Early Pregnancy DNA Methylation Signatures as Predictors of Antenatal Depressive Symptoms: A longitudinal study of DNA methylation changes
Journal:
medRxiv
Published Date:
Feb 4, 2026
Abstract
Background. Antenatal depressive symptoms (ADS) are common and underdiagnosed, particularly in low and middle income countries, and are associated with adverse maternal and offspring outcomes. Current screening relies on subjective symptom reporting, limiting early identification and prevention. Epigenetic modifications, particularly DNA methylation, offer a promising avenue for objective early biomarkers of depression risk during pregnancy. Methods. In a nested case control design within the STRiDE (Stratification of Risk of Diabetes in Early Pregnancy) prospective cohort, 189 pregnant women with no depressive symptoms in early pregnancy (less than 16 weeks of gestation, PHQ 9 score less than or equal to 4) were followed longitudinally. Eighty nine ADS individuals were identified by the emergence of depressive symptoms at 24 to 28 weeks of gestation (PHQ 9 score greater than or equal to 5), while 100 women remained symptom free (controls). Genome wide DNA methylation profiling of early pregnancy peripheral blood was performed using the Illumina EPIC 850K array. Epigenome wide association analyses were combined with machine learning approaches to identify predictive CpG panels. Model robustness was assessed using bootstrap validation, and a methylation risk score (MRS) was constructed. Functional enrichment analyses were conducted to explore biological pathways. Results. Epigenome wide analysis identified 2447 differentially methylated positions associated with subsequent ADS. A robust panel of 10 CpGs in early pregnancy predicted later ADS with excellent performance (testing AUC 0.99, bootstrap validated AUC 0.91), independent of maternal risk factors. The MRS markedly outperformed traditional clinical predictors (AUC 0.94) and further improved prediction when combined with maternal characteristics (AUC 0.95). ADS associated methylation changes were enriched in neurodevelopmental, synaptic, immune, and metabolic signaling pathways. Limited concordance with placental methylation suggested maternal specific epigenetic regulation. Conclusions. Early pregnancy DNA methylation signatures can predict antenatal depressive symptoms before clinical onset. This blood based 10 CpG biomarker panel offers a biologically informed and objective tool for early risk stratification, with the potential to enable preventive interventions and enhance perinatal mental health care, particularly in resource constrained settings.
