FKBP5 polymorphisms modify the effects of childhood trauma.
Ontology highlight
ABSTRACT:
SUBMITTER: Koenen KC
PROVIDER: S-EPMC3055470 | biostudies-literature | 2010 Jul
REPOSITORIES: biostudies-literature
Publications
FKBP5 polymorphisms modify the effects of childhood trauma.
Koenen Karestan C KC Koenen Karestan C KC Uddin Monica M
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20100701 8
Similar Datasets
Project description:Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.
| S-EPMC4136922 | biostudies-literature
Project description:While the paradigm that genetic predisposition and environmental exposures interact to shape development and function of the human brain and ultimately the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not been elucidated yet. Here we show that a functional polymorphism altering chromatin interaction between the transcription start site and long range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increases the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements (GREs) of FKBP5. This demethylation is linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global impact on the function of immune cells and brain areas associated with stress regulation. This first identification of molecular mechanisms of genotype-directed long-term environmental reactivity will also critically contribute to designing more effective treatment strategies for stress-related disorders. Effects of FKBP5 rs1360780 genotype x environment interaction on peripheral blood mRNA expression of GR responsive genes, as measured by gene expression arrays, were explored in 129 individuals (child abuse/risk allele carrier N = 40, child abuse/protective allele carrier N = 15; and no child abuse/risk allele carrier N = 60, no child abuse/protective allele carrier N = 14). In all 129 individuals, 1627 transcripts showed a significant correlation with plasma cortisol concentrations, suggesting their GR responsiveness. The correlation of 76 of these transcripts with cortisol plasma levels showed significant differences when stratifying by FKBP5 genotype in individuals with child abuse (Fisher z score ≥ 1.96) For these 76 transcripts, the mean absolute correlation coefficient with plasma cortisol was R = 0.23 in the risk allele carriers with child abuse, that is those exhibiting a demethylation of FKBP5 intron 7 as compared to R = 0.74 in the carriers of the protective genotype with child abuse where intron 7 methylation remains largely stable. This indicates a relative GR-resistance in the trauma exposed FKBP5 risk allele vs. protective genotype carriers. These 76 transcripts did not show a genotype-dependent difference in correlation coefficients in non-trauma exposed individuals suggesting that exposure to early trauma enhances FKBP5 genotype-dependent effect of GR sensitivity, most likely by epigenetic mechanisms. These findings suggest that the combination of FKBP5 risk allele carrier status and early trauma exposure alters the stress hormone-dependent regulation of several genes in peripheral blood cells, and might thereby enhance the reported association of early trauma with immune and inflammatory dysregulation, further promoting system-wide symptoms of stress-related disorders.
2012-11-03 | E-GEOD-42002 | biostudies-arrayexpress
Project description:While the paradigm that genetic predisposition and environmental exposures interact to shape development and function of the human brain and ultimately the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not been elucidated yet. Here we show that a functional polymorphism altering chromatin interaction between the transcription start site and long range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increases the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements (GREs) of FKBP5. This demethylation is linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global impact on the function of immune cells and brain areas associated with stress regulation. This first identification of molecular mechanisms of genotype-directed long-term environmental reactivity will also critically contribute to designing more effective treatment strategies for stress-related disorders. Effects of FKBP5 rs1360780 genotype x environment interaction on peripheral blood mRNA expression of GR responsive genes, as measured by gene expression arrays, were explored in 129 individuals (child abuse/risk allele carrier N = 40, child abuse/protective allele carrier N = 15; and no child abuse/risk allele carrier N = 60, no child abuse/protective allele carrier N = 14).
2012-11-03 | GSE42002 | GEO
Project description:ContextChildhood trauma may predispose individuals to aggressive behavior, and both childhood trauma and aggressive behavior are associated with hypothalamic-pituitary-adrenal axis dysregulation.ObjectiveTo determine whether there would be an interaction between genetic variation in FKBP5 and childhood trauma in predicting aggressive behavior.DesignCross-sectional study. Four FKBP5 single-nucleotide polymorphisms used in previous studies (rs3800373, rs9296158, rs1360780, and rs9470080) were genotyped. Three diplotypes were derived from 2 major putatively functional haplotypes regulating protein expression that were previously associated with glucocorticoid receptor sensitivity.SettingPenitentiary District of Abruzzo-Molise in central Italy.ParticipantsA population of 583 male Italian prisoners recruited between 2005 and 2008.Main outcome measuresA comprehensive analysis of aggression and impulsivity was undertaken using the Brown-Goodwin Lifetime History of Aggression (BGHA) questionnaire, the Buss-Durkee Hostility Inventory (BDHI), and the Barratt Impulsiveness Scale (BIS). A history of childhood trauma was investigated with the Childhood Trauma Questionnaire. The interaction between the FKBP5 diplotypes and childhood trauma on measures of aggression was analyzed. Analyses were replicated with a second behavioral measure of aggression: violent behavior in jail. Individual single-nucleotide polymorphism analysis was performed.ResultsChildhood trauma had a significant effect on BGHA and BDHI scores but not on BIS scores. We observed a significant influence of the FKBP5 high-expression diplotype on both a lifetime history of aggressive behavior (BGHA) (P = .012) and violent behavior in jail (P = .025) but only in individuals exposed to childhood trauma, in particular to physical abuse. No main effect of the FKBP5 diplotypes was observed.ConclusionThese data suggest that childhood trauma and variants in the FKBP5 gene may interact to increase the risk of overt aggressive behavior.
| S-EPMC3437943 | biostudies-literature
Project description:Despite increased attention to global mental health, psychiatric genetic research has been dominated by studies in high-income countries, especially with populations of European descent. The objective of this study was to assess single nucleotide polymorphisms (SNPs) in the FKBP5 gene in a population living in South Asia. Among adults in Nepal, depression was assessed with the Beck Depression Inventory (BDI), post-traumatic stress disorder (PTSD) with the PTSD Checklist-Civilian Version (PCL-C), and childhood maltreatment with the Childhood Trauma Questionnaire (CTQ). FKBP5 SNPs were genotyped for 682 participants. Cortisol awakening response (CAR) was assessed in a subsample of 118 participants over 3 days. The FKBP5 tag-SNP rs9296158 showed a main effect on depressive symptoms (p = 0.03). Interaction of rs9296158 and childhood maltreatment predicted adult depressive symptoms (p = 0.02) but not PTSD. Childhood maltreatment associated with endocrine response in individuals homozygous for the A allele, demonstrated by a negative CAR and overall hypocortisolaemia in the rs9296158 AA genotype and childhood maltreatment group (p < 0.001). This study replicated findings related to FKBP5 and depression but not PTSD. Gene-environment studies should take differences in prevalence and cultural significance of phenotypes and exposures into account when interpreting cross-cultural findings.
| S-EPMC4623577 | biostudies-literature
Project description:The present study aimed to investigate the possible influence of childhood trauma and its interaction effect with 10 single-nucleotide polymorphisms (SNPs) of the FK506-binding protein 51 (FKBP5) gene on brain volume in non-clinical individuals. One hundred forty-four non-clinical volunteers (44 men and 100 women) were genotyped with respect to 10 variants (rs9296158, rs3800373, rs1360780, rs9470080, rs4713916, rs4713919, rs6902321, rs56311918, rs3798345, and rs9380528) of FKBP5. Participants underwent magnetic resonance imaging (MRI) scan and psychological assessments such as the childhood Trauma Questionnaire (CTQ), Hospital Anxiety and Depression Scale, rumination response scale, and quality of life assessment instrument. Individuals with the high CTQ score showed enlarged volume of the left orbitofrontal cortex (OFC) if they have childhood trauma-susceptible genotype of FKBP5 rs3800373, rs1360780, rs4713916, rs4713919, rs6902321, and rs3798345 and enlarged volume of the left middle temporal gyrus (MTG) if they have childhood trauma-susceptible genotype of FKBP5 rs3800373, rs1360780, rs4713916, and rs3798345. Among those with the childhood trauma-susceptible genotype, the left OFC and left MTG showed significant negative correlations with positive feelings about life, and the left OFC showed significant positive correlations with negative cognition. This is one of the few studies to identify the volume alteration of the left OFC and the left MTG for the FKBP5 gene-childhood trauma interaction in non-clinical individuals.
| S-EPMC8209293 | biostudies-literature
Project description:Childhood trauma is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and is a known risk factor for suicidal behavior. In this study we sought to determine whether the impact of childhood trauma on suicide risk might be modified by FKBP5, an HPA-axis regulating gene. Sixteen FKBP5 haplotype-tagging single nucleotide polymorphisms (SNPs) were genotyped in a sample of African Americans: 398 treatment-seeking patients with substance dependence (90% men; 120 suicide attempters) and 432 nonsubstance-dependent individuals (40% men; 21 suicide attempters). In all, 474 participants (112 suicide attempters) also completed the Childhood Trauma Questionnaire (CTQ). Primary haplotype analyses were conducted with the four SNPs implicated in earlier studies: rs3800373, rs9296158, rs1360780, and rs9470080. We found that childhood trauma was associated with suicide attempt (P<0.0001). Although there was no main effect of the two major yin yang haplotypes in the four SNP haplotype blocks, there was a haplotype influence on suicide risk (p=0.006) only in individuals exposed to high levels of childhood trauma. In this group, 51% with two copies of the risk haplotype, 36% with one copy, and 20% with no copies had attempted suicide. The total logistic regression model accounted for 13% of the variance in attempted suicide. Analyses of the 16 SNPs showed significant main effects on suicide attempt of rs3777747, rs4713902, and rs9470080 and interactive effects of rs3800373, rs9296158, and rs1360780 with CTQ score on suicide attempt. These data suggest that childhood trauma and variants of the FKBP5 gene may interact to increase the risk for attempting suicide.
| S-EPMC2962602 | biostudies-literature
Project description:Trauma in childhood is a psychosocial, medical, and public policy problem with serious consequences for its victims and for society. Chronic interpersonal violence in children is common worldwide. Developmental traumatology, the systemic investigation of the psychiatric and psychobiological effects of chronic overwhelming stress on the developing child, provides a framework and principles when empirically examining the neurobiological effects of pediatric trauma. This article focuses on peer-reviewed literature on the neurobiological sequelae of childhood trauma in children and in adults with histories of childhood trauma.
| S-EPMC3968319 | biostudies-literature
Project description:Identifying subpopulations that are particularly vulnerable to long-term adverse health consequences of disaster-related trauma is needed. We examined whether adverse childhood experiences (ACEs) potentiate the association between disaster-related trauma and subsequent cognitive disability among older adult disaster survivors. Data were from a prospective cohort study of older adults who survived the 2011 Great East Japan Earthquake. The baseline survey pre-dated the disaster by 7 months. We included participants who completed follow-up surveys (2013 and 2016) and did not have a cognitive disability before the disaster (n = 602). Disaster-related traumas (i.e., home loss, loss of friends or pets) and ACEs were retrospectively assessed in 2013. Cognitive disability levels in 2016 were objectively assessed. After adjusting for pre-disaster characteristics using a machine learning-based estimation approach, home loss (0.19, 95% confidence interval (CI): 0.09, 0.28) was, on average, associated with greater cognitive disability. Among individuals with ACEs, home loss was associated with even higher cognitive disability levels (0.64, 95% CI: 0.24, 1.03). Losses of friends (0.18, 95% CI: 0.05, 0.32) and pets (0.13, 95% CI: 0.02, 0.25) were associated with higher cognitive disability levels only among those with ACEs. Our findings suggest that individuals with a history of ACEs may be particularly vulnerable to adverse health consequences related to disasters.
| S-EPMC10773476 | biostudies-literature
Project description:Childhood trauma is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Both factors increase risk for suicidal behavior. Corticotropin releasing hormone (CRH) regulates the HPA axis and its actions are moderated by a high-affinity binding protein (CRHBP). We hypothesized that CRHBP variation and interaction with childhood trauma might influence suicidal behavior. Moreover, there might be an additive effect with FKPB5, another HPA axis gene previously associated with suicidality in this dataset. African Americans were recruited: 398 treatment seeking patients with substance dependence (90% men; 120 suicide attempters) and 432 non-substance dependent individuals (40% men; 21 suicide attempters). A total of 474 participants (112 suicide attempters) completed the Childhood Trauma Questionnaire (CTQ). Haplotype-tagging SNPs were genotyped across CRHBP and, for completeness, across CRH, CRHR1 and CRHR2. FKBP5 genotypes were available. Three CRHBP SNPs rs6453267, rs7728378 and rs10474485 showed a nominally significant interaction with the continuous CTQ score to predict suicide attempt; rs7728378 remained significant after FDR correction. There was an additive effect with FKBP5: in the group exposed to high trauma, the prevalence of suicide attempt was 0.35-0.30 in carriers of either the FKBP5 rs3800373 major homozygote or the CRHBP rs7728378 major homozygote and 0.58 in carriers of both major homozygotes. Individuals without either major homozygote were resilient to the effects of childhood trauma (suicide attempt prevalence 0.24). Main effects of CRHBP rs6453267 and CRHR1 rs9900679, both unique to African ancestry, were detected. CRHBP variation may predispose, independently and additively, to suicidal behavior in individuals who have experienced childhood trauma.
| S-EPMC3506169 | biostudies-literature