Epigenetic and Structural Brain Aging and Their Associations With Major Depressive Disorder

Background A growing body of evidence suggests that Major Depressive Disorder (MDD) may be associated with premature biological aging. However, most studies to date have examined brain-based (BrainAge) and DNA methylation (DNAm) based measures (DNAmAge) of biological age (BioAge) in isolation. Method We investigated two well-studied BioAge measures in lifetime and current MDD: BrainAge and DNAmAge (4 separate DNAmAge measures based on Horvath, Hannum, GrimAge and PhenoAge clocks). We used cross-sectional cohort data from Generation Scotland (GS:STRADL; BrainAge N=833; DNAmAge N=587; 26-76 years) and used UK Biobank (UKB) data to test for replication of BrainAge associations with MDD (UKB, BrainAge N=12,018, 45-80 years). Premature brain and DNAm aging were operationalized as ‘Predicted Age Difference’ (PAD), and analyses controlled for age, sex, smoking and alcohol intake. We also tested individual and additive associations of brain and DNAm based PADs to lifetime/current MDD using logistic regression. Results Lifetime MDD individuals showed significantly higher BrainAge and DNAmAge in Generation Scotland, ranging from 1.60-2.45 years compared to individuals without MDD for all measures except for Horvath age. No differences were found for BrainAge in UKB. In terms of PAD, lifetime MDD was significantly associated with GrimAge-PAD, PhenoAge-PAD and Brain-PAD, ranging from OR=1.21-1.30 (and in UKB Brain-PAD OR=1.05). DNAm-PAD and Brain-PAD demonstrated shared and distinctive associations with lifetime MDD, where PhenoAge-PAD plus Brain-PAD explained maximum variance, AUC=0.69, R 2 =9%. No significant associations were found for current MDD. Conclusions Our findings highlight shared and distinct associations of premature brain and DNAm aging in lifetime MDD.