Mineralocorticoid receptor Iso/Val (rs5522) genotype moderates the association between previous childhood emotional neglect and amygdala reactivity

Abstract

Objective: The amygdala is especially reactive to threatening stimuli, and the degree of reactivity predicts individual differences in the expression of depression and anxiety. Emerging research suggests that emotional neglect during childhood as well as hypercortisolemia may lead to heightened threat-related amygdala reactivity. This raises the possibility that genetic variation affecting hypothalamic-pituitary-adrenal (HPA) axis function contributes to individual differences in amygdala reactivity, both independently and as a function of childhood emotional neglect.

Method: This study assessed whether the mineralocorticoid receptor iso/val polymorphism (rs5522), a functional genetic variant affecting HPA axis function, influenced threat-related amygdala reactivity in 279 individuals in late childhood and early adolescence. The study also explored the extent to which any effects of the genotype on amygdala reactivity were contingent upon previous childhood emotional neglect.

Results: Prior childhood emotional neglect and the val allele were associated with greater amygdala reactivity. Moreover, a significant genotype-by-emotional neglect interaction was observed whereby greater amygdala reactivity in val allele carriers was independent of previous childhood emotional neglect, while greater reactivity in iso homozygotes was revealed only in the context of a history of elevated emotional neglect. At relatively low levels of previous emotional neglect, val carriers had heightened amygdala reactivity relative to iso homozygotes.

Conclusions: These results suggest that relatively greater amygdala reactivity may represent a biological mechanism through which childhood adversity and functional genetic variation in HPA axis responsiveness to stress may mediate risk for psychopathology.

FIGURE 1. Effects of Childhood emotional Neglect, Mineralocorticoid Genotype, and interaction of Mineralocorticoid Genotype and Childhood emotional Neglect on Threat-related Amygdala reactivity^a

^a Panel A shows the left and right amygdala reactivity to the faces > shapes contrast (neurological format): right Montreal Neurological Institute (MNI) coordinates: x=18, y=−6, z=−18; 217 voxels; t=14.74, p<0.001, family-wise error-corrected; left MNI coordinates: x=−16, y=−6, z=−14; 146 voxels, t=10.62, p<0.001, family-wise error-corrected. Panel B shows that childhood emotional neglect is positively associated with amygdala reactivity. Panel C shows that val carriers have elevated threat-related amygdala reactivity relative to iso homozygotes. Panel D shows that childhood emotional neglect is positively associated with amygdala reactivity only in iso homozygotes. The model is plotted with raw data values, although statistics were run with mean-centered values. Highlighted areas indicate regions where the difference between the groups reaches significance. Importantly, removal of the outlier (−7 amygdala reactivity) does not change the results (overall model, F=3.40, df=5, 272, p=0.005; main effect of emotional neglect, p=0.004; main effect of val carrier status, p=0.07; interaction, p=0.04). Moreover, restricting analyses to individuals with a childhood emotional neglect score ≤15 (as no val carriers reported emotional neglect above a score of 15) produced the same pattern of results (overall model, F=3.48, df=5, 263, p=0.005; main effect of emotional neglect, p=0.02; main effect of val carrier status, p=0.03; interaction, p=0.02).