DNA methylation signatures of adolescent victimization: analysis of a longitudinal monozygotic twin sample

Accumulating evidence suggests that individuals exposed to victimization at key developmental stages may have different epigenetic fingerprints compared to those exposed to no/minimal stressful events, however results are inconclusive. This study aimed to strengthen causal inference regarding the impact of adolescent victimization on the epigenome by controlling for genetic variation, age, gender, and shared environmental exposures. We conducted longitudinal epigenome-wide association analyses (EWAS) on DNA methylation (DNAm) profiles of 118 monozygotic (MZ) twin pairs from the Environmental Risk study with and without severe adolescent victimization generated using buccal DNA collected at ages 5, 10 and 18, and the Illumina EPIC array. Additionally, we performed cross-sectional EWAS on age-18 blood and buccal DNA from the same individuals to elucidate tissue-specific signatures of severe adolescent victimization. Our analyses identified 20 suggestive differentially methylated positions (DMPs) (<i>P</i> ∆Beta range = −5.5%−5.3%). Age-18 cross-sectional analyses revealed 72 blood (<i>∆Beta range </i>= −2.2%−3.4%) and 42 buccal (<i>∆Beta range </i>= −3.6%−4.6%) suggestive severe adolescent victimization-associated DMPs, with some evidence of convergent signals between these two tissue types. Downstream regional analysis identified significant differentially methylated regions (DMRs) in <i>LGR6</i> and <i>ANK3</i> (Šidák <i>P = </i><i>5</i>e-09 and 4.07e-06), and one upstream of <i>CCL27</i> (Šidák <i>P = </i>2.80e-06) in age-18 blood and buccal EWAS, respectively. Our study represents the first longitudinal MZ twin analysis of DNAm and severe adolescent victimization, providing initial evidence for altered DNA methylomic signatures in individuals exposed to adolescent victimization.

越来越多的证据表明，在关键发育阶段遭受创伤的个体，与未遭受或仅遭受轻微应激事件的个体相比，可能具有不同的表观遗传指纹（epigenetic fingerprints），但相关研究结论尚无定论。本研究旨在通过控制遗传变异、年龄、性别及共享环境暴露因素，强化青少年期创伤对表观基因组影响的因果推断效力。我们针对来自环境风险研究（Environmental Risk study）的118对同卵双生子（MZ）开展纵向全表观基因组关联分析（EWAS），分析对象的DNA甲基化（DNAm）谱来自于5岁、10岁及18岁时采集的颊部DNA，其中部分双生子存在严重青少年期创伤暴露，实验采用Illumina EPIC芯片完成检测。此外，我们还对同一批个体18岁时采集的血液与颊部DNA开展横断面EWAS，以阐明严重青少年期创伤暴露的组织特异性特征。本研究的分析共鉴定出20个提示性差异甲基化位点（DMPs），其P值对应的ΔBeta范围为−5.5%~5.3%。18岁时的横断面分析显示，血液样本中存在72个与严重青少年期创伤暴露相关的提示性DMPs，ΔBeta范围为−2.2%~3.4%；颊部样本中则存在42个此类DMPs，ΔBeta范围为−3.6%~4.6%，且两种组织类型间存在部分重合的信号证据。后续区域分析分别在18岁时的血液与颊部EWAS中鉴定出显著差异甲基化区域（DMRs）：血液样本的显著DMRs位于LGR6与ANK3基因区域，对应的Šidák校正P值分别为5e-09与4.07e-06；颊部样本的显著DMRs则位于CCL27基因上游区域，Šidák校正P值为2.80e-06。本研究是首个针对DNA甲基化与严重青少年期创伤暴露的纵向同卵双生子分析，为遭受青少年期创伤暴露的个体存在DNA甲基化组特征改变提供了初步证据。