Hack Laura M, Nishitani Shota, Knight Anna K, Kilaru Varun, Maddox Stephanie A, Seligowski Antonia V, Jovanovic Tanja, Ressler Kerry J, Smith Alicia K, Michopoulos Vasiliki
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
Compr Psychoneuroendocrinol. 2021 Mar 9;6:100045. doi: 10.1016/j.cpnec.2021.100045. eCollection 2021 May.
17β-estradiol (E2) levels in women correlate with multiple neuropsychiatric symptoms, including those that are stress-related. Furthermore, prior work from our group has demonstrated that E2 status influences DNA methylation (DNAm) across the genome. We developed and validated a DNAm-based predictor of E2 (one of four naturally occurring estrogens) using a training set of 183 females and a test set of 79 females from the same traumatized cohort. We showed that predicted E2 levels were highly correlated with measured E2 concentrations in our testing set (r = 0.75, p = 1.8e-15). We further demonstrated that predicted E2 concentrations, in combination with measured values, negatively correlated with current post-traumatic stress disorder (PTSD) (β = -0.38, p = 0.01) and major depressive disorder (MDD) diagnoses (β = -0.45, p = 0.02), as well as a continuous measure of PTSD symptom severity (β = -2.3, p = 0.007) in females. Finally, we tested our predictor in an independent data set (n = 85) also comprised of recently traumatized female subjects to determine if the predictor would generalize to a different population than the one on which it was developed. We found that the correlation between predicted and actual E2 concentrations in the external validation data set was also high (r = 0.48, p = 3.0e-6). While further validation is warranted, a DNAm predictor of E2 concentrations will advance our understanding of hormone-epigenetic interactions. Furthermore, such a DNAm predictor may serve as an epigenetic proxy for E2 concentrations and thus provide an important biomarker to better evaluate the contribution of E2 to current and potentially future psychiatric symptoms in samples for which E2 is not measured.
女性体内的17β - 雌二醇（E2）水平与多种神经精神症状相关，包括那些与压力相关的症状。此外，我们团队之前的研究表明，E2状态会影响全基因组的DNA甲基化（DNAm）。我们利用来自同一受创伤队列的183名女性的训练集和79名女性的测试集，开发并验证了一种基于DNAm的E2（四种天然存在的雌激素之一）预测指标。我们发现，在测试集中，预测的E2水平与测量的E2浓度高度相关（r = 0.75，p = 1.8e - 15）。我们进一步证明，预测的E2浓度与测量值相结合，与当前创伤后应激障碍（PTSD）（β = -0.38，p = 0.01）和重度抑郁症（MDD）诊断呈负相关（β = -0.45，p = 0.02），并且与女性PTSD症状严重程度的连续测量值也呈负相关（β = -2.3，p = 0.007）。最后，我们在一个同样由近期受创伤女性受试者组成的独立数据集（n = 85）中测试了我们的预测指标，以确定该预测指标是否能推广到与开发它的人群不同的其他人群。我们发现，在外部验证数据集中，预测的和实际的E2浓度之间的相关性也很高（r = 0.48，p = 3.0e - 6）。虽然需要进一步验证，但E2浓度的DNAm预测指标将增进我们对激素 - 表观遗传相互作用的理解。此外，这样的DNAm预测指标可能作为E2浓度的表观遗传替代指标，从而提供一个重要的生物标志物，以便在未测量E2的样本中更好地评估E2对当前以及潜在未来精神症状的贡献。
