Abstract

Early life adversity (ELA) is a risk factor for the development of mental and physical disorders later in life (McEwen, 2003). Recent models propose DNA methylation as an underlying molecular mechanism responsible to dynamically translate and imprint these negative environmental experiences in different biological pathways (Szyf & Bick, 2013). This study focuses on the oxytocin receptor gene, OXTR, given the role of the oxytocinergic system in the modulation of social behavior, anxiety, and depression. The goal of this study is to examine the effect of ELA on CpG methylation frequency in distinct regions of the OXTR gene, and to test whether these changes in OXTR methylation are related to childhood anxiousness and disruptiveness trajectories rated from age 6 to 12. Drawing from a 27-year longitudinal cohort, we compared 46 adults with high or low early life adversity with regards to their OXTR DNA methylation frequency and their associations with teacher-rated childhood anxiousness and disruptiveness trajectories. The main findings are that in females, we observed significantly higher DNA methylation at Intron 1 CpG 4, Intron 1 CpG 5, Promoter CpG 3, Promoter CpG 7, and significantly lower DNA methylation at Enhancer 1 CpG 2 in the high ELA group, compared to the low ELA group. No significant ELA-related differences were found among males. In addition, teacher-rated childhood anxiousness trajectory was significantly associated with methylation frequency in Intron 1 CpG 5, Promoter CpG 3, Promoter CpG 7, and Enhancer 1 CpG 2 among females, but not among males. Furthermore, teacher-rated childhood anxiousness trajectory mediated the impact of ELA on Promoter CpG 7 methylation in females.
This study suggests that early social experiences impact methylation frequency of different regulatory regions within the OXTR gene among females and that these differential methylation patterns are related to phenotypic differences in anxiousness during childhood.