Genome‐wide DNA methylation study uncovers epigenetic markers associated with early life stress in individuals with major depressive disorder

Aim Early life stress (ELS) is a significant risk factor for major depressive disorder (MDD); however, the epigenetic mechanisms underlying this association remain poorly characterized, partly due to the lack of trauma‐stratified control groups in previous studies. Methods We performed genome‐wide DNA methylation profiling using Reduced‐Representative Bisulfite Sequencing (RRBS) on whole blood samples from 90 adults divided into four groups: MDD with ELS ( n = 30), MDD without ELS ( n = 30), controls with ELS ( n = 15), and controls without ELS ( n = 15). Differentially methylated regions (DMRs) were identified employing MethylKit and DMRcate (≥5 CpGs, FDR < 0.05) and annotated via FUMA GENE2FUNC and clusterProfiler. Results Our analysis revealed 551, 581, and 479 DMRs in comparisons of MDD vs. control, MDD + ELS vs. control + ELS, and MDD non‐ELS vs. control non‐ELS, respectively. Core genes SELENOO, FASN , and THOC7 were consistently differentially methylated across all groups, reflecting shared mitochondrial, metabolic, and RNA‐processing mechanisms. The MDD + ELS group demonstrated a higher DMR burden, particularly in regions associated with active promoter chromatin, with ELS‐specific genes HIVEP3 and NRL exhibiting GWAS evidence linked to treatment‐resistant depression and ADHD. Conversely, DMRs in MDD non‐ELS were enriched in repressed chromatin states, with hypermethylation in loci within CAMK4 and CALM1 suggesting constitutive silencing of calcium‐dependent neuronal signaling pathways. Our findings underscore the significant contribution of ELS to specific epigenetic changes associated with MDD, particularly in neurodevelopmental and stress‐response pathways. In contrast, MDD without ELS exhibited a distinct methylation profile that affected synapses and synaptic plasticity. Conclusion Our study, therefore, emphasizes the necessity of trauma‐informed approaches in psychiatric research.