FKBP5 moderation of the relationship between childhood trauma and maladaptive emotion regulation strategies in adolescents

doi:10.1016/j.psyneuen.2017.06.012

Psychoneuroendocrinology

Volume 84, October 2017, Pages 61-65

https://doi.org/10.1016/j.psyneuen.2017.06.012 Get rights and content

Highlights

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This study examined the G × E on transdiagnostic risk factors of psychopathology.
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FKBP5 × childhood trauma predicted rumination and catastrophizing in adolescents.
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CATT carriers exposed to trauma endorsed the highest rumination and catastrophizing.
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Findings suggest mechanisms for the vulnerability of CATT carriers to psychopathology.

Abstract

Maladaptive emotion regulation strategies, such as rumination and catastrophizing, are transdiagnostic risk factors for psychopathology. FK506-binding protein 51 (FKBP5) has been found to moderate the relationship between stressful life events and various psychiatric disorders. Given the cross-disorder moderation effect of FKBP5 at the diagnostic level, the aim of the current study was to examine whether the relationship between exposure to childhood trauma and transdiagnostic maladaptive emotion regulation processes would also be moderated by genetic FKBP5 variation in a community sample of adolescents. We hypothesized that adolescent carriers of the FKBP5 CATT haplotype composed of rs9296158, rs3800373, rs1360780, and rs9470080, that has been associated with increased risk for psychiatric disorders in adulthood, would also show higher levels of rumination and catastrophizing. Participants included 1345 genotyped adolescents (M_age = 13.95, 64.2% female; 100% European Caucasians of Portuguese descent) who completed self-report measures on exposure to childhood trauma and emotion regulation strategies. Genotypes of rs9296158, rs3800373, rs1360780, and rs9470080 were used to estimate the CATT haplotype (carriers versus non-carriers). Consistent with our hypotheses and previous findings, adolescent CATT haplotype carriers with higher levels of childhood trauma endorsed higher levels of both rumination and catastrophizing compared to non-carriers. Given the association of these maladaptive emotion regulation processes and psychiatric disorders, the findings suggest possible psychological mechanisms why FKBP5 haplotype carriers exposed to childhood trauma are more vulnerable to developing a psychiatric disorder later in life.

Introduction

Due to the rising prevalence of depression and anxiety (Mathers and Loncar, 2006), investigating factors associated with increased risk of these disorders in premorbid adolescent populations is important. Adolescence is a high-risk period for the onset of psychiatric disorders due to the accelerated psychological, biological and endocrine development occuring during this time in the lifespan, which interacts with the intensified stress and emotional responsiveness to the social environment (Paus et al., 2008). Accordingly, an increased understanding of risk and resilience factors during this sensitive developmental stage may be crucial in developing effective preventative interventions.

Maladaptive emotion regulation strategies, such as rumination and catastrophizing, have been identified as transdiagnostic risk factors for psychopathology (Gellatly and Beck, 2016, Ottaviani et al., 2016). Rumination refers to the tendency to perseverate on negative cognitions and the potential causes and consequences of distress (Nolen-Hoeksema, 2000, Ottaviani et al., 2016). Catastrophizing, on the other hand, is the tendency to overestimate negative consequences associated with an event (Gellatly and Beck, 2016). Both rumination and catastrophizing have been associated with the onset, maintenance, and recurrence of mood and anxiety disorders (Gellatly and Beck, 2016, Ottaviani et al., 2016).

Overall, risk for psychiatric disorders is associated with environmental and genetic factors, as well as their interactions (Halldorsdottir and Binder, 2017). One of the most consistent risk factors for psychopathology in adulthood is exposure to childhood trauma, and various genetic polymorphisms have been described to moderate this relationship. Among these genetic markers are variants within the gene encoding the FK506-binding protein 51 FKBP5, which plays an important role in the hypothalamic-pituitary-adrenal (HPA) axis through its regulatory role of glucocorticoid receptor sensitivity (Binder, 2009). Gene-by-environment interaction (G × E) studies have found that minor allele carriers of a haplotype derived of 4 variants (rs9296158, rs3800373, rs1360780, and rs9470080), referred to as CATT carriers, are at greater risk of developing a range of psychiatric disorders in adulthood following childhood trauma relative to major allele carriers (Zannas et al., 2016). Only few studies have, however, examined the moderating role of FKBP5 on transdiagnostic psychological risk factors for psychopathology in youth, especially adolescents (Comasco et al., 2015, Isaksson et al., 2016). Toward bridging this gap, the current study investigated the combined predictive effect of this FKBP5 haplotype and exposure to childhood trauma on the maladaptive emotion regulation strategies described above. Given that this FKBP5 haplotype has shown moderating effects of childhood adversities across psychiatric disorders, we hypothesized that these transdiagnostic emotion regulation processes would also be affected in that CATT haplotype carriers exposed to higher levels of childhood trauma would present with the higher level of rumination and catastrophizing compared to non-carriers.

Section snippets

Participants

Participants were drawn from a larger study comprising 1459 students between the ages 12–17 and their parents recruited from 31 schools in Portugal in 2011–2012 and 2013–2014. A total of 1345 genotyped adolescents between the ages 12–17 (M_age = 13.95, 64.2% female; 100% European Caucasians of Portuguese nationality) completed the measures required for the present study (see Table 1 for sample characteristics). All subjects’ parents completed consent forms and students completed assent forms prior

Results

Demographic and clinical characteristics of the sample are presented in Table 1. No significant differences were noted based on FKBP5 genotype. Higher levels of rumination and catastrophizing were however observed among participants with lower socioeconomic status (SES) status (p < 0.001). Additionally, females endorsed higher levels of rumination and catastrophizing than males (p < 0.001). SES and biological sex and their interaction with the independent variables (i.e., exposure to childhood

Discussion

We found that FKBP5 haplotype interacted with exposure to childhood trauma to predict both rumination and catastrophizing in adolescents. Consistent with our hypotheses and previous findings (Zannas et al., 2016), CATT haplotype carriers exposed to higher levels of childhood trauma reported higher levels of both rumination and catastrophizing, whereas this pattern was not observed in non-carriers. As noted previously, rumination and catastrophizing have been identified as transdiagnostic risk

Role of funding source

This work was supported by the Fundação para a Ciência e a Tecnologia (Portuguese Foundation for Science and Technology) within the project “Prevention of depression in Portuguese adolescents: efficacy study of an intervention with adolescents and parents” (PTDC/MHC-PCL/4824/2012) and in part by an ERC starting grant, G × E molmech, grant number 281338 to EBB and the Fuqua family foundations.

Conflict of interest/disclosure

WEC is a board member of Hugarheill ehf, an Icelandic company dedicated to the prevention of depression, and he receives book royalties from John Wiley & Sons. His research is also supported by the NIH, the Mary and John Brock Foundation, and the Fuqua family foundations. He is a consultant to the George West Mental Health Foundation that oversees Skyland Trail, a residential treatment facility in Atlanta, Georgia.

EBB is co-inventor on FKBP5: a novel target for antidepressant therapy, European

Acknowledgements

We would like to thank the adolescents who gave their time to participate in this study. We would also like to thank the assessors at the University of Coimbra and technicians involved in the processing of the genetic data at the Max Planck Institute of Psychiatry.

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Citation Excerpt :
SNP rs4713916 was in modest LD with the LD block (r² ≥ .55). This LD structure has also been found in previous studies (e.g., Halldorsdottir et al., 2017; Scheuer et al., 2016; Zimmermann et al., 2011) and is depicted in Supplementary Fig. S.1. The CATT haplotypes derived from the four SNPs forming a LD block (rs3800373, rs9296158, rs1360780, rs9470080) were computed using PLINK and the number of copies (0, 1, 2) of the CATT haplotype was calculated for each participant.
Major Depression (MD) results from a complex interplay between environmental stressors and biological factors. Previous studies in adults have shown that adverse life events interact with genetic variation in FKBP5, a gene implicated in the stress-response system, to predict depressive symptoms and MD. This is the first study to investigate interactions between FKBP5 variants and a range of environmental stressors in adolescents with a clinical diagnosis of MD.
148 male and female adolescents with MD and 143 typically developing (TD) controls (13-18 years) were included in the present study. For self-reported environmental stressors, subjective severity was assessed to allow a classification of these factors as mild, moderate and severe. Sociodemographic stressors were assessed via parental-report.
With a heightened number of sociodemographic, moderate and total number of stressors, participants carrying at least one copy of the FKBP5 CATT haplotype or at least one minor allele of various FKBP5 SNPs had the highest risk for being in the MD group. No genetic main effects were found. Sociodemographic stressors as well as self-reported mild, moderate, and severe stressors were more common in depressed than in TD adolescents.
This is the first study to show interactions between genetic variation in FKBP5 and environmental stressors in a sample of clinically depressed adolescents. The current study provides important starting-points for preventive efforts and highlights the need for a fine-grained analysis of different forms and severities of environmental stressors and their interplay with genetic variation for understanding the complex etiology of (youth) MD.
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This divergent effect shown by patients and controls may be the consequence of a combination of genetic predisposition and social characteristics/environment of individuals vulnerable to psychosis which may impact the way the HPA axis modifies cortisol production in response to extreme stress (Miller et al., 2007; Morgan and Gayer-Anderson, 2016). For example in PTSD and depression, mutations of the FK506-binding protein (which modulates the activity of the glucocorticoid receptors) have been associated with increased risk of depression and PTSD in the presence of childhood abuse (Zannas et al., 2016; Halldorsdottir et al., 2017). Supporting this hypothesis, the increased risk of developing psychosis after exposure to early physical abuse in the AESOP study was lower among participants who had a large support network (Gayer-Anderson et al., 2015).
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We recruited 169 FEP patients and 133 controls with different degrees of childhood physical and sexual abuse (i.e. no abuse exposure, non-severe abuse exposure, and severe abuse exposure). Saliva samples were collected to measure cortisol awakening response with respect to ground (CARg), increase (CARi) and diurnal (CDD) cortisol levels. Two-way ANOVA analyses were conducted to test the relationships between severity of childhood abuse and psychosis on cortisol levels in individuals with psychosis and healthy controls with and without childhood abuse history.
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Previously, it was shown that polymorphisms in FKBP5 are associated with a greater number of depressive episodes [58]. Recently, it was observed that, in adolescents, the FKBP5 gene moderates the relationship between negative childhood experiences and dysfunctional emotional regulation [59]. Another gene connected with the HPA axis is the corticotropin-releasing hormone type 1 receptor (CRHR1) gene.
A contemporary model for the pathogenesis of mood disorders (bipolar and depressive disorders) involves gene-environmental interaction, with genetic predisposition, epigenetic regulation, and environmental effects. Among multiple environmental factors, the experience of childhood trauma can be connected with the pathogenesis, course and the treatment of mood disorders. Patients with mood disorders have the greater frequency of childhood trauma compared with the general population, and adverse childhood experiences can exert a negative impact on their clinical course. In this article, the neurobiological mechanisms of childhood trauma are presented. The influence of negative childhood experiences on the central nervous system can result in many structural and functional changes of the brain, including such structures as hippocampus and amygdala, associated with the development of bipolar and depressive illnesses. Interaction of several genes with childhood trauma to produce pathological, clinical phenomena in adulthood has been demonstrated, the most important in this respect being the serotonin transporter gene and the FKBP5 gene playing an important role in the pathogenesis of mood disorders. Neurobiological effects can also involve epigenetic mechanisms such as DNA methylation which can exert an effect on brain function over long-term periods. Somatic effects of childhood trauma include disturbances of stress axis and immune-inflammatory mechanisms as well as metabolic dysregulation. Negative childhood experiences may also bear implications for the treatment of mood disorders. In the article, the impact of such experiences on the treatment of mood disorders will be discussed, especially in the context of treatment -resistance to antidepressants and mood-stabilizing drugs.

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¹: These authors contributed equally to the project.

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Short CommunicationFKBP5 moderation of the relationship between childhood trauma and maladaptive emotion regulation strategies in adolescents

Highlights

Abstract

Introduction

Section snippets

Participants

Results

Discussion

Role of funding source

Conflict of interest/disclosure

Acknowledgements

Curr. Opin. Neurobiol.

Child Abuse Neglect

Psychoneuroendocrinology

Person. Individ. Diff.

Psychoneuroendocrinology

Biol. Psychiatry

Am. J. Hum. Genet.

Questionário da Regulação Emocional Cognitiva: Validação para a População Portuguesa Cognitive Emotional Regulation Questionnaire: Validation of the Portuguese Version

Psiquiatria Clinica

Psychiatric symptoms in adolescents: FKBP5 genotype–early life adversity interaction effects

Eur. Child Adolesc. Psychiatry

Short Communication
FKBP5 moderation of the relationship between childhood trauma and maladaptive emotion regulation strategies in adolescents