Effects of childhood trauma on aggressive behaviors and hippocampal function: the modulation of COMT haplotypes

Abstract

Background: Aggression is a commonly hostile behavior linked to the hippocampal activity. Childhood trauma (CT) exposure has been associated with altered sensitization of the hypothalamic-pituitary-adrenal (HPA) axis and hippocampal volume，which could increase violent aggressive behaviors. Additionally, Catechol-O-methyltransferase (COMT), the major dopamine metabolism enzyme, is implicated in stress responsivity, including aggression. Hence, CT exposure may affect aggression through the effect on the hippocampal function, which might also be modulated by the COMT variations.

Objectives: This study examined whether both CT and haplotypes of COMT moderate hippocampal function and thus affect human aggressive behavior.

Methods: We obtained bilateral hippocampal functional connectivity maps using resting state functional magnetic resonance imaging (MRI) data. COMT haplotype estimation was performed using Haploview 4.2 and PHASE 2.1. Then we constructed a moderated mediation model to study the effect of the CTQ × COMT on aggressive behavior.

Results: Three major haplotypes were generated from thirteen single nucleotide polymorphisms (SNPs) within the COMT gene and formed three haplotypes corresponding to high, medium, and low enzymatic activity of COMT. The results showed interactive relationships between the Childhood Trauma Questionnaire (CTQ) and COMT with respect to the functional connectivity (FC) of the bilateral hippocampus (HIP)-orbital frontal cortex (OFC). Specifically, CT experience predicted lower negative HIP-OFC coupling in the APS and HPS haplotypes corresponding to the medium and high enzymatic activity of COMT, but greater FC in the LPS haplotypes corresponding to the low enzymatic activity. We also observed a conditional mediation effect of the right HIP-OFC coupling in the link between COMT and aggressive behavior that was moderated by CT experience.

Conclusions: These results suggest that CT and COMT have a combined effect on aggressive behavior through hippocampal function. This mediation analysis sheds light on the influence of childhood experience on aggressive behavior in different genetic backgrounds.

Keywords: COMT; aggression; childhood trauma; hippocampus.

Figure 1:

LD map of the 13 SNPs in our sample. Using varying shades of red and the D' statistic value, the map shows the LD level of the corresponding two SNPs.

Figure 2:

Interaction of COMT haplotypes and the CTQ results on bilateral hippocampal FC. (A) The significant region shows the effect of the CTQ × COMT interaction on the FC between the right HIP and right OFC (GRF correction, voxel level P < 0.001, cluster level P < 0.01). (B) Mean ± SE FC of R.HIP–OFC in (A) across all participants (post hoc t-test, Bonferroni corrected). (C) The significant region shows the effect of the CTQ × COMT interaction on the FC between the left HIP and right OFC (GRF correction, voxel level P < 0.001, cluster level P < 0.01). (D) Mean ± SE FC of R.HIP–OFC in (C) across all participants (post hoc t-test, Bonferroni corrected). R., right, L., left, SE, **P < 0.01, ***P < 0.001.

Figure 3:

The moderated mediation analysis. (A) Moderated mediated model between CTQ, COMT haplotypes, FC of R.HIP–OFC, and aggressive behaviors. (B) Results of moderated mediated model between CTQ, COMT haplotypes, FC of R.HIP–OFC, and aggressive behaviors. The conditional direct effects of CTQ on aggressive behaviors was significant in individuals with APS haplotypes [LPS haplotypes: direct effect estimate = 1.848, SE = 1.482, 95% CI (−1.068, 4.765); APS haplotypes: direct effect estimate = 1.973, SE = 0.879, 95% CI (0.243, 3.702); HPS haplotypes: direct effect estimate = 2.098, SE = 1.375, 95% CI (−0.608, 4.803)]. The results showed a significant moderated mediation effect of the CTQ and COMT results on aggressive behaviors through the FC of the right HIP–OFC (indirect effect estimate = 0.538, SE = 0.285, 95% CI (0.035, 1.153)]. The conditional indirect effects of CTQ on aggressive behaviors through the FC of the right HIP–OFC were also significant in individuals with LPS haplotypes and with HPS haplotypes [LPS haplotypes: indirect effect estimate = −0.611, SE = 0.327, 95% CI (−1.317, −0.042); APS haplotypes: indirect effect estimate = −0.073, SE = 0.112, 95% CI (−0.317, 0.140); HPS haplotypes: indirect effect estimate = 0.465, SE = 0.283, 95% CI (0.021, 1.111)].