Divya Mehta1, Monika Rex-Haffner2, Helle Bach Søndergaard3, Anja Pinborg4, Elisabeth B Binder5, Vibe G Frokjaer6. 1. Senior Research Fellow, School of Psychology and Counselling, Faculty of Health and Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia. 2. Laboratory Manager, Department of Translational Psychiatry, Max Planck Institute of Psychiatry, Germany. 3. Senior Researcher, Molecular Biologist, Danish Multiple Sclerosis Center, Copenhagen University Hospital Rigshospitalet, Denmark. 4. Professor, Fertility Clinic, Copenhagen University Hospital Rigshospitalet and Gynecology and Obstetrics, Copenhagen University Hospital Hvidovre, Denmark. 5. Director, Department of Translational Psychiatry, Max Planck Institute of Psychiatry, Germany and Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, US. 6. Senior Researcher, Neurobiology Research Unit, Center for Integrated Molecular Brain Imaging and Mental Health Services Copenhagen, Copenhagen University Hospital Rigshospitalet, Denmark.
Abstract
BACKGROUND: Enhanced sensitivity to oestrogen signalling may drive increased risk for depressive symptoms when exposed to peripartum sex-steroid hormone fluctuations. AIM: Testing if 116 pre-identified sex steroid-responsive transcripts that predicted perinatal depression (PND) translates to a pharmacological model of hormone-induced mood changes. METHOD: We generated longitudinal, genome-wide gene-expression and DNA-methylation data from 60 women exposed to agonadotrophin-releasing hormone agonist (GnRHa) or placebo. We used linear mixed-effect models to assess differences between baseline and follow-up for gene expression and DNA methylation in the biphasic ovarian response to GnRHa. RESULTS: Of the 116 PND-predictive transcripts, a significant (19%) overlap was observed with those differentially expressed post-GnRHa at both early and later follow-up, indicating sustained effects. Similarly, 49% of tested genes were differentially methylated post-GnRHa at the late follow-up. Within the GnRHa group, a large proportion of PND genes were significantly associated (gene expression; DNA methylation) with changes in depressive symptoms (28%; 66%), oestradiol levels (49%; 66%) and neocortex serotonin transporter binding (8%; 45%) between baseline and follow-up. CONCLUSIONS: Our data bridge clinical PND biomarkers with a pharmacological model of sex hormone-induced mood changes and directly relate oestrogen-induced biological changes with depressive symptoms and associated serotonin-signalling changes. Our data highlight that individual variations in molecular sensitivity to oestrogen associate with susceptibility to hormone-induced mood changes and hold promise for candidate biomarkers. DECLARATION OF INTEREST: V.G.F. received honorarium for being a speaker for H. Lundbeck A/S. E.B.B. receives research funding from Böhringer Ingelheim to investigate FKBP5 as a potential drug target for depression.
RCT Entities:
BACKGROUND: Enhanced sensitivity to oestrogen signalling may drive increased risk for depressive symptoms when exposed to peripartum sex-steroid hormone fluctuations. AIM: Testing if 116 pre-identified sex steroid-responsive transcripts that predicted perinatal depression (PND) translates to a pharmacological model of hormone-induced mood changes. METHOD: We generated longitudinal, genome-wide gene-expression and DNA-methylation data from 60 women exposed to a gonadotrophin-releasing hormone agonist (GnRHa) or placebo. We used linear mixed-effect models to assess differences between baseline and follow-up for gene expression and DNA methylation in the biphasic ovarian response to GnRHa. RESULTS: Of the 116 PND-predictive transcripts, a significant (19%) overlap was observed with those differentially expressed post-GnRHa at both early and later follow-up, indicating sustained effects. Similarly, 49% of tested genes were differentially methylated post-GnRHa at the late follow-up. Within the GnRHa group, a large proportion of PND genes were significantly associated (gene expression; DNA methylation) with changes in depressive symptoms (28%; 66%), oestradiol levels (49%; 66%) and neocortex serotonin transporter binding (8%; 45%) between baseline and follow-up. CONCLUSIONS: Our data bridge clinical PND biomarkers with a pharmacological model of sex hormone-induced mood changes and directly relate oestrogen-induced biological changes with depressive symptoms and associated serotonin-signalling changes. Our data highlight that individual variations in molecular sensitivity to oestrogen associate with susceptibility to hormone-induced mood changes and hold promise for candidate biomarkers. DECLARATION OF INTEREST: V.G.F. received honorarium for being a speaker for H. Lundbeck A/S. E.B.B. receives research funding from Böhringer Ingelheim to investigate FKBP5 as a potential drug target for depression.
Entities:
Keywords:
DNA methylation; Perinatal depression; biomarkers; gene expression; oestrogen
Authors: Michelle Z L Kee; Ai Ling Teh; Andrew Clappison; Irina Pokhvisneva; Julie L MacIssac; David T S Lin; Katia E Ramadori; Birit F P Broekman; Helen Chen; Mary Lourdes Daniel; Neerja Karnani; Michael S Kobor; Peter D Gluckman; Yap Seng Chong; Jonathan Y Huang; Michael J Meaney Journal: iScience Date: 2022-08-04