Longitudinal blood DNA methylation profiling reveals disrupted immune-epigenetic adaptation and candidate stress related loci in postpartum depression

Postpartum depression (PPD) arises during a period of profound endocrine and immune reorganisation, yet it is unclear whether women who develop PPD show distinct trajectories of immune-related DNA methylation compared to euthymic mothers. In a longitudinal cohort, women with PPD (n = 17) and healthy postpartum controls (n = 24) were followed from birth to 12 weeks postpartum, with repeated assessment of depressive symptoms and perceived stress and whole-blood sampling at 2-3 days (T0) and 12 weeks (T4) for Infinium MethylationEPIC array profiling. Healthy postpartum women showed a widespread gain in DNA methylation from T0 to T4 with strong enrichment of genes involved in neutrophil activation, chemokine signalling and interleukin-1 production, consistent with a normative immune-epigenetic down-tuning after childbirth. Women with PPD also exhibited immune-related changes, but with fewer differentially methylated CpGs and increased variance at sites that were stably hypermethylated in controls, indicating an attenuated and more heterogeneous epigenetic response. Although no CpG reached epigenome-wide significance in direct case-control contrasts, longitudinal consistency analyses highlighted a small set of CpGs with reproducible PPD-associated hypermethylation in stress- and signalling-related genes, including FKBP5 and AVP, suggesting that disrupted immune-epigenetic adaptation and altered regulation at these loci may contribute to postpartum vulnerability.