Mineralocorticoid receptor Iso/Val (rs5522) genotype moderates the association between previous childhood emotional neglect and amygdala reactivity.
paper
Cited
Public
- Authors
- Bogdan, Ryan; Williamson, Douglas E; Hariri, Ahmad R
- Year
- 2012
- Journal
- The American journal of psychiatry
- PMID
- 22407082
- DOI
- 10.1176/appi.ajp.2011.11060855
- PMCID
- PMC4700829
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.
Effects of Childhood emotional Neglect, Mineralocorticoid Genotype, and interaction of Mineralocorticoid Genotype and Childhood emotional Neglect on Threat-related Amygdala reactivityaa 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).
LLM interpretation
This figure consists of four panels analyzing threat-related amygdala reactivity. Panel A shows brain imaging (MNI coordinates) with highlighted activation in the left and right amygdala. Panel B is a scatter plot showing a positive correlation between childhood emotional neglect scores and right amygdala reactivity. Panel C is a bar chart comparing right amygdala reactivity between Mineralocorticoid Receptor genotypes, showing higher reactivity in Val Carriers compared to Iso/Iso homozygotes. Panel D is a scatter plot with regression lines showing that the positive association between emotional neglect and amygdala reactivity is present for Iso/Iso homozygotes (red) but not for Val Carriers (blue).
| # | Section | Preview |
|---|---|---|
| 20 | Discussion — Childhood Emotional Neglect | At the cellular level, animal research suggests that stress may potentiate amygdala reactivity to… |
| 21 | Discussion — Mineralocorticoid Receptor Genotype Effects and Moderation of Childhood Emotional Neglect | Mineralocorticoid receptor val carriers had heightened amygdala reactivity relative to iso… |
| 22 | Discussion — Mineralocorticoid Receptor Genotype Effects and Moderation of Childhood Emotional Neglect | Childhood emotional neglect was positively associated with amygdala reactivity only in iso… |
| 23 | Discussion — Mineralocorticoid Receptor Genotype Effects and Moderation of Childhood Emotional Neglect | The overall effect of task was associated with left and right amygdala reactivity, consistent with a… |
| 24 | Discussion — Mineralocorticoid Receptor Genotype Effects and Moderation of Childhood Emotional Neglect | The amygdala can be divided into anatomically defined ventral (containing the basolateral complex)… |
| 25 | Discussion — Mineralocorticoid Receptor Genotype Effects and Moderation of Childhood Emotional Neglect | Emotional neglect alone and in interaction with mineralocorticoid receptor genotype was associated… |
| 26 | Discussion — Mineralocorticoid Receptor Genotype Effects and Moderation of Childhood Emotional Neglect | because emotional neglect leaves individuals with fewer support resources to buffer the negative… |
| 27 | Discussion — Mineralocorticoid Receptor Genotype Effects and Moderation of Childhood Emotional Neglect | This is one of the first imaging gene-by-environment interaction studies. It provides an example of… |
| 28 | Discussion — Mineralocorticoid Receptor Genotype Effects and Moderation of Childhood Emotional Neglect | overall model it still demonstrates significant predictive utility for questions of basic science… |
| 29 | Discussion — Mineralocorticoid Receptor Genotype Effects and Moderation of Childhood Emotional Neglect | However, the small amount of additional variance also demonstrates the need for other techniques,… |
| 30 | Discussion — Mineralocorticoid Receptor Genotype Effects and Moderation of Childhood Emotional Neglect | Our study is not without limitations. First, while we speculated on the relationship between HPA… |
| 31 | Discussion — Mineralocorticoid Receptor Genotype Effects and Moderation of Childhood Emotional Neglect | Limitations notwithstanding, this study provides important evidence demonstrating that a common… |
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