FKBP5 polymorphisms moderate the influence of adverse life events on the risk of anxiety and depressive disorders in preschool children

Highlights

• FKBP5 interacts with adverse events to predict the risk of anxiety/depressive disorders in children.

• Minor allele carriers who experienced many adverse events had the highest disease risk.

• Our results are in line with findings in adults suggesting a FKBP5-dependent vulnerability for the effects of adverse events.

• Epigenetic modification of FKBP5 might be involved in the observed gene-environment effects.

Abstract

FKBP5 is thought to be involved in the pathogenesis of stress-related disorders. Studies have shown that FKBP5 genotypes moderate the risk of post-traumatic stress disorder and depression in traumatized adults. We aimed to replicate this finding in a sample of preschool children. Parents of preschoolers (N = 186) were interviewed using the Preschool Age Psychiatric Assessment (PAPA) to evaluate the presence of anxiety and depressive disorders and to quantify the child's exposure to adverse events. All FKBP5 polymorphisms showed significant interactions with mild to moderate life events, but not with severe life events, in predicting the risk of anxiety and/or depressive disorders (p = 0.003–0.019). Children who experienced a high number of mild to moderate life events had a higher risk of developing an anxiety and/or depressive disorder if they were carriers of the minor allele compared to major allele homozygotes. Results indicate that genetic variation in FKBP5 influences the risk of anxiety and/or depressive disorders in preschool age by altering the sensitivity to the deleterious effects of mild to moderate adverse events. In case of severe life events, the FKBP5 genotype does not seem to play a role, suggesting that severe life events might influence directly the risk of anxiety and/or depressive disorders independent of an FKBP5 genotype-dependent vulnerability.

Introduction

While anxiety disorders are among the most common psychiatric disorders of early childhood, with prevalence rates ranging from 1% (Keenan et al., 1997) up to 19% (Franz et al., 2013), the rate of depressive disorders is estimated consistently across studies as below 2% (Lavigne et al., 2009, Wichstrøm et al., 2012). Recent studies suggested that anxiety and depression in children and adolescents often co-occur concurrently (Wichstrøm et al., 2012) as well as sequentially (Bufferd et al., 2012), with higher levels of psychosocial impairment for comorbid anxiety and depression compared to either condition alone (Franco et al., 2007, Von Klitzing et al., 2014). Considering that the presence of an anxiety disorder may increase the risk of developing depression and vice versa (Goodwin et al., 2004, Bittner et al., 2007), a better understanding of the etiology of anxiety and depressive disorders in early childhood is urgently needed. This may help to apply the appropriate therapeutic intervention at an early age in order to prevent the later onset of other psychiatric disorders.

Heritability estimates derived from twin studies indicate that genetic factors play a moderate role in the development of anxiety (Eaves et al., 1997, Legrand et al., 1999, Lau et al., 2006) and depression (Thapar and McGuffin, 1994, Ehringer et al., 2006) in children. Genetic association studies of depression and anxiety disorders in children gave inconsistent results, and specific risk genes have not so far been identified. By contrast, a large number of environmental factors contributing to the risk of developing mental disorders have been identified. These factors include poverty (McLeod and Shanahan, 1996), negative family environment (Repetti et al., 2002), and stressful life events (Kessler, 1997) including abuse during childhood (Chapman et al., 2004, Widom et al., 2007). However, individuals vary in their responses to such negative environmental influences. While some children develop various mental problems or disorders, others report no symptoms and seem to be resilient to trauma exposure. Given this heterogeneity in response to stress, examining gene-environment interactions seems an appropriate approach to understanding the development of anxiety and depressive disorders during childhood. Of the few studies that have examined gene-environment interactions in childhood anxiety and depression, most have focused on the serotonin transporter variant 5-HTTLPR (Eley et al., 2004, Barry et al., 2009). One recent study investigated variants of three candidate genes including 5-HTTLPR and their interaction with various environmental factors in terms of symptoms of childhood anxiety, depression and oppositional behavior (Lavigne et al., 2013). It has been shown that 5-HTTLPR interacts with caregiver depression, socioeconomic status, and family conflict to predict individual differences in both anxious and depressive symptomatology. Dunn et al. (2011), who reviewed studies of gene-environment interaction in adolescent depression, concluded that the majority of these studies support the relevance of gene-environment interactions at early ages as well.

With the exception of these findings, gene-environment studies in children are relatively uncommon and studies investigating other potentially relevant genetic variants are scarce. Stressful life events are assumed to be implicated in the development of depressive and anxious disorders (Heim et al., 2004, Lupien et al., 2009). As these effects are presumably modulated by individual stress responsiveness, the hypothalamic-pituitary-adrenal (HPA) axis, the neuroendocrine stress response system, might represent a promising source of candidate genes for a gene-environment interaction approach. Indeed, a recent study provides some evidence for the corresponding molecular mechanisms that mediate the association between adverse events and the development of psychiatric disorders (Klengel et al., 2013). It was shown that childhood maltreatment influenced biological processes through allele-specific epigenetic modification of the FK506 binding protein 5 (FKBP5) gene, which is an important regulator of the HPA axis.

FKBP5 is a co-chaperone of the heat shock protein 90 (hsp90) which regulates glucocorticoid receptor (GR) sensitivity (Binder, 2009). Binder et al. (2004) were the first to demonstrate that homozygous carriers of the minor allele on rs1360780 (recessive model) exhibited increased FKBP5 activity leading to changes of the GR sensitivity. Subsequent studies showed that healthy subjects who are homozygous carriers of the minor allele at selected FKBP5 variants displayed an impaired normalization of the stress hormone cortisol after exposure to psychosocial stress (Ising et al., 2008, Buchmann et al., 2014). Similar findings have also been reported for a sample of 14-month-old infants (Luijk et al., 2010). Further support for a dysregulation of the HPA axis comes from Menke et al. (2013) who found depressed patients carrying the minor allele on rs1360780 to have a reduced induction of FKBP5 activity as well as a reduced suppression of cortisol and adrenocorticotropic hormone after dexamethasone stimulation. These studies point towards a genotype-dependent risk of chronically elevated cortisol levels after repeated stress, which in turn may increase the risk of stress-related disorders like anxiety and depression.

Considering FKBP5 as a promising candidate for gene-environment interactions, studies have shown that the same FKBP5 variant which previously has been associated with impaired stress recovery (Ising et al., 2008) predicted an increased risk of depression in subjects who experienced severe traumatic events (Appel et al., 2011, Zimmermann et al., 2011). Furthermore, it has been shown that polymorphisms within FKBP5 modulated the effect of childhood trauma on the risk of developing a post-traumatic stress disorder (PTSD) following a dominant (homozygous and heterozygous minor allele carriers) (Binder et al., 2008), or recessive genetic model (Xie et al., 2010). To our knowledge, only one study has investigated the influence of FKBP5 polymorphisms on mental health in childhood (Koenen et al., 2005). In line with findings in adults, they found that children who are homozygous for the minor rs1360780 allele have a higher risk to develop peritraumatic dissociation after a severe injury compared to children with other genotypes. As studies on adults have suggested that FKBP5 variants moderate the influence of early life stress on the incidence of stress-related disorders, an interaction between FKBP5 and adverse life events could also be of relevance to predict the incidence of anxiety and depressive disorders in early childhood.

Our aim therefore was to assess whether the risk of developing any anxiety and/or depressive disorder during early childhood is influenced by an interaction between FKBP5 polymorphisms and adverse life events.