Co-methylation Networks Associated with Cognition and Structural Brain Development During Adolescence

Typical adolescent neurodevelopment is marked by decreases in grey matter (GM) volume, increases in myelination, measured by fractional anisotropy (FA), and improvement in cognitive performance. To understand how epigenetic changes, methylation (DNAm) in particular, may be involved during this phase of development, we studied cognitive assessments, DNAm from saliva, and neuroimaging data from a longitudinal cohort of normally developing adolescents, aged nine to fourteen. We extracted networks of methylation with patterns of correlated change using a weighted gene correlation network analysis (WCGNA). Modules from these analyses, consisting of co-methylation networks, were then used in multivariate analyses with GM, FA, and cognitive measures to assess the nature of their relationships with cognitive improvement and brain development in adolescence. This longitudinal exploration of co-methylated networks revealed an increase in correlated epigenetic changes as subjects progressed into adolescence. Co-methylation networks enriched for pathways involved in neuronal systems, potassium channels, neurexins and neuroligins were both conserved across time as well as associated with maturation patterns in GM, FA, and cognition, revealing epigenetic mechanisms that could be involved in adolescent neural development. Networks of correlated methylation change were calculated using a WCGNA on difference scores of beta values collected from three time points. Modules of DNAm change with significant gene enrichment results were included in a multivariate analysis as the independent variable, while changes in gray matter volume, fractional anisotropy, and cognitive performance were the dependent variables. Baseline age and sex were included as covariates, after ruling out significant effects for race, SES, and family ID.