409. Epigenetic signatures of adolescent depression: unraveling the role of parental maltreatment

Abstract

Abstract Background Major depressive disorder (MDD) in adolescents is a growing public health concern, yet objective biomarkers for diagnosis remain elusive. Epigenetic modifications, particularly DNA methylation at CpG sites, offer promising avenues for biomarker discovery due to their dynamic and environmentally responsive nature. Aims & Objectives This study aimed to identify CpG methylation signatures associated with depression and to explore the mediating role of DNA methylation in the relationship between parental maltreatment and adolescent depression. Method The study design, candidate genes, and machine-learning-based analysis plan were pre-registered. Buccal cells were collected from adolescents with clinical depression and healthy controls. DNA methylation profiling was performed using Illumina EPIC 850K BeadChip arrays. Analysis prioritized DNA methylation levels for CpGs annotated to five genes previously implicated in depression (BDNF, SLC6A4, FKBP5, NR3C1, CRH). A Poly CpG Risk Score was computed as a weighted sum of methylation levels at selected CpGs using a LASSO (Least Absolute Shrinkage and Selection Operator) regression model. Data were split into training (70%) and testing (30%) sets. Subsequently, using the same Poly CpG Risk Score in an independent cohort, the findings were successfully replicated in a sex-dependent manner. In a secondary analysis, pathway enrichment was performed on the top 500 differentially methylated CpGs, with cross-validation using hippocampal methylome data from an animal model of maternal neglect. Results The Poly CpG Risk Score significantly distinguished between depressed and healthy individuals in the training set. In the internal validation, the score showed marginal significance in the test set (p = 0.056, Cohen's d = 1.16). Critically, a significant effect (p < 0.05) was observed in the independent replication cohort, driven specifically by findings in females. Key CpGs were located in regulatory regions of NR3C1, FKBP5, and BDNF. Mediation analysis revealed that the DNA methylation Poly CpG Risk Score significantly mediated the relationship between parental maltreatment and adolescent depression. Enrichment analyses identified pathways related to neurodevelopment and mood disorders. A cross-species comparison supported the conservation of methylation patterns in stress-related genes. Discussion & Conclusions Machine learning-enabled analysis of CpG methylation profiles revealed robust epigenetic biomarkers of depression. These findings support the development of non-invasive, methylation-based screening tools and provide insight into the molecular underpinnings of adolescent depression.