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Overview of Perinatal Maternal Stress
Published in Rosa Maria Quatraro, Pietro Grussu, Handbook of Perinatal Clinical Psychology, 2020
Dawn Kingston, Muhammad Kashif Mughal
Second, FK506 Binding Protein 5 (FKBP5), the gene responsible for encoding an immunophilin protein, is responsible for regulating the immune system and glucocorticoid receptors (Cao-Lei et al., 2017). In a study of 61 pregnant women in their second and third trimesters, DNA methylation of this gene was correlated with perceived prenatal stress, and further associated with reduced fetal coupling (i.e., the relationship between fetal movement and heart rate) – a precursor to poor neurodevelopmental outcomes (Monk et al., 2016).
Candidate Genes, Gene × Environment Interactions, and Epigenetics
Published in Gail S. Anderson, Biological Influences on Criminal Behavior, 2019
There are a multitude of examples of G × E interactions that are now being studied. One example is seen in the development of schizophrenia and bipolar disorder. Numerous studies have shown both environmental and genetic causes for these psychiatric disorders, and a large number of genes have been implicated, with each contributing only a small level of susceptibility.26 More recently a G × E interaction has been proposed, and a large number of studies have looked at genetic interactions with a range of environmental factors. In a review of such studies, the majority considered variation in genes that code for catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), and FK506-binding protein (FKBP5).26 COMT is an enzyme that breaks down a number of substances in the body, such as some neurotransmitters and certain drugs, and is implicated in several psychiatric disorders.33 BDNF is involved in growth and survival of brain neurons.34 FKBP5 is a binding protein that regulates steroid receptors, and methylation of the gene is thought to moderate the effects of genetic and environmental risk factors for psychiatric diseases.35 Most of these studies found significant interactions between certain alleles of these genes and cannabis use, as well as early-life stress or childhood trauma, which increased risk for schizophrenia and bipolar disorder, although there were far fewer studies on bipolar disorder. A few studies also found some interactions between the alleles and infectious diseases, birth complications, and season of birth.26
The Role of Epigenetics
Published in Dr. Ather Muneer, Mood Disorders, 2018
Finally, future studies should also provide novel understandings on the reversibility of the damage associated with childhood stressful experiences. The early life social environment can induce stable changes that influence neurodevelopment and mental health. The HPA axis is sensitive to changes in the early life environment that associate with DNA methylation of a neuron-specific exon 17 promoter of the GR (NR3C1). While stress responses and related outcomes vary markedly across individuals, elucidating the molecular underpinnings of this variability is of great relevance for developing individualized prevention strategies and treatments for stress-related disorders. An important modulator of stress responses is the FK506-binding protein 51 (FKBP5/FKBP51). FKBP5 acts as a co-chaperone that modulates not only GR activity in response to stressors but also a multitude of other cellular processes in both the brain and periphery. Notably, the FKBP5 gene is regulated via complex interactions among environmental stressors, FKBP5 genetic variants, and epigenetic modifications of glucocorticoid-responsive genomic sites. These interactions can result in FKBP5 disinhibition that has been shown to contribute to a number of aberrant phenotypes in both rodents and humans. Consequently, FKBP5 blockade may hold promise as treatment intervention for stress-related disorders, and recently developed selective FKBP5 blockers show encouraging results in in-vitro and ex-vivo rodent models. Although risk for stress-related disorders is conferred by multiple environmental and genetic factors, the findings related to FKBP5 illustrate how a deeper understanding of the molecular and systemic mechanisms underlying specific gene-environment interactions may provide insights into the pathogenesis of stress-related disorders. As a concluding note, future studies should elucidate whether pharmacological and non-pharmacological interventions could revert back the aberrations induced by childhood adversities on the functioning of systems involved in physiological responses. Such research should suggest strategies to minimize the risk for mood disorders, both in the individuals affected and in the next generations.
Epigenetic alterations associated with childhood trauma and adult mental health outcomes: A systematic review
Published in The World Journal of Biological Psychiatry, 2020
Jani Nöthling, Stefanie Malan-Müller, Naeemah Abrahams, Sian Megan Joanna Hemmings, Soraya Seedat
FKBP5 was the only other gene with consistent findings across studies. CT was not associated with FKBP5 methylation at an overlapping intron 7 region in one PTSD and two depression studies (Yehuda et al. 2016; Tozzi et al. 2018; Bustamante et al. 2018). FKBP5 is activated in response to elevated glucocorticoid levels and FKBP5 expression, in turn, suppresses glucocorticoid receptor activity by decreasing ligand binding and translocation of the receptor (Jaaskelainen et al. 2011; Szyf 2013). Previous studies have reported a link between differential methylation of FKBP5, disruption of the HPA axis and the development of psychiatric disorders. However, CT does not seem to mediate this relationship in PTSD and depression although studies using larger sample sizes may prove otherwise (Mehta et al. 2013; Szyf 2013).
Female HPA axis displays heightened sensitivity to pre-pubertal stress
Published in Stress, 2020
Nichola M. Brydges, Caroline Best, Kerrie L. Thomas
The present study investigated the effects of PPS on long-term neurochemical and molecular alterations in the adult HPA axis in male and female animals by measuring the brain regional expression of CR (GR and MR), AVP, OXT and their receptors (AVP receptor 1a (AVPR1a) and oxytocin receptor (OXTR)) and FKBP5. FKBP5 encodes the FK506 binding protein 51 co-chaperone protein of the GR complex, and is extremely responsive to stress (Wochnik et al., 2005). When FKBP5 is bound to the GR complex, CORT binds with lower affinity and nuclear translocation of the receptor is less efficient, decreasing negative feedback regulation of the HPA axis (Wochnik et al., 2005). There is evidence that genetic modifications in FKBP5 interact with childhood, but not adulthood stress to increase risk for several psychiatric disorders (Matosin, Halldorsdottir, & Binder, 2018). We also measured plasma corticosterone following a social test in adult rats as a behavioral measure of altered HPA axis function. Altered social function is a core component of several adult psychiatric illnesses and ELS has been shown to impact on social behavior and functioning in both animal and human studies (Nicol, Pope, Romaniuk, & Hall, 2015; Palmier-Claus et al., 2016; Sandi & Haller, 2015). Furthermore, early life trauma is associated with blunted cortisol responses to social stress in humans, particularly in women (Bunea et al., 2017). For this reason, we elected to focus on corticosterone rather than other components of the HPA axis, such as ACTH.
Convergent neurobiological predictors of mood and anxiety symptoms and treatment response
Published in Expert Review of Neurotherapeutics, 2019
Mbemba Jabbi, Charles B. Nemeroff
This gene is a component of the glucocorticoid receptor regulatory network. In line with the activation of immune processes during environmentally induced stress and affective responses, CNVs of this FK506 binding protein 5 (FKBP5) gene, a member of the immunophilin protein family, has been implicated in anxious phenotypes in mice [52]. This gene has been suggested to be at the center of gene-by-environment determinants of stress and anxiety-related disorders [53]. In support of these findings, both a GWAS meta-analysis [54] and postmortem brain gene expression analysis [55] suggest FKBP5 involvement in affective disorders. FKBP5 has also been identified as an important regulator of the HPA axis and post trauma-related anxiety disorder vulnerability [56]. Allelic variations of FKBP5 have been associated with developing stress-related psychiatric disorders in adulthood [57]. Individuals with post-traumatic stress disorder (PTSD) demonstrated a structurally anchored hippocampus-anterior cingulate functional connectivity as a function of FKBP5 allelic variation [58]. Functional interactions between FKBP5 and monoaminergic genes at the SNP levels were also shown to predict adaptive peripheral corticotropin-releasing hormone (CRH) response [59]. These results are in line with evidence showing that SNP variations (1) in monoaminergic genes impact endocrine and behavioral stress responses [60,61], and (2) in the corticotropin-releasing hormone receptor (CRHR) gene interactions with environmental adversity [62] to impact later-onset mood disorders [63].