Brain serotonin 1A receptor binding: relationship to peripheral blood DNA methylation, recent life stress and childhood adversity in unmedicated major depression.

Abstract

Childhood and lifetime adversity may reduce brain serotonergic (5-HT) neurotransmission by epigenetic mechanisms. We tested the relationships of childhood adversity and recent stress to serotonin 1A (5-HT_1A) receptor genotype, DNA methylation of this gene in peripheral blood monocytes and <i>in vivo</i> 5-HT_1A receptor binding potential (BP_F) determined by positron emission tomography (PET) in 13 <i>a priori</i> brain regions, in participants with major depressive disorder (MDD) and healthy volunteers (controls). Medication-free participants with MDD (<i>n</i> = 192: 110 female, 81 male, 1 other) and controls (<i>n</i> = 88: 48 female, 40 male) were interviewed about childhood adversity and recent stressors and genotyped for rs6295. DNA methylation was assayed at three upstream promoter sites (-1019, -1007, -681) of the 5-HT_1A receptor gene. A subgroup (<i>n</i> = 119) had regional brain 5-HT_1A receptor BP_F quantified by PET. Multi-predictor models were used to test associations between diagnosis, recent stress, childhood adversity, genotype, methylation and BP_F. Recent stress correlated positively with blood monocyte methylation at the -681 CpG site, adjusted for diagnosis, and had positive and region-specific correlations with 5-HT_1A BP_F in participants with MDD, but not in controls. In participants with MDD, but not in controls, methylation at the -1007 CpG site had positive and region-specific correlations with binding potential. Childhood adversity was not associated with methylation or BP_F in participants with MDD. These findings support a model in which recent stress increases 5-HT_1A receptor binding, via methylation of promoter sites, thus affecting MDD psychopathology.