The Peripheral Epigenome Predicts White Matter Volume Contingent on Developmental Stage: An ECHO Study.

White matter (WM) development is crucial for efficient neural connectivity, and disruptions in its maturation are associated with neurocognitive and psychiatric disorders. Emerging evidence suggests that epigenetic mechanisms, particularly DNA methylation (DNAm), regulate WM structure, yet little is known about these relationships in pediatric populations. Using data from the Environmental Influences on Child Health Outcomes (ECHO) study, we investigated the association between peripheral DNAm of WM-related genes and WM volume (WMV) across development. Salivary DNAm profiles were obtained from 205 children (2 months-15.5 years) using the Infinium MethylationEPIC array, and T1-weighted MRI was used to quantify WMV. A targeted-epigenome analysis identified 1867 CpG sites across 352 genes significantly predicting WMV (FDR q < 0.05). Notably, 11,611 CpG sites exhibited age-dependent associations, with effects strongest in early childhood. Further, DNAm in saliva significantly correlated with DNAm in brain tissue (r = 0.915). These findings suggest that peripheral epigenetic markers may serve as biomarkers of neurodevelopmental trajectories, with potential applications in early detection of WM-related disorders. Our study highlights the importance of developmental timing in DNAm-WMV associations and underscores the utility of saliva-based DNAm in pediatric neuroimaging research.