Epigenetic age acceleration is associated with brain connectivity changes and the risk of major depression after trauma

Background: Major depressive disorder (MDD) is associated with brain dysfunction and age-related diseases. Epigenetic clocks based on DNA methylation patterns estimate biological aging and aim to predict morbidity and mortality. Although MDD has been linked to epigenetic age acceleration (EAA) cross-sectionally, it is unknown whether EAA is associated with MDD after trauma. Methods: We included 706 participants (66% non-white, 64% female) from the multi-ancestry AURORA study, enrolled at emergency departments (ED) within 72 hours after trauma, from whom three age-adjusted epigenetic clocks were measured at enrollment: PhenoAge, GrimAge, and DunedinPACE. Functional MRI and assessment for probable MDD were conducted two weeks and six months later, respectively. Logistic and linear regression models tested the association of EAA with MDD and functional neuroimaging endpoints. Results: A total of 660 participants had available assessments of probable MDD six months after trauma, and from those 160 screened positively (24.2%) after trauma. EAA calculated by GrimAge (OR = 1.44, 95% CI = 1.12 - 1.85, p-adj= 0.012) and DunedinPACE (OR = 1.46, 95% CI = 1.15 - 1.85, p-adj = 0.005), but not PhenoAge (p-adj= 0.239), was significantly associated with MDD 6-months after trauma. Associations remained significant after adjusting for additional confounders, including prior trauma and disability (p= 0.008 for GrimAge, p= 0.010 for DunedinPACE). Subgroup analysis based on a median age split revealed these effects were only observed in participants 35 years of age or older. DunedinPACE was significantly associated with altered connectivity of fourteen brain network pairs after FDR correction (n = 217). Conclusions: EAA is associated with a higher risk of MDD after trauma and with concomitant brain connectivity changes. Calculation of GrimAge and DunedinPACE at the time of ED presentation may help recognize patients at risk for MDD, potentially improving personalized care after trauma.