U-Shaped Relationship between HPA Axis Genes and Aggression: Moderating Roles of Parent-Child Relationship and Mediating Roles of Impulsivity

Abstract: Aggression, which is a common and remarkably damaging problem, has its roots in stress-responsive systems. Although children display a wide range of individual differences in the hypothalamic–pituitary–adrenal (HPA) axis function, numerous initial conditions of stress reactivity may reach the same end state. In other words, both hyper- and hypo-responses to stress tend to induce heightened risks for aggressive behavior. Informed by the concept of equifinality in developmental psychopathology, this study, through its focus on hypothalamic–pituitary–adrenocortical (HPA) genetic susceptibility, examines the nonlinear (U-shaped) relationship between stress responsiveness and the severity of aggression. Additionally, since it remains unclear whether the equifinality phenomenon is evident in distal behavioral phenotypes or proximal endophenotypes, this study also evaluated, on the basis of “gene–endophenotypes–behavior” framework, a mediated moderation model to examine the effects of the HPA axis genes on aggression, as moderated by the parent–child relationship and mediated by impulsivity. A total of 530 participants (mean age 19.35 ± 1.59 years at Time 1, 53.4% females) completed two assessments at a one-year interval. Data on self-reported aggression, parent–child relationship, and impulsivity were collected, and DNA was extracted from saliva. All of the measures exhibited good reliability. The multilocus genetic profile score (MGPS) was calculated using four polymorphisms within HPA axis–related genes, namely NR3C1 rs41423247, CRHR1 rs110402, COMT rs4680, and BDNF rs6265. For each participant, genotyping of the four HPA axis genes was performed using improved multiplex ligation detection reaction. This was followed by a series of hierarchical regressions that were conducted to examine the U-shaped relationship between MGPS and aggression, and the mediated moderation model. The results revealed a quadratic, U-shaped relationship between the additive genetic risk of HPA and aggression, with both low and high MPGS carriers exhibiting high aggression when exposure to higher levels of parent–child conflict. Nevertheless, parent–child cohesion did not exhibit such moderating effects. Furthermore, the moderating effect was mediated by impulsivity. Similarly, there was a significant quadratic relationship between MGPS and impulsivity when parent–child conflicts were at comparatively high levels, with results displaying a U-shaped relationship (i.e., relatively high or low MGPS-predicted impulsivity). Specifically, impulsivity was a significant risk factor for aggression, with high impulsivity predicting high levels of aggression. These findings inform our understanding of how additive genetic variants in the HPA axis, as well as its response to adversity, is involved in the etiology of aggressive behavior. It is likely that, because of the U-shaped relationship, the association between HPA genetic function and aggression is more complex than what the general perspectives — “the more the genetic risk variants, the higher the likelihood of aggressive behavior.” Moreover, these findings provide support for the phenomenon of equifinality in developmental psychopathology.