Department of Clinical and Social Sciences in Psychology, University of Rochester, Rochester, NY, USA.
Department of Psychology, Williams College, Williamstown, MA, USA.
Dev Psychopathol. 2021 Oct;33(4):1264-1278. doi: 10.1017/S0954579420000474.
Childhood adversity appears to sensitize youth to stress, increasing depression risk following stressful life events occurring throughout the lifespan. Some evidence suggests hypothalamic-pituitary-adrenal (HPA) axis-related and serotonergic genetic variation moderates this effect, in a "gene-by-environment-by-environment" interaction (G × E × E). However, prior research has tested single genetic variants, limiting power. The current study uses a multilocus genetic profile score (MGPS) approach to capture polygenic risk relevant to HPA axis and serotonergic functioning. Adolescents (N = 241, Mage = 15.90) completed contextual-threat-based interviews assessing childhood adversity and acute life events, and diagnostic interviews assessing depression. Established MGPSs indexed genetic variation linked to HPA axis (10 single nucleotide polymorphisms [SNPs]) and serotonergic (five SNPs) functioning. Results showed significant MGPS × Childhood Adversity × Recent Life Stress interactions predicting depression for both HPA axis and serotonergic MGPSs, with both risk scores predicting stronger Childhood Adversity × Recent Stress interactions. Serotonergic genetic risk specifically predicted sensitization to major interpersonal stressors. The serotonergic MGPS G × E × E was re-tested in an independent replication sample of early adolescent girls, with comparable results. Findings support the notion that genetic variation linked to these two neurobiological symptoms alters stress sensitization, and that gene-by-environment (G × E) interactions may be qualified by environmental exposures occurring at different points in development.
童年逆境似乎使年轻人对压力敏感，增加了一生中发生压力性生活事件后抑郁的风险。一些证据表明，下丘脑-垂体-肾上腺（HPA）轴相关和 5-羟色胺能遗传变异调节了这种效应，即“基因-环境-环境”相互作用（G×E×E）。然而，先前的研究仅测试了单一的遗传变异，限制了研究的效力。本研究使用多基因风险评分（MGPS）方法来捕获与 HPA 轴和 5-羟色胺能功能相关的多基因风险。青少年（N=241，Mage=15.90）完成了基于情境威胁的访谈，评估了童年逆境和急性生活事件，并进行了诊断访谈以评估抑郁。已建立的 MGPS 指数与 HPA 轴（10 个单核苷酸多态性 [SNP]）和 5-羟色胺能（5 个 SNP）功能相关的遗传变异。结果表明，HPA 轴和 5-羟色胺能 MGPS 的 MGPS×童年逆境×近期生活压力相互作用显著预测抑郁，两个风险评分都预测了更强的童年逆境×近期压力相互作用。5-羟色胺能遗传风险特别预测了对主要人际压力源的敏感化。在另一项独立的早期青春期女孩样本中重新测试了 5-羟色胺能 MGPS 的 G×E×E，结果相似。研究结果支持了这样一种观点，即与这两种神经生物学症状相关的遗传变异改变了压力敏感化，并且基因-环境（G×E）相互作用可能受到不同发育阶段环境暴露的限制。
