosis, intervention and prevention of early adolescent depression.

抑郁具有多基因遗传基础并受环境因素的影响。单基因—环境研究无法考察多基因对抑郁的联合效应及其与环境对抑郁的作用机制。本项目采用多基因—环境设计，以“不同易感性模型”和“基因—脑/中间表型—行为”为理论框架，选取5-羟色胺和多巴胺系统的16个基因位点为遗传指标，母亲教养（积极与消极）与同伴关系（同伴接纳、同伴拒绝、同伴侵害）为环境指标，进行历时3年的追踪研究,考察多基因联合效应与环境因素对青少年早期(7-9年级)抑郁的影响及其作用机制。具体研究问题包括：（1）多基因对抑郁的联合影响（包括单倍型、多基因交互效应、多基因累加效应）；（2）多基因与环境对抑郁的即时和纵向影响及其交互作用模式；（3）多基因与环境对抑郁的动态性影响；（4）执行功能在基因和环境与抑郁间的中介作用。本项目能够深化和拓展对青少年抑郁遗传基础及其复杂机制的科学认识，并对青少年早期抑郁的科学诊断、有效预防和干预具有重要意义。

青少年抑郁的遗传与环境作用机制是发展心理病理学的重要热点研究课题。近十几年来，多数研究采用单基因—环境范式考察青少年抑郁的发生发展机制，但是忽视了抑郁的多基因遗传特征，并且具有低效应量、低可重复性的局限性。伴随着对“遗传率缺失”的探索，采用多基因—环境设计成为探索抑郁遗传机制和作用过程的新兴范式。本项目的主要研究目的在于采用追踪研究设计，以“不同易感性模型”和“基因—脑/中间表型—行为”为理论框架，系统揭示5-羟色胺和多巴胺系统多基因、母亲教养行为和同伴关系（同伴接纳、同伴拒绝、同伴侵害）对青少年早期抑郁的影响及其中介机制。. 通过对1090名正常青少年3年的追踪研究，本项目的主要成果和研究发现如下：（1）建立了涵盖5-羟色胺、多巴胺神经递质合成、传导、转运、代谢等生化过程的大型候选基因数据库，为多基因研究筛选遗传指标提供了基础；获得了12岁-15岁青少年抑郁症状、家庭环境、同伴关系、执行功能等方面的丰富数据；（2）系统揭示了5-羟色胺、多巴胺系统多基因对青少年早期抑郁的联合效应；（3）揭示了多基因与家庭、同伴环境对青少年抑郁的交互作用模式，譬如相比携带较少风险等位基因的个体，携带较多风险等位基因的个体在经历消极环境时报告了更多的抑郁症状；（4）首次采用动态发展视角，揭示了多基因—环境影响青少年抑郁的年龄差异。譬如，多基因联合效应（5-HTTLPR基因和BDNF基因）与母亲教养的交互作用仅能预测13岁青少年抑郁症状，而不能预测15岁青少年抑郁症状；（5）多巴胺和5-羟色胺系统基因与环境的交互作用能够通过个体的抑制控制间接影响青少年抑郁，为“基因—内表型—行为”理论模型提供了实证依据。本项目能够深化和拓展对青少年抑郁遗传基础及其复杂机制的科学认识，并对青少年早期抑郁的科学诊断、有效预防和干预具有重要意义。