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Background: Studies in adult depressed patients have indicated that altered DNA methylation patterns at genes related to serotonin and HPA axis functioning (e.g., SLC6A4, FKBP5) are associated with changes in frontolimbic functional connectivity and structure. Here, we examined whether these associations can be generalized to adolescents.Methods: 25 adolescents with depression (Mean age = 15.72 ± 0.94 SD; 20 girls) and 20 healthy controls (Mean age = 16.05 ± 1.5 SD; 16 girls) underwent a functional and structural magnetic resonance imaging protocol, which included a resting-state assessment and measures of brain morphometry. DNA was obtained from saliva. Levels of SLC6A4 and FKBP5 methylation were determined using pyrosequencing.Results: SLC6A4 methylation was linked to amygdala-frontal operculum resting-state functional connectivity (rs-FC), regardless of diagnosis, and was differentially associated with inferior orbitofrontal gyrus (IFOG) gray matter (GM) volume in adolescents with depression and controls. Replicating and extending previous findings in adults, FKBP5 methylation was associated with IFOG GM volume in depressed and healthy adolescents, as well as orbitofrontal cortex (OFC)-rostral prefrontal cortex (RPFC) connectivity in healthy adolescents only.Limitations: Effects of medication use or genotype cannot be ruled out. Further, the relatively small sample size and predominately female sample may limit generalizability.Conclusions: These findings suggest that previously observed associations between SLC6A4 and FKBP5 methylation and frontolimbic processes in adult depressed patients can be in part generalized to adolescent patients. Further, findings suggest that measuring peripheral methylation at these genes deserves further attention as potential markers of typical and atypical development. [ABSTRACT FROM AUTHOR]

Early adversity can influence gene expression via epigenetic mechanisms, including DNA methylation. Peripheral tissues are essential in psychiatric epigenetics, as methylation generally cannot be assessed in the living human brain. Several magnetic resonance imaging (MRI) studies show associations of peripheral serotonin transporter gene (SLC6A4) methylation with function and/or structure of frontal-limbic circuits and brain's resting-state. Commonly used samples are derived from blood, saliva or buccal cells. However, little is known regarding which peripheral tissue is most strongly associated with human brain processes. The aim of the current study was to compare the extent of the association between peripheral SLC6A4 promoter methylation and frontal-limbic function, structure and resting-state in healthy individuals across peripheral tissues. Forty healthy prospectively-followed adults underwent anatomical, resting-state and functional MRI. Saliva-, blood- and buccal-derived DNA methylation was assessed by pyrosequencing. Blood-derived SLC6A4 methylation was positively associated with superior frontal gray matter (GM) volume and with right lateral parietal area (RLP)-frontal pole regional resting-state functional connectivity (rsFC). Saliva-derived SLC6A4 methylation was positively associated with superior frontal GM volume. Buccal-derived SLC6A4 methylation was positively associated with superior and inferior frontal and anterior cingulate cortical (ACC) GM volumes, and with RLP-ACC, frontal pole and medial prefrontal regional rsFC. Current results confirmed the relevance of peripheral methylation for frontal-limbic processes in humans. Buccal cells may be the most sensitive cell type when studying SLC6A4 promoter methylation and its associated risk for neural vulnerability and resilience for psychopathologies in which serotonin is implicated. These data should be further validated in clinical populations. [ABSTRACT FROM AUTHOR]