早期父母教养方式与FKBP5、NR3C1基因多态性及交互作用对青少年抑郁症状影响的纵向研究

Depressive symptoms usually start in adolescence and may cause clinical depression and suicidal behavior. It has been a public concern that threatens the adolescent mental health. Depressive symptoms are elicited through a combination of environmental stress and genetic factors, but the pathological mechanism is still unclear. The family is the main environment for the developing adolescent, and early parenting style is thought as one of the most important factors that affect adolescent depressive symptoms. Additionally, although the present evidence suggests that there are significant associations between depressive symptoms and single nucleotide polymorphisms (SNPs) in FKBP5 and NR3C1 genes which play an important role in regulating glucocorticoid receptor (GR) signaling pathway and hypothalamic-pituitary-adrenal (HPA) axis, most of these studies are animal experiments or case-control studies in adults. Prospective longitudinal evidence is needed to estimate the individual effects of both early parenting style and polymorphisms in the FKBP5 and NR3C1 genes, the gene-early parenting style interaction effects, and the gene-gene interaction effects on adolescent depressive symptoms. Based on our previous studies that focus on the influences of environmental stress (including negative experiences with parents) on adolescent depressive symptoms, we prepare to conduct a prospective longitudinal study to estimate the effects and possible mechanisms of early parenting style and polymorphisms in the FKBP5 and NR3C1 genes on adolescent depressive symptoms, and to offer scientific basis for exploring potential biomarkers and establishing early targeted intervention programs of vulnerable adolescents to depressive symptoms.

抑郁症状通常始发于青少年期，可导致抑郁症及自杀行为的发生，已严重威胁我国青少年心理健康。抑郁症状受到环境应激和遗传因素共同作用，发病机理尚不明确。家庭是青少年成长的主环境，早期父母教养方式被认为是影响青少年抑郁症状最主要的早期环境应激因素之一。此外，现有研究发现调控糖皮质激素受体信号通路及下丘脑-垂体-肾上腺轴的关键基因FKBP5、NR3C1单核苷酸多态性与抑郁症状存在关联，但相关研究主要为动物实验或基于成年人群的病例对照研究，有待前瞻性研究探讨上述基因、基因-早期父母教养方式及基因-基因交互作用对青少年抑郁症状的影响。在课题组前期研究儿童期遭受父母不良对待等环境应激因素对青少年抑郁症状影响的基础上，本项目拟采用纵向研究设计，探讨早期父母教养方式与FKBP5、NR3C1基因多态性对青少年抑郁症状的影响及作用机制，为进一步探索青少年抑郁症状生物标志物以及易感人群的早期干预措施提供科学依据。

抑郁症状通常始发于青少年期，可导致抑郁症及自杀行为的发生，已严重威胁我国青少年心理健康。本研究采用纵向研究设计，探讨家庭早期父母教养方式等环境应激因素与下丘脑-垂体-肾上腺轴的关键基因FKBP5/NR3C1对青少年抑郁症状的影响及两者间的相互作用。本研究基线共纳入1952名学生完成问卷调查，采集血液样本1853份；基线后第1次（1836名）和第2次（1792名）随访调查学生的应答率和随访率均达90%以上。本研究的主要结果发现相比于父母独裁型的教养方式，父亲和母亲宽容型及权威型的教养方式均是青少年抑郁症状的保护因素(OR<1, P<0.05)；除此，FKBP5基因rs7757037在共显性遗传模式(AG vs. GG; AOR = 2.56, 95% CI = 1.13–5.78)和显性遗传模式下(AA+AG vs. GG; AOR = 2.38, 95% CI = 1.11–5.120)均可以增加抑郁症状的发生风险，以及rs7757037 和父亲教养方式在共显性遗传模式(P= 0.043) 和显性遗传模式(P= 0.043)下对青少年抑郁症状存在交互作用, 但是进行多重校正后交互作用没有统计学意义; 以及没有发现FKBP5基因甲基化水平与青少年抑郁症状的独立关联以及多重校正后早期家庭教养方式及早期创伤经历对FKBP5基因甲基化水平的影响。基于本研究结果，我们认为参与家长应意识到青少年抑郁症状等心理健康问题的危害，关注学生在情绪、行为方面的变化，关注家庭氛围、家庭关系等对青少年心理健康的影响，营造良好的家庭环境，必要时予以相关的干预措施。