Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins

Abstract

Background: Childhood adverse experiences are known to induce persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress. However, the mechanisms by which these experiences shape the neuroendocrine response to stress remain unclear. Method We tested whether bullying victimization influenced serotonin transporter gene (SERT) DNA methylation using a discordant monozygotic (MZ) twin design. A subsample of 28 MZ twin pairs discordant for bullying victimization, with data on cortisol and DNA methylation, were identified in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative 1994-1995 cohort of families with twins.

Results: Bullied twins had higher SERT DNA methylation at the age of 10 years compared with their non-bullied MZ co-twins. This group difference cannot be attributed to the children's genetic makeup or their shared familial environments because of the study design. Bullied twins also showed increasing methylation levels between the age of 5 years, prior to bullying victimization, and the age of 10 years whereas no such increase was detected in non-bullied twins across time. Moreover, children with higher SERT methylation levels had blunted cortisol responses to stress.

Conclusions: Our study extends findings drawn from animal models, supports the hypothesis that early-life stress modifies DNA methylation at a specific cytosine-phosphate-guanine (CpG) site in the SERT promoter and HPA functioning and suggests that these two systems may be functionally associated.

Fig. 1

Average and cytosine–phosphate–guanine (CpG ) unit serotonin transporter gene (SERT) DNA methylation in bullied and non-bullied monozygotic twins at 10 years of age (28 twin pairs). Values are means, with standard errors represented by vertical bars. * Mean value was significantly different from that for non-bullied twins (p < 0.05).

Fig. 2

Average and cytosine–phosphate–guanine (CpG ) unit serotonin transporter gene (SERT) DNA methylation in bullied and non-bullied monozygotic twins from the age of 5 to 10 years (22 twin pairs). Values are means, with standard errors represented by vertical bars. ** Mean value was significantly different from that at age 5 years (p < 0.01).

Fig. 3

Association between cytosine–phosphate–guanine (CpG) unit 8 serotonin transporter gene (SERT) DNA methylation and cortisol response to the Psychosocial Stress Test (56 twins). Standardized residuals (Z) were used to take into account the cortisol covariates. AUC_i, Area under the curve with respect to increase; % 5meC, % 5-methylcytosine.