青少年早期焦虑和抑郁的共发机制：“多基因—内表型—共发性”研究

Early adolescence is a crucial stage for the etiology of anxiety and depression, with ubiquitous comorbidity of anxiety and depression during this period. It has been documented that comorbidity reflects a general psychopathology liability among various symptoms, labeled p factor, which estimates shared variance across all measured symptoms. Furthermore, several studies demonstrated that shared variance between anxiety and depression was explained by common genetic and environmental factors. However, understanding comorbidity is not simply a matter of identifying shared genetic vulnerabilities and environments. Gaps remain in understanding how risk factors to confer risk for comorbidity. .To address these gaps, a recent heuristic model suggested that genetic factors affect p factor through endphenotypes, such as neural/endocrine substrates and temperament. Recent empirical evidence supports this contention. Both theoretical considerations and new empirical evidence have implied negative affectivity (NA) is positively associated with the p factor. Twins’ studies indicated that common genetic factors appear to be at least partially mediated by negative affectivity, which is mediated by serotoninergic and HPA axis system at the neural and endocrine level respectively. Based on above gene-endphenotype-behavior framework, it is reasonable to assume that genes implicated in serotoninergic (5-HT) and HPA axis system may be candidate genes underlying comorbidity. Notably, the majority of molecular genetic studies on anxiety/depression only captured a limited amount of genetic variance by focusing on a single SNP. Critical reflections on the single gene approach have recently inspired a shift away from monogenic approaches to polygenic approaches. Therefore, this study aims to investigate the combine effects of 5-HT and HPA axis candidate genes on comorbidity through negative affectivity. .Additionally, genes or negative affectivity may not act in isolation, but interact with environment in their effects on comorbidity. It is therefore important to evaluate complex Biology by Environment interactions in the development of comorbidities. Moreover, whether these potential G × E or NA × E interactions would be consistent with the diathesis-stress or the differential susceptibility hypothesis remain unclear..In sum, the current study aims to investigate the mechanism of anxiety-depression comorbidity by employing a “multilocus – endophenotype - comorbidity” framework. Participants are 900 early adolescents and their mothers in a general population. The research aims to: (1) investigate whether the p factor captures the comorbidity of anxiety and depression; (2) test whether negative affectivity mediated the association between multilocus and p factor, as moderated by interpersonal factors; (3) test two competing hypotheses about G × E or NA × E interactions: diathesis-stress and differential susceptibility model.

青少年早期不仅是焦虑、抑郁等情绪障碍发生的高危时期，而且该时期个体的焦虑、抑郁具有共发性特点。焦虑抑郁共发性障碍对个体身体健康、心理适应及社会功能的破坏性影响更甚于单一障碍。然而，已有研究主要集中于考察焦虑和抑郁间共同的遗传和环境风险因素，对共同风险因素如何影响共发性的潜在机制尚不清楚。本研究拟以“基因—内表型—共发性”为理论框架，采用多基因研究方法，以5-HT系统和HPA轴系统候选基因为遗传指标，消极情绪性为内表型指标，亲子关系和同伴关系为环境指标，深入考察青少年早期焦虑抑郁的共发机制。具体研究问题包括：(1)描述焦虑和抑郁的潜在共发因子；(2)考察“多基因联合效应—消极情绪性—共发性”中介机制及人际因素在其中的调节作用；(3)通过考察基因×环境、气质×环境交互模式来检验“素质—压力”和“不同易感性”竞争模型。本研究将有助于深化共发性问题的科学理解，并能为共发问题的干预实践提供理论依据。

青少年早期不仅是焦虑、抑郁等情绪障碍发生的高危时期，而且该时期个体的焦虑、抑郁具有共发性特点。焦虑抑郁共发性障碍对个体身体健康、心理适应及社会功能的破坏性影响更甚于单一障碍。然而，已有研究主要集中于考察焦虑和抑郁间共同的遗传和环境风险因素，对共同风险因素如何影响共发性的潜在机制尚不清楚。本课题以“基因—内表型—共发性”为理论框架，采用多基因研究方法，以5-HT系统和HPA轴系统候选基因为遗传指标，消极情绪性为内表型指标，亲子关系和同伴关系为环境指标，深入考察青少年早期焦虑抑郁的共发机制。本课题的主要成果和研究发现如下：（1）建立了青少年焦虑-抑郁共发的候选基因数据库，数据库涵盖5-羟色胺系统、HPA系统的6个基因12个基因位点、多种人际环境与内表型变量；（2）揭示了焦虑和抑郁共发因子结构，两种情绪障碍间既具有共发成分也具有独特成分，但是不同共发亚组间的差异主要体现在焦虑—抑郁的共发严重程度上；（3）系统揭示了5-羟色胺、HPA系统多基因累加得分经由消极情绪性影响焦虑-抑郁共发因子的中介机制以及亲子关系、同伴关系的调节作用机制；（4）“基因—环境”交互作用模式存在发展动态性，在发展早期阶段更符合“不同易感性”模型，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情绪问题，随着年龄增长，“基因—环境”交互模式更可能向“素质—压力”或“优势敏感”模型转变；（5）除情绪反应性内表型（消极情绪性）外，认知控制性内表型（抑制控制）亦是基因及其与环境交互作用影响青少年焦虑、抑郁等情绪障碍的重要中介机制，这丰富“基因—内表型—共发”模型。本课题将有助于深化共发性问题的科学理解，并能为共发性问题的干预实践提供理论依据。