Adolescent White Matter Maturation Mediates Epigenetic Associations With Cognitive Development

One hallmark of brain maturation in adolescence is increased myelination (fractional anisotropy [FA]) of the axons, although the epigenetic drivers of this stage of neurodevelopment are as yet poorly understood. Our previous study of a longitudinal cohort of normally developing adolescents, aged nine to fourteen, established the connections between changes in DNA methylation (DNAm) at seven cytosine-phosphate-guanine (CpG) sites in genes highly expressed in the brain to grey matter maturation as well as cognitive improvement. Continuing that work, we investigate the relationships between the changes in DNAm of these genes (GRIN2D, GABRB3, KCNC1, SLC12A9, CHD5, STXBP5, and NFASC), four networks of FA change, and scores from seven cognitive tests. The demethylation of the CpGs over time was significantly related to a brain network highlighting FA increases in regions associated with maturation of interhemispheric connectivity. Mediation analysis found that this same network mediated the relationship between decreases in DNAm of four of these genes and increases in overall cognitive performance. These relationships suggest that changes in DNAm of genes involved in myelination and the excitatory/inhibitory balance in the brain might be driving maturation of white matter, which in turn is implicated in the improved cognitive performance seen in adolescents.