SEX-SPECIFIC AND STAGE-DEPENDENT EPIGENETIC REGULATION OF BDNF IN BIPOLAR DISORDER: INTEGRATING TRANSCRIPTIONAL AND METHYLATION SIGNATURES

Bipolar disorder (BD) represents a heterogeneous neuropsychiatric condition shaped by gene-environment interactions, yet current diagnostic approaches remain predominantly symptom-based, contributing to delayed recognition and suboptimal therapeutic targeting. Disease progression through clinical stages correlates with symptom severity and treatment response, underscoring the need for molecular stratification tools that complement phenotypic assessment.
We investigated epigenetic regulation of brain-derived neurotrophic factor (BDNF) through integrated analysis of gene expression and promoter methylation patterns to identify stage-specific and sex-specific biomarkers in BD.
PBMCs were isolated from 120 BD patients and 60 healthy controls. Following genomic DNA and RNA extraction, we performed qRT-PCR for BDNF transcript levels and bisulfite pyrosequencing to assess methylation status at two promoter regions (I and IV) and the functional CpG site associated with the rs6265 polymorphism.
BDNF gene expression revealed sex-specific dysregulation, with significant transcriptional downregulation exclusively in female BD patients, while male subjects showed no significant alterations. This sex-dimorphic pattern extended to epigenetic regulation: female patients at disease stage 3 exhibited hypermethylation at promoter I, whereas promoter IV remained unaffected across patient groups. Male patients and earlier disease stages showed no significant methylation changes at either promoter region.
The selective involvement of promoter I, with preserved promoter IV, indicates targeted rather than global BDNF suppression. These sex-dimorphic, stage-linked signatures support BDNF epigenetic profiling as a stratification tool for precision psychiatry, informing personalized treatments and critical intervention windows in BD. Complementary analyses of post-transcriptional regulation and polymorphism-associated methylation may further refine this framework.