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

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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Oquendo receives royalties from the Research Foundation for Mental Hygiene for the commercial use of the Columbia Suicide Severity Rating Scale. She serves as an advisor to Alkermes, Mind Medicine, Sage Therapeutics, St. George's University and Fundación Jimenez Diaz. Her family owns stock in Bristol Myers Squibb. Dr. Mann receives royalties from the Research Foundation for Mental Hygiene for commercial use of the C-SSRS. Dr. Sullivan is currently an employee of Tonix Pharmaceuticals Holding Corp and owns stock and stock options in the company. All other authors have no disclosures or competing interests to report. Dr. Miller has received research support from Evecxia and AbbVie Pharmaceuticals.
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