A Longitudinal Study of Epigenetic Associations with Adolescent Brain and Cognitive Development

Typical adolescent neurodevelopment is marked by decreases in grey matter (GM) volume, increases in fractional anisotropy (FA), a measure of white matter integrity, and improvement in cognitive performance. To understanding how epigenetic changes, methylation (DNAm) in particular, may be involved in this phase of development, we used data from a longitudinal cohort of normally developing adolescents, aged nine to fourteen. This data, from three time points roughly one year apart, was used to first explore the relationships between seven cytosinephosphateguanine (CpG) sites in genes highly expressed in brain tissues (GRIN2D, GABRB3, KCNC1, SLC12A9, CHD5, STXBP5, and NFASC), seven networks of GM change, four networks of FA change, and scores from seven cognitive tests. The demethylation of these CpGs as well as the rates of change in DNAm were significantly related to improvements in total, crystalized, and fluid cognition scores, executive function, episodic memory, and processing speed, as well as several networks of GM maturation. The changes in DNAm over time were also significantly related to a brain network highlighting FA maturation of inter-hemispheric connectivity. This same network was found to mediate the relationship between decreases in DNAm of four of these genes and increases in overall cognitive performance. Next we explored how larger networks of correlated methylation change across time were associated with cognition and brain development. A weighted correlation network analysis was applied the dynamic DNAm changes across timepoints. Modules from this analyses were used in multivariate analyses with GM, FA, and cognitive measures. Modules that were significantly enriched for pathways that involved potassium channels, neuronal systems, neuroexins, and neuroligins were conserved across time as well as significantly related to networks of GM maturation, increases in FA, and increased processing speed. The synergistic interactions of these genes and gene pathways experiencing changes in DNAm all play important roles in the excitatory and inhibitory balance, suggesting they may be part of the epigenetic mechanisms of adolescent brain and cognitive maturation.