Epigenetic signatures of childhood trauma in females: a cross-stage study across adolescence and pregnancy

Childhood trauma is a major transdiagnostic risk factor for psychiatric disorders, yet the biological mechanisms underlying its long-term embedding remain insufficiently characterised, particularly in females [1,2]. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have emerged as promising peripheral biomarkers of stress-related neurobiological processes [3,4]. They are involved in neurodevelopment, immune regulation, and stress responsivity, and may reflect dynamic interactions between environmental exposures and biological systems. However, it remains unclear whether trauma-associated miRNA signatures are shared across developmental stages or specific to particular windows of vulnerability, and to what extent they reflect trauma exposure rather than psychiatric state.

This study aims to identify circulating miRNA expression profiles associated with childhood trauma in females with psychiatric disorders and to determine whether these molecular patterns are shared or stage-specific across two critical developmental periods: adolescence and pregnancy. These periods represent key windows of biological and psychosocial vulnerability, characterised by major hormonal and neurodevelopmental changes. Secondary objectives include examining associations between miRNA profiles and suicidal behaviours, symptom severity, and protective factors, as well as distinguishing trauma-related biological signatures from psychiatric-state–related modulation.

We will conduct a multicohort translational study integrating harmonised clinical and biological data from two complementary cohorts: (1) adolescent girls hospitalised in child and adolescent psychiatry (n≈120), and (2) pregnant women recruited from the general population (n≈140). Childhood trauma exposure will be assessed using validated instruments, and psychiatric diagnoses established through structured interviews. Blood-derived biological samples (whole blood and serum) will be analysed, allowing for comparison across biological matrices and increasing robustness of biomarker identification.

A discovery-driven approach using small RNA sequencing will first identify trauma-associated miRNA signatures within each cohort. Differential expression analyses will be conducted, followed by penalised logistic regression (least absolute shrinkage and selection operator) to derive multimiRNA signatures predictive of trauma exposure. Discriminative performance will be evaluated using area under the receiver operating characteristic curve (AUC), with internal validation by bootstrap resampling and correction for multiple testing.

A complementary hypothesis-driven validation phase will assess candidate miRNAs previously identified in human trauma-exposed cohorts, including markers such as miR-223-3p, notably reported in maternal biological matrices, suggesting potential relevance for stress-related and intergenerational mechanisms [5]. Expression patterns of these candidates will be tested using quantitative polymerase chain reaction across both cohorts, enabling evaluation of their developmental robustness and clinical relevance.

Comparative analyses will examine shared versus stage-specific molecular patterns, as well as associations with clinical phenotypes including suicidal behaviours and resilience-related factors. As data collection is ongoing, preliminary analyses are expected to identify candidate miRNA signatures associated with childhood trauma exposure, with moderate-to-high discriminative performance.

This study provides an original developmental and female-focused approach to trauma-related biomarker research. By integrating exposomic assessment, clinical phenotyping, and molecular profiling, it aims to disentangle trauma-specific biological embedding from psychiatric-state effects. Ultimately, this work may contribute to refining biologically informed models of vulnerability and resilience, and support the development of stage-sensitive biomarkers to guide early identification and personalised intervention strategies in trauma-exposed populations.

References

1. Walsh, K., McLaughlin, K.A., Hamilton, A., Keyes, K.M., 2017. Trauma exposure, incident psychiatric disorders, and disorder transitions in a longitudinal population representative sample. J. Psychiatr. Res. 92, 212–218.
2. McLaughlin, K.A., Greif Green, J., Gruber, M.J., Sampson, N.A., Zaslavsky, A.M., Kessler, R.C., 2012. Childhood adversities and first onset of psychiatric disorders in a national sample of US adolescents. Arch. Gen. Psychiatry 69 (11), 1151–1160.
3. Ochi, S., Dwivedi, Y., 2023. Dissecting early life stress-induced adolescent depression through epigenomic approach. Mol. Psychiatry 28 (1), 141–153.
4. Allen, L., Dwivedi, Y., 2020. MicroRNA mediators of early life stress vulnerability to depression and suicidal behavior. Mol. Psychiatry 25 (2), 308–320.
5. Tomaszewska, W., Apanasewicz, A., Gomółka, M., Matyas, M., Rojek, P., Szołtysik, M., Babiszewska-Aksamit, M., Gielniewski, B., Wojtas, B., Ziomkiewicz, A., Jawaid, A., 2025. Differential microRNAs and metabolites in the breast milk of mothers with adverse childhood experiences. Transl. Psychiatry 15 (1), 367.