Abstract
BACKGROUND: 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). METHODS: 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. RESULTS: 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). LIMITATIONS: Small sample size, childhood trauma assessment instrument used, and assay of peripheral, rather than CNS, methylation. CONCLUSIONS: 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.