Elsevier

Psychoneuroendocrinology

Volume 99, January 2019, Pages 28-37
Psychoneuroendocrinology

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

https://doi.org/10.1016/j.psyneuen.2018.08.030Get rights and content

Highlights

Abstract

Background

Early life stress (ELS) affects facial emotion recognition (FER), as well as the underlying brain network. However, there is considerable inter-individual variability in these ELS-caused alterations. As the hypothalamic-pituitary-adrenal (HPA) axis is assumed to mediate neural and behavioural sequelae of ELS, the genetic disposition towards HPA axis reactivity might explain differential vulnerabilities.

Methods

An additive genetic profile score (GPS) of HPA axis reactivity was built from 6 SNPs in 3 HPA axis-related genes (FKBP5, CRHR1, NR3C1). We studied two independent samples. As a proof of concept, GPS was tested as a predictor of cortisol increase to a psychosocial challenge (MIST) in a healthy community sample of n = 40. For the main study, a sample of n = 170 completed a video-based FER task and retrospectively reported ELS experiences in the Childhood Trauma Questionnaire (CTQ).

Results

GPS positively predicted cortisol increase in the stress challenge over and above covariates. CTQ and genetic profile scores interacted to predict facial emotion recognition, such that ELS had a detrimental effect on emotion processing only in individuals with higher GPS. Post-hoc moderation analyses revealed that, while a less stress-responsive genetic profile was protective against ELS effects, individuals carrying a moderate to high GPS were affected by ELS in their ability to infer emotion from facial expressions.

Discussion

These results suggest that a biologically informed genetic profile score can capture the genetic disposition to HPA axis reactivity and moderates the influence of early environmental factors on facial emotion recognition. Further research should investigate the neural mechanisms underlying this moderation. The GPS used here might prove a powerful tool for studying inter-individual differences in vulnerability to early life stress.

Introduction

For humans navigating a social world, facial expressions are a valuable source of information about other’s emotional states and adequate behaviour in social interactions. Competency in inferring emotions from facial expressions (facial emotion recognition; FER) emerges already in infancy and continues to develop with increasing refinement until adolescence (Leppänen and Nelson, 2009). Early life stress (ELS; i.e. conditions during childhood that threaten the emotional or physical well-being and exceed the child’s coping resources), however, affects this development (da Silva Ferreira et al., 2014). Children who underwent maltreatment show a generally poorer performance in FER tasks than their non-maltreated peers (Pollak et al., 2000), and adults with a history of ELS show similar impairments (Germine et al., 2015; Jedd et al., 2015), suggesting that ELS effects on emotion processing persist throughout the lifespan.

Such enduring alterations in emotion processing following ELS point to potential changes in emotion-related brain circuits. Facial emotion recognition involves a network of regions that critically comprises the amygdala (Fusar-Poli et al., 2009). Although neurogenesis in the amygdala is completed by birth, it undergoes substantial changes to its anatomy and connectivity with prefrontal regions postnatally (Leppänen and Nelson, 2009), making it susceptible to disruptive effects of early life stress. A growing body of literature indeed documents structural, functional and connectomic changes of the amygdala following ELS (Fareri and Tottenham, 2016; Teicher et al., 2016). Specifically, ELS has been associated with an increased excitability of the amygdala towards emotional faces (Dannlowski et al., 2012; McCrory et al., 2011; van Harmelen et al., 2013), as well as changed amygdala-prefrontal connectivity during emotion processing (Jedd et al., 2015).

Although these lines of evidence consistently demonstrate changes in emotion processing and the involved brain network following ELS, it is still not fully understood what causes this altered development. Moreover, there are considerable inter-individual differences in how severely people are affected by ELS, both regarding behaviour and neural endophenotypes (da Silva Ferreira et al., 2014; Teicher et al., 2016), the origins of which remain unclear. Investigating this variability may help to identify the neurobiological mechanisms underlying the sequelae of early life stress and may inform preventive and therapeutic interventions.

The neuroendocrine stress response has been suggested as the main mediating factor in ELS-caused changes to the amygdala, as it is rich in glucocorticoid receptors (Lupien et al., 2009) and both endogenous cortisol and pharmacologic agonism of the HPA axis trigger amygdala activation (Bogdan et al., 2016). In animals, protracted GR stimulation in the amygdala alters synaptic functioning between the amygdala and frontal regions in a pattern similar to ELS-caused changes in humans (Myers et al., 2014). These data suggest that the HPA axis plays a role in how early life stress brings about changes to the core structure in facial emotion recognition. Accordingly, individual differences in HPA axis function might be moderating the effects environmental stress exerts on FER.

HPA axis activity is highly heritable (Federenko et al., 2004) and multiple genetic association studies have identified polymorphisms in genes coding for HPA axis-related proteins that are associated with variability in the cortisol response to a psychosocial or pharmacological challenge (Supplementary Table S3; for an overview see DeRijk, 2009). Single nucleotide polymorphisms (SNPs) in three such genes, CRHR1, NR3C1, and FKBP5, are studied here (the selection process is outlined below). The CRHR1 gene codes for a receptor that binds corticotropin-releasing hormone and is thus a mediator of HPA axis activation. By contrast, the NR3C1 gene which codes for the glucocorticoid receptor and the FKBP5 gene which codes for a binding protein fine-tuning GR availability, are involved in the negative feedback loop of the HPA axis (Pagliaccio et al., 2014).

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; Pagliaccio et al., 2015a, 2014; White et al., 2012). Similarly, SNPs conferring greater HPA axis activity might also moderate the impairments of emotion recognition following ELS. Specifically, SNPs coding for important switch points of the HPA axis could potentiate the neuroendocrine and subsequent downstream effects of exposure to environmental stress, but otherwise have little differential effect in the absence of stress.

Based on these previous findings, the present study examined whether a genetic profile score (GPS) reflecting functionally relevant variation in 6 loci in 3 genes coding for integral HPA axis proteins moderated the relationship between ELS and facial emotion recognition. This approach of building biologically informed genetic profile scores has previously been capable to significantly explain variance of endophenotypes when individual SNPs would not (Nikolova et al., 2011; Pagliaccio et al., 2014). This approach is especially valuable for G-x-E-interaction studies that are constrained by both the low frequency of risk-conferring variants and the frequency of environmental stressors. Genetic profile scores have the advantage of assessing higher-order function of a signalling cascade instead of the effects on single components of a signalling cascade that single SNPs might exert. The phenotype of HPA axis activity has previously been mapped in different polygenic score models (Bogdan et al., 2016) that we used to guide our approach (Pagliaccio et al., 2014). As a proof of concept, we tested whether the here proposed genetic profile predicted cortisol increase towards a psychosocial stress challenge.

The aims of the present study were twofold. (1) Build a genetic profile score that captures the disposition to greater HPA axis activity and determine its validity by testing it as a predictor of the endocrine stress response after a trigger. We hypothesized that the genetic profile score would positively predict cortisol increase towards a psychosocial stress challenge. (2) Investigate whether genetic variation in the HPA axis as captured by the GPS could explain inter-individual differences in facial emotion recognition impairments following early life stress. We hypothesized that the genetic profile score would moderate the relationship between ELS and performance in the FER task, such that for individuals carrying higher GPS the impact of ELS on facial emotion recognition in adult life is more severe.

Section snippets

Population

Two independent subsamples from a large-scale (n = 541) study conducted at Charité Universitätsmedizin Berlin were analysed for this study. The samples followed different protocols, and thus had different measures available. Sample 1 consisted of 64 participants who participated in a psychosocial stress challenge. Sample 2 consisted of 234 individuals who were presented a FER task. Sample characteristics are described in the results section and Supplementary Table 1. Inclusion criteria were age

Genetic profile score of HPA axis genes predicts cortisol response

64 participants completed the MIST, 61 of which met the inclusion criteria. For 14 subjects, cortisol data was missing from T0 or T1 or both, and for another 6 genotyping was not successful for all 6 SNPs of interest (missing values were missing completely at random (MCAR), Little’s MCAR test χ²(6,N = 64) = 11.162 p = 0.083). One subject was detected as a multivariate outlier, leaving a final sample of n = 40 (18–62 years, M = 30.8 ± 9.93, 75% male). For each subject, a genetic profile score

Discussion

The present study adopted a biologically-informed genetic profile score approach (Nikolova et al., 2011) to examine whether functionally relevant genetic variation within the HPA axis interacts with ELS to predict facial emotion recognition ability. Our results show that an additive genetic profile score of canonical HPA axis gene variants is predictive of the increase of cortisol towards a psychosocial stress challenges and moderates the negative effect that self-reported early life stress

Conclusion and future directions

Limitations notwithstanding, this study provides evidence suggesting that a profile of genetic variance associated with variability in HPA axis activity moderates the impact of early life stress on facial emotion recognition. If replicated in an independent sample, the effect described here may indicate a biological mechanism of vulnerability towards the detrimental effects that ELS has on social and emotional functioning. The present study contributes to a growing body of literature

Financialsupport

The study was supported by the Deutsche Forschungsgemeinschaft (DFG) [DFG-Grant GR 4510/2-1 to Simone Grimm]

Conflict of interest

None

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