Relationships between serotonin 1A receptor DNA methylation, self-reported history of childhood abuse and gray matter volume in major depression.

Early life adversity is a risk factor for psychopathology and is associated with epigenetic alterations in the 5-HT 1A receptor gene promoter. The 5-HT 1A receptor mediates neurotrophic effects, which could affect brain structure and function. We examined relationships between self-reported early childhood abuse, 5-HT 1A receptor promoter DNA methylation, and gray matter volume (GMV) in Major Depressive Disorder (MDD). Peripheral DNA methylation of 5-HT 1A receptor promoter CpG sites −681 and −1007 was assayed in 50 individuals with MDD, including 18 with a history of childhood abuse. T1-weighted structural magnetic resonance imaging (MRI) was performed. Voxel-based morphometry (VBM) was quantified in amygdala, hippocampus, insula, occipital lobe, orbitofrontal cortex, temporal lobe, parietal lobe, and at the voxel level. No relationship was observed between DNA methylation and history of childhood abuse. We observed regional heterogeneity comparing −681 CpG site methylation and GMV (p = 0.014), with a positive relationship to GMV in orbitofrontal cortex (p = 0.035). Childhood abuse history was associated with higher GMV considering all ROIs simultaneously (p < 0.01). In whole-brain analyses, childhood abuse history was positively correlated with GMV in multiple clusters, including insula and orbitofrontal cortex (p FWE = 0.005), and negatively in intracalcarine cortex (p FWE = 0.001). Small sample size, childhood trauma assessment instrument used, and assay of peripheral, rather than CNS, methylation. These cross-sectional findings support hypotheses of 5-HT 1A receptor-related neurotrophic effects, and of increased regional GMV as a potential regulatory mechanism in the setting of childhood abuse. Orbitofrontal cortex was uniquely associated with both childhood abuse history and 5-HT 1A receptor methylation. • Methylation positively correlated with orbitofrontal cortex gray matter volume • Supports neurotrophic effects of serotonin 1A receptors in major depressive disorder • Orbitofrontal cortex may be susceptible to stress-associated epigenetic changes • History of childhood abuse associated with higher gray matter volume • May be compensatory response after childhood adversity [ABSTRACT FROM AUTHOR]