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Adolescent White Matter Maturation Mediates Epigenetic Associations With Cognitive Development
Dawn Jensen1,2, Jiayu Chen1,3, Jessica A Turner4
1Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS): (Georgia State University, Georgia Institute of Technology, and Emory University), Atlanta, Georgia, USA.
Developmental Neurobiology
|November 22, 2025
Summary
Adolescent brain development involves increased myelination, influenced by DNA methylation changes in specific genes. These epigenetic changes are linked to white matter maturation and improved cognitive performance during adolescence.
Area of Science:
- Neuroscience
- Epigenetics
- Developmental Biology
Background:
- Adolescent brain maturation is characterized by increased myelination (fractional anisotropy [FA]).
- Epigenetic drivers, specifically DNA methylation (DNAm), are crucial for neurodevelopment but poorly understood.
- Previous research linked DNAm changes at specific CpG sites to grey matter maturation and cognitive gains in adolescents.
Purpose of the Study:
- To investigate the relationship between DNAm changes in seven key genes and FA changes in adolescent brain networks.
- To explore how these DNAm and FA changes relate to cognitive performance in adolescents.
- To determine if white matter maturation mediates the link between epigenetic changes and cognitive development.
Main Methods:
- Longitudinal study of normally developing adolescents (aged 9-14).
- Analysis of DNAm at seven CpG sites in genes (GRIN2D, GABRB3, KCNC1, SLC12A9, CHD5, STXBP5, NFASC).
- Correlation and mediation analyses with fractional anisotropy (FA) networks and cognitive test scores.
Main Results:
- Demethylation over time significantly correlated with an FA increase network in regions of maturing interhemispheric connectivity.
- Mediation analysis revealed this network links decreased DNAm in four genes to enhanced cognitive performance.
- These findings suggest DNAm changes in genes related to myelination and neural balance drive white matter maturation.
Conclusions:
- DNA methylation changes in specific genes are associated with white matter maturation during adolescence.
- Maturation of white matter, indicated by FA increases, mediates the effect of DNAm on cognitive performance.
- Epigenetic mechanisms play a significant role in adolescent neurodevelopment and cognitive enhancement.
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