Peripheral DNA Methylation of Stress-Related Genes Predicts Hippocampal Volume in a Healthy, Pediatric Sample

Brain volume increases throughout early development in predictable patterns and is an important indicator of brain health. Hippocampal development and volume are related to many complex phenotypes, such as depression and anxiety. While basic brain development is genetically driven, environmental influences also influence individualized brain growth and regression. Epigenetics is one mechanism by which development is impacted by environment. Both animal and post-mortem human studies suggest that early life environments shape epigenetic regulation of genes involved in depression and anxiety in the hippocampus. Further, much research suggests that these environmentally driven changes in epigenetics are also reflected in buccal cells. However, little is known about the relationship between peripheral and brain epigenetics, especially in young and healthy cohorts. In an effort to close the gap between the peripheral epigenome and brain structure in a pediatric population, it was investigated whether DNA methylation (DNAm) levels of stress-related genes (NR3C1, FKBP5, and SLC6A4) measured in buccal cells predict hippocampal volume in a healthy, pediatric population (N = 255; females = 113; age range < 2 months – 14 years, Mage = 5.17, SDage = 3.61). Using multiple linear regression, results indicate that DNAm values across the whole gene and individual CpG sites of NR3C1, FKBP5, and SLC6A4 predict bilateral hippocampal volume. Results also indicate an age interaction such that the relationship between hippocampal volume and HPA gene DNAm is stronger in younger participants (0-6 years old), whereas serotonin transporter gene DNAm is stronger in older participants (6-14 years old). These results indicate that buccal DNAm of NR3C1, FKBP5, and SLC6A4 may be useful predictors of hippocampal volume early in development. These results validate the utility of peripheral epigenetics in the study of early life stress and brain structure. Further, these results emphasize the importance of considering developmental stages between which the relationship between brain and peripheral epigenetics may differ and highlight the possibility that diverse biological systems may be more or less relevant at different ages.