Hypothalamic-pituitary-adrenal axis genetic variation and early stress moderates amygdala function

Abstract

Early life stress may precipitate psychopathology, at least in part, by influencing amygdala function. Converging evidence across species suggests that links between childhood stress and amygdala function may be dependent upon hypothalamic-pituitary-adrenal (HPA) axis function. Using data from college-attending non-Hispanic European-Americans (n=308) who completed the Duke Neurogenetics Study, we examined whether early life stress (ELS) and HPA axis genetic variation interact to predict threat-related amygdala function as well as psychopathology symptoms. A biologically-informed multilocus profile score (BIMPS) captured HPA axis genetic variation (FKBP5 rs1360780, CRHR1 rs110402; NR3C2 rs5522/rs4635799) previously associated with its function (higher BIMPS are reflective of higher HPA axis activity). BOLD fMRI data were acquired while participants completed an emotional face matching task. ELS and depression and anxiety symptoms were measured using the childhood trauma questionnaire and the mood and anxiety symptom questionnaire, respectively. The interaction between HPA axis BIMPS and ELS was associated with right amygdala reactivity to threat-related stimuli, after accounting for multiple testing (empirical-p=0.016). Among individuals with higher BIMPS (i.e., the upper 21.4%), ELS was positively coupled with threat-related amygdala reactivity, which was absent among those with average or low BIMPS. Further, higher BIMPS were associated with greater self-reported anxious arousal, though there was no evidence that amygdala function mediated this relationship. Polygenic variation linked to HPA axis function may moderate the effects of early life stress on threat-related amygdala function and confer risk for anxiety symptomatology. However, what, if any, neural mechanisms may mediate the relationship between HPA axis BIMPS and anxiety symptomatology remains unclear.

HPA axis multilocus genetic profile score moderates the impact of interpersonal stress on prospective increases in depressive symptoms for offspring of depressed mothers.

“…The current study exhibited several strengths including the use of a theoretically-derived, biological pathway based MGPS established in previous research (Di Iorio et al, 2017), semi-structured life stress interview assessments, and a multi-wave prospective study design. However, there were also some limitations which should be acknowledged.…”

“…We utilized a MGPS approach focusing on the combined influence of polymorphisms in genes known to affect HPA axis functioning ( CRHR1 , FKBP5 , and NR3C2 ). We chose to focus specifically on these three genes due to their known influence on HPA axis functioning and to replicate a previously established, theoretically and biologically-driven MGPS utilized in previous research (Di Iorio et al, 2017). 1 As noted earlier, the MGPS approach is consistent with recent research highlighting the importance of examining the aggregate influence of multiple SNPs as opposed to examining candidate genes in isolation (Nikolova et al, 2011; Owens et al, 2016; Pagliaccio et al, 2014).…”

Interaction of HPA axis genetics and early life stress shapes emotion recognition in healthy adults

“…Further, HPA axis relevant SNPs moderate the effects of early life stress exposure. In particular, neural ecophenotypes of early life stress (increased amygdala volume, increased reactivity to emotional stimuli, and decreased connectivity with prefrontal regions) are more pronounced in individuals with a genetic disposition towards greater HPA axis activity (Di Iorio et al, 2017;Holz et al, 2015 , 2015a, 2014White et al, 2012). Similarly, SNPs conferring greater HPA axis activity might also moderate the impairments of emotion recognition following ELS.…”

Neonatal pain and stress disrupts later‐life pavlovian fear conditioning and sensory function in rats: Evidence for a two‐hit model

“…Preterm infants who experienced more painful procedures had significantly elevated cortisol levels when they were school-aged (Brummelte et al, 2015). It has also been demonstrated that early life stress can alter HPA and amydgalar activity in humans (Heim & Nemeroff, 2002;Iorio et al, 2017).…”