Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

Abstract

BackgroundHypothalamic–pituitary–adrenal (HPA) axis functioning has been implicated in the development of stress‐related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT).MethodsChildren with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response).ResultsTreatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response.ConclusionsAllele‐specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype‐dependent manner.

Dynamic stress-related epigenetic regulation of the glucocorticoid receptor gene promoter during early development: The role of child maltreatment

“…The primary aim of the current study was to begin to address the lack of longitudinal methylation designs in environmental epigenetic research by utilizing a short-term longitudinal model to examine predictors of change in methylation of saliva DNA NR3C1 in a sample of children. While others have examined change in NR3C1 DNAm after non-randomized psychological intervention with small samples (Roberts et al, 2015; Yehuda et al, 2013), the current study is the first to examine early environmental adversity as a predictor of NR3C1 DNAm change. Further, though several studies have examined the influence of child maltreatment and other early environmental adversity on later NR3C1 DNAm in adulthood (e.g., Tyrka, Parade et al, 2016; Tyrka et al, 2012), the current study is the first to explicitly model NR3C1 promoter methylation change in early childhood proximal to a documented incidence of child maltreatment or current adversity inherent within environments of poverty.…”

Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders

“…An interesting avenue for further research is to investigate epigenetic and gene expression predictors and correlates of psychological treatment response, as these approaches may allow us to get closer to the biological mechanisms of CBT response. This work while in its infancy has shown early promise [Perroud et al, ; Roberts et al, , ; Yehuda et al, ]. Of relevance, a recent study investigating gene expression change in response to exposure‐based CBT for anxiety disorders reported that an increase in DALGB gene expression (diacylglycerol lipase beta gene), which is involved in the biosynthesis of 2‐AG (an endogenous endocannabinoid), was associated with greater reductions in severity while a reduction in DALGB expression corresponded with lower reductions in severity [Roberts et al, ].…”

DNA methylation in adolescents with anxiety disorder: a longitudinal study

“…The few studies that explored a longitudinal approach involving the genome-wide DNA methylation in early development suggested that adversities in childhood are associated to differences in DNA methylation and risk to mental health 67 , 68 . In parallel to the influence of early adversities, DNA methylation changes may be observed as a result of therapeutic treatment using the same concept of environmental interference in DNA regulation 69 . An interesting study compared changes in SLC6A4 methylation after Cognitive Behavior Treatment (CBT) in anxious children, considering those that remitted as compared to those that did not remit from their primary anxiety diagnoses.…”