487. Genome-wide DNA methylation analysis reveals epigenetic signatures of early life stress in major depressive disorder patients

Abstract

Abstract Background Major Depressive Disorder (MDD) is a pervasive condition, affecting over 20% of the global population. ELS, encompassing events like abuse and neglect, is a well-documented risk factor for the development of MDD in later life. A significant dimension of this relationship involves epigenetic modifications, which are increasingly recognized as key mechanisms through which environmental exposures, such as ELS, interact with an individual's genetic predispositions to shape the depression phenotype. Aims & Objectives The present study investigated genome-wide DNA methylation profiles in individuals with MDD, stratified by ELS exposure, and included trauma-matched control groups. By comparing MDD and control participants with and without ELS, this study aimed to identify differentially methylated regions (DMRs) that are specifically associated with ELS-related depression. Method The participants included 90 male and female adult patients aged 18-65 who met DSM-5 diagnostic criteria for MDD or volunteer controls as determined by the MINI International Neuropsychiatric Interview. Subjects comprised of MDD with ELS (n=30), MDD without ELS (n=30), and non-psychiatric controls with and without ELS (n=30). The UAB IRB approved the protocol, and written informed consent was obtained from all participants. Early life trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Genome-wide methylation using reduced representation bisulfite sequencing. Differential methylation was evaluated by statistical tests conducted at each CpG location to determine significance, subsequently followed by the identification of differentially methylated regions (DMRs). Individual CpG sites were tested using the Wald test in Dispersion Shrinkage for Sequencing Data and Fisher’s exact test in MethylKit, with raw p-values (p<0.05) used for initial filtering, as is standard in DMR detection pipelines to avoid overly conservative thresholds at the single-CpG level. The omics annotations derived from the ANNOVAR framework were integrated to determine biological implications and the CNS trait association of the DMR genes. Given the dense distribution of CpGs in and around the quantified DMR regions, localized genomic visualization models were created using the UCSC genome Browser to investigate the support of a strong DMR signal. To explore the functional relevance of genes associated with the DMRs, GENE2FUNC module in the Functional Mapping and Annotation (FUMA) platform was used. Results We identified 128 DMRs in MDD vs. control, 29 in MDD+ELS vs. control+ELS, and 13 in MDD non-ELS vs. control non-ELS comparisons. Notable genes exhibiting DMRs in MDD+ELS included LONRF1, MAPK8IP1, SELENOO, PDXP, and CNNM3, showing strong enrichment in brain-related tissues and regulatory elements. Functional enrichment highlighted MAPK, synaptic vesicle, and JAK-STAT pathways. In contrast, MDD non-ELS DMRs included genes such as BCL7B, BLCAP, and NNAT, which exhibited elevated expression in multiple brain regions and were enriched in Hippo, Wnt, and Ras signaling pathways and chromatin remodeling. Discussion & Conclusions This study provides compelling evidence of distinct DNA methylation signatures associated with ELS-induced MDD and MDD without ELS exposure, highlighting the complex interplay between genetic and environmental factors in the etiology of this complex disorder. These results also contribute to our understanding of the molecular mechanisms underlying ELS-induced MDD and may have implications for the development of novel diagnostic and therapeutic strategies.