Interaction between hypothalamic-pituitary-adrenal axis genetic variation and maternal behavior in the prediction of amygdala connectivity in children
Introduction
Internalizing symptoms during childhood increase the risk of developing depression later in life (Kovacs and Devlin, 1998), underscoring the importance of understanding etiological factors to inform preventive efforts. High levels of negative parenting behaviors (e.g. parental over-involvement; aversiveness) and low levels of positive behaviors and warmth have been related to increased levels of internalizing symptoms during childhood (Yap and Jorm, 2015). However, individuals show significant variability in their susceptibility to such environmental factors (Ellis et al., 2011). A possible explanation is that genetic factors may play a role in influencing sensitivity to environmental exposure (i.e., gene-environment (G × E)) (Uher, 2014).
In particular, genes related to the hypothalamic–pituitary–adrenal (HPA) axis are promising candidates for a mechanism that may determine individual differences in sensitivity to stressful family environments. The HPA axis is the key biological stress response system (McEwen, 2007), and dysregulation of this system has been found in depressed patients (Pariante and Lightman, 2008). Previous research has found associations between depression and variations in genes key to HPA axis function, such as the corticotrophin-releasing hormone receptor 1 (CRHR1) (Liu et al., 2006), the glucorticoid receptor (NR3C1) (Zobel et al., 2008) and the FK506 Binding Protein 5 (FKBP5) (Lavebratt et al., 2010). Importantly, several studies have found associations between HPA axis-related genes and depression only when in interaction with childhood adverse experiences, supporting a G × E framework (Appel et al., 2011; Bradley et al., 2008; Zimmermann et al., 2011). However, no research to date investigating HPA axis-related G × E predictors of internalizing symptoms has a) been done in children, and b) investigated parenting as the environmental exposure.
The specific pathways linking G × E and risk for internalizing symptoms are still unclear. One fruitful approach to understanding such mechanistic pathways is to investigate brain function (Insel et al., 2010). Dysfunction of corticolimbic circuits underlying emotion processing, especially those involving the amygdala, have been suggested to represent potential neurobiological mechanism that might underlie the association between G × E effects and depressive/internalizing symptoms (Swartz et al., 2015). The amygdala is intrinsically involved in HPA axis function (Ledoux, 2000) and it has been proposed that HPA axis genetic variation may moderate the effect of the environment on amygdala reactivity and connectivity of related emotional circuits (Bogdan et al., 2016).
Indeed, studies have found that HPA axis-related genes interact with environmental factors to predict amygdala reactivity/connectivity. Two studies adopted a ‘cumulative genetic risk’ approach, combining 5 and 10 single nucleotide polymorphisms (SNPs), respectively, from four different genes (FKBP5, CRHR1, NR3C2 and NRC31) to create HPA axis genetic ‘risk’ scores (Iorio et al., 2017; Pagliaccio et al., 2015a). One study found that early life stress was associated with amygdala response to emotional faces only in young adults with higher HPA axis genetic risk (Iorio et al., 2017). The other study found that HPA axis genetic risk interacted with number of stressful events in predicting connectivity between the amygdala and the frontal cortex, caudate, and parahippocampal gyrus, in children (Pagliaccio et al., 2015a). Two further studies focused on a single SNP of the FKBP5 gene: rs1360780 (Holz et al., 2014; White et al., 2012). One of these studies found that individuals homozygous for the ‘risk’ T-allele, in the context of emotional neglect, showed increased amygdala reactivity to fearful and angry faces, and positive coupling between amygdala and orbitofrontal cortex, compared to young adults heterozygous/homozygous for the non-risk C-allele (Holz et al., 2014). The other study found that emotional neglect in those with the FKBP5 rs1360780 T-allele predicted greater dorsal amygdala reactivity to an emotional faces task (White et al., 2012). Finally, another study investigated the mineralcorticoid receptor (NR3C2) rs5522 polymorphism and found that although the A-allele was associated with amygdala reactivity in the context of emotional neglect, carriers of the G-allele showed the greatest amygdala reactivity (Bogdan et al., 2012).
While evidence to date suggests a moderating role of HPA axis genetic variation in the association between environmental adversity and functioning of emotional circuits, none investigated parenting behaviors, despite the fact that such behaviors are thought to modulate the development of the HPA axis (Caldji et al., 2000), as well as the same emotional circuits implicated in depression (Callaghan and Tottenham, 2015). Focusing on the childhood period is of particular interest given that it is thought to be a sensitive period for parental modulation of child frontoamygdala circuitry (Gee, 2016). Further, none of the aforementioned G × E studies provided evidence that effects on brain function were in turn associated with internalizing symptoms.
This study aimed to investigate the interaction between observed measures of maternal parenting behaviors and HPA axis genetic variation in relation to amygdala reactivity and connectivity during emotion processing, and in turn internalizing symptoms, in a community sample of children. Parenting is particularly important for emotional development during childhood (Callaghan and Tottenham, 2015), and understanding the link between parenting behaviors and internalizing symptoms in this sensitive period is important to understand risk processes for depression. Examining a combination of several SNPs is thought have more predictive power, compared to individual polymorphisms (Bogdan et al., 2016). As such, we adopted a cumulative genetic risk approach similarly to previous studies (Iorio et al., 2017; Pagliaccio et al., 2015a). Given previous findings, we expected that higher negative and lower positive maternal parenting behaviors, in particular in those with higher HPA axis genetic risk, would be associated with increased amygdala reactivity and connectivity with regions involved in emotion processing, including the prefrontal cortex. We also hypothesized that these alterations in amygdala reactivity and connectivity would in turn be associated with higher internalizing symptoms in children (see Fig. 1 for a representation of our model).
Section snippets
Materials and methods
The sample consisted of 80 participants taking part in the Family and Childhood Transition Study (FACTS), who were recruited from Melbourne, Australia, as described elsewhere (Simmons et al., 2017). Social disadvantage increases the risk of negative life events and stressors and poses challenges for parenting practices (McLoyd, 1998). Thus, to maximize the variance in parenting behaviors, participants were recruited from metropolitan areas of Melbourne falling within the lower tertile of
Demographic characteristics
See Table 2 for demographics and descriptive information for the sample. See Supplementary Table S1 for correlation between variables.
HPA axis function
There was no association between HPA genetic risk score and morning cortisol at Wave 1 (p > 0.05).
Region of interest (ROI) analysis
There was no association between HPA axis genetic score and left or right amygdala activity in response to angry and fearful faces, and no association between HPA axis genetic score in interaction with any of the four parenting behaviors and left or right amygdala
Discussion
In this study, we investigated the association between HPA-related genetic variation, maternal parenting behaviors and amygdala activity and connectivity during implicit emotion processing in a community sample of children. Our analysis revealed three main findings: first, higher HPA genetic risk score was associated with greater amygdala-precuneus connectivity, which in turn was associated with greater child self-reported levels of depressive symptoms. Second, the interaction between HPA axis
Funding and disclosure
This study was funded by a Discovery Project grant from the Australian Research Council (ARC; DP130103551). Ms. Pozzi was supported by a Melbourne International Research Scholarship. Dr. Bousman was supported by the Alberta Children's Hospital Research Foundation and the University of Calgary Cumming School of Medicine. Dr. Whittle was supported by an NHMRC Career Development Fellowship (1007716). Dr. Seal was supported by the Royal Children's Hospital Foundation. The authors report no
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