Early Pregnancy DNA Methylation Signatures as Predictors of Antenatal Depressive Symptoms: A longitudinal study of DNA methylation changes

BackgroundAntenatal 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. MethodsIn this nested case-control design within the STRiDE (Stratification of Risk of Diabetes in Early Pregnancy study) prospective cohort, 189 pregnant women with no depressive symptoms in early pregnancy (<16 weeks of gestation. PHQ-9 [&le;]4) were followed longitudinally. 89 ADS individuals were identified by the emergence of depressive symptoms at 24-28 weeks of gestation (PHQ-9 [&ge;]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. ResultsEpigenome-wide analysis identified 2,447 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. ConclusionsEarly-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.