Epigenetic prediction of 17β-estradiol and relationship to trauma-related outcomes in women

• Type of Material: Article
• Authors: Laura M Hack, Emory University; Shota Nishitani, Emory University; Anna Knight, Emory University; Varun Kilaru, Emory University School of Medicine; Stephanie A Maddox, McLean Hospital; Antonia V Seligowski, McLean Hospital; Tanja Jovanovic, Emory University; Kerry Ressler, Emory University; Alicia Smith, Emory University; Vasiliki Michopoulos, Emory University
• Language: English
• Date: 2021-05-01
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.cpnec.2021.100045
• Title of Journal or Parent Work: Comprehensive Psychoneuroendocrinology
• Volume: 6
• Start Page: 100045
• End Page: 100045
• Grant/Funding Information: This research was supported by the National Institutes of Health Grants MH094757 (KJR), MH071537 (KJR), MH096764 (KJR), HD085850 (VM), MH115174 (VM), MH085806 (AKS), NARSAD YI award #19233 (AKS), and the training grant MH101079. The funding source did not participate in the study design, data collection, analysis, interpretation, or preparation of the manuscript.
• Keywords: DNA methylation; Random forests (RFs); Estrogen; Trauma; Machine learning; Biomarker
• Research Categories: Health Sciences, Obstetrics and Gynecology; Health Sciences, Mental Health

Abstract

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.