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118.1 Effect of the Interaction Between Childhood Abuse and FKBP5 Gene Polymorphism on Cortisol Awakening Response and Diurnal Cortisol Levels in First-Episode Psychosis

ABSTRACT: 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.

SUBMITTER: Mondelli V

PROVIDER: S-EPMC5475630 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Project description:BackgroundFailure to account for the etiological diversity that typically occurs in psychiatric cohorts may increase the potential for confounding as a proportion of genetic variance will be specific to exposures that have varying distributions in cases. This study investigated whether minimizing the potential for such confounding strengthened the evidence for a genetic candidate currently unsupported at the genome-wide level.MethodsTwo hundred and ninety-one first-episode psychosis cases from South London, UK and 218 unaffected controls were evaluated for a functional polymorphism at the rs1360780 locus in FKBP5. The relationship between FKBP5 and psychosis was modeled using logistic regression. Cannabis use (Cannabis Experiences Questionnaire) and parental separation (Childhood Experience of Care and Abuse Questionnaire) were included as confounders in the analysis.ResultsAssociation at rs1360780 was not detected until the effects of the two environmental factors had been adjusted for in the model (OR = 2.81, 95% CI 1.23-6.43, p = 0.02). A statistical interaction between rs1360780 and parental separation was confirmed by stratified tests (OR = 2.8, p = 0.02 vs. OR = 0.89, p = 0.80). The genetic main effect was directionally consistent with findings in other (stress-related) clinical phenotypes. Moreover, the variation in effect magnitude was explained by the level of power associated with different cannabis constructs used in the model (r = 0.95).ConclusionOur results suggest that the extent to which genetic variants in FKBP5 can influence susceptibility to psychosis may depend on other etiological factors. This finding requires further validation in large independent cohorts. Potentially this work could have translational implications; the ability to discriminate between genetic etiologies based on a case-by-case understanding of previous environmental exposures would confer an important clinical advantage that would benefit the delivery of personalizable treatment strategies.

Project description:Abnormal hypothalamic-pituitary-adrenal (HPA) axis function, as indexed by elevated diurnal cortisol levels and/or a blunted cortisol awakening response (CAR), has been observed among patients with first episode psychosis and associated with neurocognitive deficits in this population. However, the extent to which these features precede illness onset is unclear. The current study aimed to determine whether children who are at putatively elevated risk for psychosis because they present multiple antecedents of schizophrenia (ASz), and high-risk children with a family history of illness (FHx), are characterized by abnormal cortisol levels when compared with their typically developing (TD) peers. A further aim was to investigate the extent to which cortisol levels are associated with psychosocial stress and neurocognitive function. Thirty-three ASz children, 22 FHx children, and 40 TD children were identified at age 9-12 years using a novel community-based screening procedure or as relatives of individuals with schizophrenia. All participants were antipsychotic-naive and not currently seeking treatment for their symptoms. At age 11-14 years, participants provided salivary cortisol samples and completed psychosocial stress measures and tests of memory and executive function. Results indicated that FHx children, but not ASz children, were characterized by a blunted CAR relative to their TD peers (effect size=-0.73, p=0.01) that was not explained by psychosocial stress exposure or by distress relating to these experiences. Neither FHx nor ASz children were characterized by elevated diurnal cortisol. Among both FHx and ASz children, more pronounced HPA axis function abnormalities (i.e., higher diurnal cortisol levels and greater blunting of the CAR) were associated with poorer performance on tests of verbal memory and executive function. These findings support the notion that at least some HPA axis abnormalities described in psychosis precede illness onset, rather than being a subsequent epiphenomenon. We speculate that the blunted CAR may constitute an early (potentially genetically mediated) marker of psychosis vulnerability, whilst elevated diurnal cortisol levels may emerge only proximally to disease onset.

Project description:IntroductionCortisol levels in adults show a sharp decrease from mid-morning to mid-afternoon. Most toddlers take afternoon naps, which is associated with a less mature diurnal pattern characterized by a midday plateau in cortisol secretion. Napping in preschoolers produces a robust cortisol awakening response (CAR), which may account for such maturational differences. This experimental study extends prior work by examining whether the presence and timing of the nap-dependent CAR influences the diurnal cortisol pattern in toddlers.MethodsToddlers (n = 28; 13 females; 30-36 months) followed a strict biphasic sleep schedule (≥ 12.5h time in bed; ≥ 90 min nap) for ≥ 3 days before each of four randomly ordered, in-home cortisol assessments. For each assessment, saliva samples were obtained at morning awakening, ∼ 09:30, pre-nap, 0, 15, 30, 45, 90, and 135 min post-nap awakening (verified with actigraphy), and ∼ 19:30. On one day, children napped at their scheduled time, and parents collected saliva samples. On another day, children missed their nap, and parents collected saliva samples at matched times. On two other days, children napped 4h (morning) and 7h (afternoon) after awakening in the morning, during which time researchers collected pre- and post-nap saliva samples. Saliva was assayed for cortisol (μg/dl).ResultsThree-level multilevel models were used to estimate the CAR and diurnal cortisol patterns in all four conditions. Compared to the no-nap condition (no observed CAR; b = -0.78, p = 0.65), we found a pronounced cortisol rise following the morning nap (b = 11.00, p < 0.001) and both afternoon naps whether samples were collected by parents (b = 5.19, p < 0.01) or experimenters (b = 4.97, p < 0.01). Napping in the morning resulted in the most robust post-nap cortisol rise (b = 10.21, p < 0.001). Diurnal patterns were analyzed using piecewise growth modeling that estimated linear coefficients for five separate periods throughout the day (corresponding to morning decline, noon decline, post-nap rise, post-nap decline, and evening decline). We observed a significant post-nap rise in cortisol values on the parent-collected afternoon nap (b = 3.41, p < 0.01) and the experimenter-collected morning nap (b = 7.50, p < 0.01) days as compared to the no-nap day (b = -0.17, p = 0.82). No other differences in diurnal profiles were observed between the parent-collected nap and no-nap conditions; however, toddlers had a steeper evening decline on the day of the morning nap compared to the parent-collected afternoon nap (b = 0.30, p < 0.05) and no-nap conditions (b = 0.27, p < 0.05).DiscussionThese well-controlled findings suggest that the presence and timing of daytime naps influence the pattern of diurnal cortisol secretion in toddlers. They also provide support for the hypothesis that napping is the primary state driving the immature midday plateau in cortisol secretion, which becomes more adult-like across childhood. Prior studies of the diurnal cortisol pattern have employed a cubic model, and therefore, have not detected all possible variations due to napping. Our experimental data have important methodological implications for researchers examining associations between the slope of the diurnal cortisol pattern and developmental outcomes, as well as those utilizing afternoon cortisol reactivity protocols in napping children.

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118.1 Effect of the Interaction Between Childhood Abuse and FKBP5 Gene Polymorphism on Cortisol Awakening Response and Diurnal Cortisol Levels in First-Episode Psychosis

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