A longitudinal DNA methylation atlas and its link to brain structure and mental health

Epigenetic mechanisms are thought to contribute to neurodevelopmental vulnerability for psychiatric disorders, yet longitudinal evidence linking DNA methylation (DNAm) to brain maturation and psychopathology is limited. Using epigenome-wide DNAm (372,582 CpGs) and whole-brain structural MRI data from the IMAGEN cohort (n = 506, ages 14-19), we identified 18 co-regulated DNAm clusters, ten enriched for brain-expressed genes involved in neuronal development and signalling. The clusters showed consistent longitudinal change and were reproducible in independent adult samples (PPMI, n = 513; ADNI, n = 606). Multivariate analyses revealed coordinated coupling between DNAm change and cortical-subcortical maturation, such that greater DNAm reductions in brain-related clusters associated with greater cortical thinning and subcortical volume changes in the fronto-limbic-striatal axis. Increases in depressive symptoms, and frequency of cannabis use and binge drinking were linked to DNAm changes, with mediation models supporting DNAm as a mechanistic bridge between behaviour and brain change. Two clusters (C1 and C7) were associated with depressive and negative psychotic symptoms across adolescence. Associations of these clusters with depressive symptoms replicated in the PPMI dataset. Their coupling with amygdala-striatal maturation suggests that these DNAm signatures index environmentally shaped affective-motivational neurodevelopment.