University of Nevada, Reno, School of Public Health, 1664 N. Virginia Street, Reno, NV 89557, USA.
Insight Policy Research, USA.
Psychoneuroendocrinology. 2024 Dec;170:107181. doi: 10.1016/j.psyneuen.2024.107181. Epub 2024 Sep 14.
Epigenetic modifications, including DNA methylation (DNAm), can play a role in the biological embedding of early-life adversity (ELA) through serotonergic mechanisms. The current study examines methylation of the CpG island in the promoter region of the stress-responsive serotonin transporter gene (SLC6A4) and is the first to jointly assess how it is influenced by ELA severity, timing, and type-specifically, deprivation and threat.
We use data from 627 Youth Emotion Project study participants, recruited from two US high schools. Using adjusted linear regressions, we analyze DNA collected in early adulthood from 410 participants and ELA based on interviewer-rated responses from concurrent Childhood Trauma Interviews, adjusting for survey-measured covariates.
ELA robustly predicted mean CpG island SLC6A4 DNAm percent across 71 CpG sites. Each additional major-severity ELA event was associated with a 0.121-percentage-point increase (p<0.001), equating to a 0.177 standard deviation (sd) higher DNAm level (95 % CI: 0.080, 0.274) with each 1-sd higher adversity score. When modeled separately, both childhood and adolescent ELA predicted SLC6A4 DNAm. When modeled jointly, adolescent ELA was most strongly predictive, and child adversity remained significantly associated with DNAm through indirect associations via adolescent adversity. Additionally, the ELA-SLC6A4 DNAm association may vary by adversity type. Across separate models for childhood and adolescent exposures, deprivation coefficients are positive and statistically significant. Meanwhile, threat coefficients are positive and not significantly significant but do not statistically differ from deprivation coefficients. In models including all ELA dimensions, one major adolescent deprivation event is associated with a 0.222-percentage-point increased SLC6A4 DNAm (p<0.05), or a 1-sd higher deprivation score with a 0.157-sd increased DNAm.
Results further implicate epigenetic modification on serotonergic neurotransmission via DNAm in the downstream sequelae of ELA-particularly adolescent deprivation-and support preventive interventions in adolescence to mitigate biological embedding.
表观遗传修饰，包括 DNA 甲基化（DNAm），可以通过血清素能机制在早期生活逆境（ELA）的生物学嵌入中发挥作用。本研究检测了应激反应性 5-羟色胺转运体基因（SLC6A4）启动子区域内 CpG 岛的甲基化情况，这是首次联合评估 ELA 严重程度、时间和特定类型——剥夺和威胁如何影响它。
我们使用了来自美国两所高中的 627 名青年情绪项目研究参与者的数据。使用调整后的线性回归，我们分析了来自 410 名参与者的早期成年期采集的 DNA 和根据同期儿童创伤访谈中采访者评定的 ELA，同时调整了调查测量的协变量。
ELA 强烈预测了 71 个 CpG 位点中 SLC6A4 CpG 岛 DNAm 百分比的平均值。每增加一次重大严重程度的 ELA 事件，与 0.121 个百分点的增加相关（p<0.001），相当于 1-sd 更高的逆境评分与每个 0.177 标准偏差（sd）更高的 DNAm 水平（95%CI：0.080，0.274）。当分别建模时，儿童期和青春期的 ELA 都预测了 SLC6A4 DNAm。当联合建模时，青春期 ELA 的预测能力最强，而儿童期逆境仍然通过青春期逆境的间接关联与 DNAm 显著相关。此外，ELA-SLC6A4 DNAm 关联可能因逆境类型而异。在儿童期和青春期暴露的单独模型中，剥夺系数为正且具有统计学意义。与此同时，威胁系数为正且不显著，但与剥夺系数无统计学差异。在包括所有 ELA 维度的模型中，一次主要的青春期剥夺事件与 SLC6A4 DNAm 增加 0.222 个百分点相关（p<0.05），或 1-sd 更高的剥夺评分与 0.157-sd 更高的 DNAm 相关。
结果进一步暗示了通过 DNAm 在 ELA 的下游后果，特别是青春期剥夺中，对血清素能神经传递的表观遗传修饰，并支持在青春期进行预防性干预，以减轻生物嵌入。
