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Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder.

ABSTRACT: FKBP5 regulates the cortisol-binding affinity and nuclear translocation of the glucocorticoid receptor. Polymorphisms at the FKBP5 locus have been associated with increased recurrence risk of depressive episodes and rapid response to antidepressant treatment. A recent study showed that FKBP5 genotypes moderated the risk of post-traumatic stress disorder (PTSD) symptoms associated with childhood maltreatment. One thousand one hundred forty-three European Americans (EAs) and 1284 African Americans (AAs) recruited for studies of the genetics of substance dependence were also screened for lifetime PTSD. Four single-nucleotide polymorphisms (SNPs) in FKBP5, rs3800373, rs9296158, rs1360780, and rs9470080, were genotyped on the complete sample. Logistic regression analyses were performed to explore the interactive effect of FKBP5 polymorphisms and childhood adversity on the risk for PTSD. After correction for multiple testing, childhood adversity significantly increased the risk for PTSD. FKBP5 genotypes were not associated with the development of the disorder. In AAs, one of the SNPs, rs9470080, moderated the risk of PTSD that was associated with childhood abuse. Without childhood adverse experiences, participants with the TT genotype of this SNP had the lowest risk for PTSD, whereas they had the highest risk for PTSD after childhood adversity exposure. In addition, in EAs, alcohol dependence was observed to interact with childhood adverse experiences, and also FKBP5 polymorphisms, to increase the risk for PTSD. This study provides further evidence of a gene x environment effect of FKBP5 and childhood abuse on the risk for PTSD in AAs. Further study is required in other populations.

SUBMITTER: Xie P

PROVIDER: S-EPMC2946626 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A greater understanding of why some people are more at risk of developing PTSD is required. We examine the relationship between temperament traits in early childhood and subsequent trauma exposure and risk of PTSD. We used data on 2017 participants from the Avon Longitudinal Study of Parents and Children (ALSPAC). Temperament was measured using the Carey Infant Temperament Scale (average score from ages 6 and 24 months). This provided data on 9 individuals traits, and Easy, Medium, and Difficult temperament clusters. Trauma exposure was measured from 0 to 17 years, and PTSD at age 23 years using the PTSD Checklist for DSM-V (PCL-5). Regression models were used to estimate associations between temperament and both trauma and PTSD, and to examine mediation (of temperament to PTSD pathway) and interaction (temperament X trauma on PTSD) effects. 1178 (58.4%) individuals were exposed to a trauma in childhood and 112 (5.5%) had PTSD. Higher levels of Intensity were associated with a small increase in trauma exposure (ORadjusted 1.23, 95% CI 1.12, 1.34; p < 0.001) and PTSD (ORadjusted 1.27, 95% CI 1.05, 1.54; p = 0.012). Higher levels of Activity, Adaptability, Mood and Threshold temperament traits were also associated with trauma exposure. Medium (ORadjusted 1.49, 95% CI 1.21, 1.84; p < 0.001) and Difficult (ORadjusted 1.47, 95% CI 1.18, 1.84; p = 0.001) temperament clusters were associated with increased trauma exposure compared to an Easy cluster, but were not associated with PTSD. The relationship between trait Intensity and adult PTSD was partially mediated by childhood/adolescent trauma (Indirect ORadjusted 1.08, 95% CI 1.01, 1.16, p = 0.024, proportion mediated 26.2%). There was some evidence that trait Intensity modified the relationship between trauma and PTSD (ORadjusted 1.66, 95% CI 1.07, 2.55, p = 0.023). PTSD in early adulthood is more common in those with intense stimuli responsiveness in childhood. Temperament traits might be useful predictors of trauma exposure and mental health outcomes and offer potential targets for supportive interventions.

Project description:ContextIn addition to trauma exposure, other factors contribute to risk for development of posttraumatic stress disorder (PTSD) in adulthood. Both genetic and environmental factors are contributory, with child abuse providing significant risk liability.ObjectiveTo increase understanding of genetic and environmental risk factors as well as their interaction in the development of PTSD by gene x environment interactions of child abuse, level of non-child abuse trauma exposure, and genetic polymorphisms at the stress-related gene FKBP5.Design, setting, and participantsA cross-sectional study examining genetic and psychological risk factors in 900 nonpsychiatric clinic patients (762 included for all genotype studies) with significant levels of childhood abuse as well as non-child abuse trauma using a verbally presented survey combined with single-nucleotide polymorphism (SNP) genotyping. Participants were primarily urban, low-income, black (>95%) men and women seeking care in the general medical care and obstetrics-gynecology clinics of an urban public hospital in Atlanta, Georgia, between 2005 and 2007.Main outcome measuresSeverity of adult PTSD symptomatology, measured with the modified PTSD Symptom Scale, non-child abuse (primarily adult) trauma exposure and child abuse measured using the traumatic events inventory and 8 SNPs spanning the FKBP5 locus.ResultsLevel of child abuse and non-child abuse trauma each separately predicted level of adult PTSD symptomatology (mean [SD], PTSD Symptom Scale for no child abuse, 8.03 [10.48] vs > or =2 types of abuse, 20.93 [14.32]; and for no non-child abuse trauma, 3.58 [6.27] vs > or =4 types, 16.74 [12.90]; P < .001). Although FKBP5 SNPs did not directly predict PTSD symptom outcome or interact with level of non-child abuse trauma to predict PTSD symptom severity, 4 SNPs in the FKBP5 locus significantly interacted (rs9296158, rs3800373, rs1360780, and rs9470080; minimum P = .0004) with the severity of child abuse to predict level of adult PTSD symptoms after correcting for multiple testing. This gene x environment interaction remained significant when controlling for depression severity scores, age, sex, levels of non-child abuse trauma exposure, and genetic ancestry. This genetic interaction was also paralleled by FKBP5 genotype-dependent and PTSD-dependent effects on glucocorticoid receptor sensitivity, measured by the dexamethasone suppression test.ConclusionsFour SNPs of the FKBP5 gene interacted with severity of child abuse as a predictor of adult PTSD symptoms. There were no main effects of the SNPs on PTSD symptoms and no significant genetic interactions with level of non-child abuse trauma as predictor of adult PTSD symptoms, suggesting a potential gene-childhood environment interaction for adult PTSD.

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Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder.

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