Epigenetic biomarker status, negative valence, and HPA-axis dysregulation: mechanisms underlying risk for postpartum depression

The National Institute of Mental Health awarded the University of Virginia $234,660 on September 28, 2025, under the Mental Health Research Grants program (CFDA 93.242) to investigate epigenetic biomarkers, negative valence symptomatology, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction as mechanisms underlying risk for postpartum depression.

The research examines two estrogen-responsive epigenetic biomarkers at established risk loci for postpartum depression and their relationship to negative valence domain constructs—fear, anxiety, and sustained threat responses—and HPA-axis function across the perinatal period. Preliminary data indicate that individuals carrying the identified biomarkers display greater anxiety and fear symptoms with higher prevalence of new perinatal-onset depression, while those without the biomarkers exhibit chronic lifetime depression. The project will clarify the mechanistic pathways by which these epigenetic changes produce depressive symptoms distinct from those observed in individuals without biomarker status, with particular attention to how perinatal estrogen fluctuation modulates HPA-axis responsiveness under acute versus chronic stress conditions.

Performance occurs in Charlottesville, Virginia, over a three-year project period running through September 27, 2028. The award is structured as a project grant, the standard assistance type for investigator-initiated NIMH research.

Abstract

A key factor in the development of postpartum depression (PPD) is sensitivity to fluctuating reproductive HOR- mones. Consistent with this, prior work has identified two epigenetic biomarkers at estrogen-responsive genes that predict PPD with consistent replicability with an area under the receiver operator curve >80%. However, the mechanism(s) by which these epigenetic changes lead to depressive symptoms are unknown, and are likely distinct from those leading to symptoms in individuals without the epigenetic biomarkers. The research domain criteria (rdoc) negative valence domain describes responses to aversive and stressful situations, including fear, anxiety, and sustained threat. Prior literature suggests an "anxious depression" phenotype is prevalent in PPD, and the applicant has previously shown that negative valence measures have a strong association with depression severity. Our preliminary data show differing negative valence-related symptoms in those with and without identified epigenetic biomarkers. Those with the biomarkers display greater anxiety/fear and have a higher prevalence of new perinatal-onset depression, while those without the biomarkers exhibit chronic lifetime depression. The hypothalamic-pituitary-adrenal (HPA) axis is a key component of negative valence and is differentially affected by acute and chronic stress - acute stress upregulates the HPA-axis; chronic stress leads to HPA-axis hypoactivity. The HPA-axis changes perinatally, and estrogen, which surges during pregnancy and falls postpartum, stimulates HPA-axis activation. However, there is limited knowledge of HPA-axis function- ING in PPD, especially in the context of identified estrogen-responsive epigenetic biomarkers of risk. Given DIF- fering presentation of negative valence symptoms (acute VS. Chronic stress) in biomarker groups, we propose that there is a unique HPA-axis vulnerability to PPD, and that this vulnerability differs between those with and without the biomarkers. We will compare negative valence symptoms and HPA-axis function between biomarker groups in the context of an ongoing longitudinal study. Our research goal is to confirm stress phenotypes in biomarker groups and understand what HPA-axis mechanisms contribute to depression severity in each group. The specific aims are to (1) investigate constructs of fear, anxiety, and chronic stress, and their relationship with depression severity, in those with and without the epigenetic biomarkers using rdoc self-report measures; (2) investigate HPA-axis functioning and depression severity in those with and without the biomarkers using biological/physiologic rdoc measures of stress hormones and heart rate variability; and (3) investigate the HPA- axis response to a paradigm of induced, acute stress in a subset of individuals with and without the biomarkers. The training goals are to (1) acquire advanced training in epigenetics; (2) acquire advanced training in HPA- axis measurement and analysis; (3) develop a thorough understanding of clinical phenotyping in mental health research; and (4) develop a comprehensive research framework with clinical translation. This training will ad- vance the applicant towards an independent academic research career in the field of perinatal mental health.