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

Childhood adverse experiences, including abuse and neglect, increase risk for major depressive disorder (MDD) and suicidal behaviour in adulthood.¹ Childhood adversity reduces brain serotonergic (5-HT) neurotransmission implicated in MDD, aggressive behaviour and suicidal behaviour.² However, it is not clear how childhood adversity or recent life stressors may affect the serotonergic system via epigenetics or how epigenetic effects may increase the risk for MDD and other psychopathology in adulthood. Genetic polymorphisms of the 5-HT_1A receptor gene have been associated with MDD in a meta-analysis,³ and early-life stress may moderate this association,⁴ potentially via epigenetic effects, as it has been associated with DNA methylation of serotonergic pathway genes.⁵ One of the single nucleotide polymorphisms (SNPs) of the 5-HT_1A receptor gene (−1019C/G; rs6295)⁶ that regulate its expression⁷ has a G allele with lower affinity for inhibitory transcription factors.⁸ MDD is associated with a higher frequency of the rs6295 G/G genotype,⁷ and this genotype has been associated with greater 5-HT_1A binding in the raphe nuclei.⁹ Methylation of two CpG sites (−681 and −1007) increases autoreceptor expression, reducing serotonin release and affecting psychiatric illness and treatment response.¹⁰

We hypothesised a potential mediator role for DNA methylation at the regulatory sites listed above in the upstream promoter region of this gene (−681, −1007 and −1019) for the effect of childhood and recent stress on expression in the brain, potentially moderated by diagnosis for recent stress. To our knowledge, this is the first study to examine associations between (a) 5-HT_1A promoter genotype, childhood and recent life stress and (b) blood mononuclear cell DNA methylation and 5-HT_1A binding potential in brain, in order to better understand the role of 5-HT_1A binding as it relates to effects of stress on MDD.

Method

Participants

The sample included 192 participants with MDD (165 in a current major depressive episode) and 88 healthy volunteers (controls). MDD diagnosis was determined by DSM-IV criteria according to the Structured Clinical Interview for Axis I Disorders.¹¹ Positron emission tomography (PET) 5-HT_1A receptor binding potential (BP_F) was available for 119 participants (62%), including 69 with MDD and 50 controls. Subsets of the PET imaging data have been previously utilised in papers...