Dataset Information

Cross-cultural gene- environment interactions in depression, post-traumatic stress disorder, and the cortisol awakening response: FKBP5 polymorphisms and childhood trauma in South Asia.

ABSTRACT: 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.

SUBMITTER: Kohrt BA

PROVIDER: S-EPMC4623577 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Cross-cultural gene- environment interactions in depression, post-traumatic stress disorder, and the cortisol awakening response: FKBP5 polymorphisms and childhood trauma in South Asia.

Kohrt Brandon A BA Worthman Carol M CM Ressler Kerry J KJ Mercer Kristina B KB Upadhaya Nawaraj N Koirala Suraj S Nepal Mahendra K MK Sharma Vidya Dev VD Binder Elisabeth B EB

International review of psychiatry (Abingdon, England) 20150623 3

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), ...[more]

PMID: 26100613

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Project description:Abstract Background: We have previously shown elevated cortisol levels during the day and a blunted cortisol awakening response (CAR) at the onset of psychosis. Although stressful events and childhood abuse have been suggested to possibly play a role in these abnormalities, the evidence behind this link remains inconsistent, and it has been suggested that these could be partly due to genetic predisposition. The aim of this study was to test interaction between history of childhood abuse and rs1360780 FKBP5 genotype on cortisol levels during the day and cortisol awakening response. Methods: Eighty-two first-episode psychosis patients and 53 controls were enrolled in the study. Saliva samples were collected at multiple time points during the day to measure diurnal cortisol levels and cortisol awakening response (CAR); DNA was extracted from blood or saliva samples and evaluated for a functional polymorphism at the rs1360780 locus in FKBP5. Information about presence of absence childhood physical or sexual abuse was collected using the Childhood Experience of Care and Abuse questionnaire. Univariate analyses were performed to test the effects of the interaction between presence of childhood abuse and FKBP5 genotype on cortisol measurements. Results: We found a significant interaction between history of childhood abuse and FKBP5 genotype on the CAR in first episode psychosis (F = 1.132, P = .01) but not in controls (P = .3). In particular patients with T allele (CT or TT) and history of childhood abuse had higher CAR than those with the same allele but without childhood abuse, while patients with CC genotype and history of childhood abuse had lower CAR than those with the same genotype but without childhood abuse. We also found a trend for interaction between history of childhood abuse and FKBP5 genotype on the cortisol levels during the day (F = 3.604, P = .06) in first episode psychosis but in controls (P = .3). In particular patients with T allele (CT or TT) and history of childhood abuse had higher diurnal cortisol levels than those with the same allele but without childhood abuse, while patients with CC genotype and history of childhood abuse had lower diurnal cortisol levels than those with the same genotype but without childhood abuse. Conclusion: Our findings suggest a role of interaction between childhood abuse and FKBP5 genotype in determining HPA axis abnormalities observed at the onset of psychosis.

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.

Project description:CONTEXT:Childhood trauma may predispose individuals to aggressive behavior, and both childhood trauma and aggressive behavior are associated with hypothalamic-pituitary-adrenal axis dysregulation. OBJECTIVE:To determine whether there would be an interaction between genetic variation in FKBP5 and childhood trauma in predicting aggressive behavior. DESIGN:Cross-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. SETTING:Penitentiary District of Abruzzo-Molise in central Italy. PARTICIPANTS:A population of 583 male Italian prisoners recruited between 2005 and 2008. MAIN OUTCOME MEASURES:A 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. RESULTS:Childhood 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. CONCLUSION:These data suggest that childhood trauma and variants in the FKBP5 gene may interact to increase the risk of overt aggressive behavior.

Dataset Information

Cross-cultural gene- environment interactions in depression, post-traumatic stress disorder, and the cortisol awakening response: FKBP5 polymorphisms and childhood trauma in South Asia.

Publications

Cross-cultural gene- environment interactions in depression, post-traumatic stress disorder, and the cortisol awakening response: FKBP5 polymorphisms and childhood trauma in South Asia.

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