Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Medical Scholars Program, University of Illinois College of Medicine, Urbana, IL, USA.
Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA, USA; Department of Gynecology and Obstetrics, Emory University, Atlanta, GA, USA.
Brain Behav Immun. 2019 Oct;81:280-291. doi: 10.1016/j.bbi.2019.06.025. Epub 2019 Jun 19.
Post-traumatic stress disorder (PTSD) is a debilitating mental disorder precipitated by trauma exposure. However, only some persons exposed to trauma develop PTSD. There are sex differences in risk; twice as many women as men develop a lifetime diagnosis of PTSD. Methylomic profiles derived from peripheral blood are well-suited for investigating PTSD because DNA methylation (DNAm) encodes individual response to trauma and may play a key role in the immune dysregulation characteristic of PTSD pathophysiology. In the current study, we leveraged recent methodological advances to investigate sex-specific differences in DNAm-based leukocyte composition that are associated with lifetime PTSD. We estimated leukocyte composition on a combined methylation array dataset (483 participants, ∼450 k CpG sites) consisting of two civilian cohorts, the Detroit Neighborhood Health Study and Grady Trauma Project. Sex-stratified Mann-Whitney U test and two-way ANCOVA revealed that lifetime PTSD was associated with significantly higher monocyte proportions in males, but not in females (Holm-adjusted p-val < 0.05). No difference in monocyte proportions was observed between current and remitted PTSD cases in males, suggesting that this sex-specific difference may reflect a long-standing trait of lifetime history of PTSD, rather than current state of PTSD. Associations with lifetime PTSD or PTSD status were not observed in any other leukocyte subtype and our finding in monocytes was confirmed using cell estimates based on a different deconvolution algorithm, suggesting that our sex-specific findings are robust across cell estimation approaches. Overall, our main finding of elevated monocyte proportions in males, but not in females with lifetime history of PTSD provides evidence for a sex-specific difference in peripheral blood leukocyte composition that is detectable in methylomic profiles and that may reflect long-standing changes associated with PTSD diagnosis.
创伤后应激障碍（PTSD）是一种由创伤暴露引发的使人衰弱的精神障碍。然而，只有部分暴露于创伤的人会发展为 PTSD。在风险方面存在性别差异；有两倍之多的女性比男性会被诊断出患有 PTSD。源自外周血的甲基化组谱非常适合研究 PTSD，因为 DNA 甲基化（DNAm）可以编码个体对创伤的反应，并且可能在 PTSD 病理生理学中特征性的免疫失调中发挥关键作用。在当前的研究中，我们利用最近的方法学进展来研究与 PTSD 终生诊断相关的基于白细胞的 DNAm 组成的性别特异性差异。我们在一个由两个平民队列（底特律社区健康研究和 Grady 创伤项目）组成的综合甲基化阵列数据集（483 名参与者，约 450k CpG 位点）上估计了白细胞组成。性别分层的 Mann-Whitney U 检验和双向 ANCOVA 表明，终生 PTSD 与男性单核细胞比例显著升高相关，但女性中无此关联（经 Holm 调整的 p 值<0.05）。在男性中，当前和缓解的 PTSD 病例之间的单核细胞比例没有差异，这表明这种性别特异性差异可能反映了 PTSD 终生史的长期特征，而不是当前的 PTSD 状态。在任何其他白细胞亚型中都没有观察到与 PTSD 终生史或 PTSD 状态相关的关联，并且我们基于不同去卷积算法的细胞估计验证了我们在单核细胞中的发现，这表明我们的性别特异性发现在细胞估计方法上具有稳健性。总体而言，我们的主要发现是在有 PTSD 终生史的男性中单核细胞比例升高，而女性中则无此现象，这为外周血白细胞组成中的性别特异性差异提供了证据，这种差异可以在甲基化组谱中检测到，并且可能反映了与 PTSD 诊断相关的长期变化。
