FKBP5 Methylation Research Articles

Personality vulnerability to depression, resilience, and depressive symptoms: epigenetic markers among perinatal women.

We examined differences in DNA methylation patterns in the NR3C1 and FKBP5 genes in relation to personality vulnerability to depression, resilience, and perinatal depressive symptoms, whilst also considering possible moderating effects of childhood traumatic events. N = 160 perinatal women were assessed at late pregnancy and 1 year postpartum for personality vulnerability to depression, resilience, depressive symptoms, and childhood traumatic events with self-reported questionnaires. NR3C1 and FKBP5 methylation markers were analyzed via sodium bisulfite sequencing. Associations of methylation markers with the above mentioned variables were tested using multivariable regressions. NR3C1 methylation at CpGs 1, 4 and average methylation sites were negatively associated with resilience; NR3C1 methylation at CpG 2 was positively associated with postpartum depressive symptoms; methylation at CpG 4 was positively associated with prenatal depressive symptoms. The interaction between current distress due to interpersonal traumatic events and NR3C1 CpG sites in relation to personality vulnerability was significant on CpG sites 3 and 4, whereas the interaction between current distress due to total traumatic events and NR3C1 in relation to personality vulnerability was significant on CpG site 2. FKBP5 showed no significant associations with the outcomes. This study identified associations between NR3C1 methylation and resilience as well as perinatal depressive symptoms. Interestingly, an interaction between early trauma and personality vulnerability was noted. Our findings on these specific DNA methylation markers may, if replicated and integrated into risk prediction models, contribute to early diagnosis of mothers at risk, targeted health promotion, and early interventions.

FKBP5 methylation in adrenal insufficiency: New insights into assessing the quality of glucocorticoid replacement

FKBP5 methylation in adrenal insufficiency: New insights into assessing the quality of glucocorticoid replacement

Differential impact of prenatal PTSD symptoms and preconception trauma exposure on placental NR3C1 and FKBP5 methylation

Perinatal stress is associated with altered placental methylation, which plays a critical role in fetal development and infant outcomes. This proof-of-concept pilot study investigated the impact of lifetime trauma exposure and perinatal PTSD symptoms on epigenetic regulation of placenta glucocorticoid signaling genes (NR3C1 and FKBP5). Lifetime trauma exposure and PTSD symptoms during pregnancy were assessed in a racially/ethnically diverse sample of pregnant women (N = 198). Participants were categorized into three groups: (1) No Trauma (−T); (2) Trauma, No Symptoms (T − S); and (3) Trauma and Symptoms (T + S). Placental tissue was analyzed via bisulfite pyrosequencing for degree of methylation at the NR3C1 promoter and FKBP5 regulatory regions. Analyses of covariance were used to test group differences in percentages of NR3C1 and FKBP5 methylation overall and at each CpG site. We found a significant impact of PTSD symptoms on placental NR3C1 methylation. Compared to the −T group, the T + S group had greater NR3C1 methylation overall and at CpG6, CpG8, CpG9, and CpG13, but lower methylation at CpG5. The T + S group had significantly higher NR3C1 methylation overall and at CpG8 compared to the T − S group. There were no differences between the T − S group and − T group. Additionally, no group differences emerged for FKBP5 methylation. Pregnant trauma survivors with PTSD symptoms exhibited differential patterns of placental NR3C1 methylation compared to trauma survivors without PTSD symptoms and pregnant women unexposed to trauma. Results highlight the critical importance of interventions to address the mental health of pregnant trauma survivors.

Multimodal Associations of FKBP5 Methylation With Emotion-Regulatory Brain Circuits

BackgroundUnderstanding the biological processes that underlie individual differences in emotion regulation and stress responsivity is a key challenge for translational neuroscience. The gene FKBP5 is a core regulator in molecular stress signaling that is implicated in the development of psychiatric disorders. However, it remains unclear how FKBP5 DNA methylation in peripheral blood is related to individual differences in measures of neural structure and function and their relevance to daily-life stress responsivity. MethodsHere, we characterized multimodal correlates of FKBP5 DNA methylation by combining epigenetic data with neuroimaging and ambulatory assessment in a sample of 395 healthy individuals. ResultsFirst, we showed that FKBP5 demethylation as a psychiatric risk factor was related to an anxiety-associated reduction of gray matter volume in the ventromedial prefrontal cortex, a brain area that is involved in emotion regulation and mental health risk and resilience. This effect of epigenetic upregulation of FKBP5 on neuronal structure is more pronounced where FKBP5 is epigenetically downregulated at baseline. Leveraging 208 functional magnetic resonance imaging scans during a well-established emotion-processing task, we found that FKBP5 DNA methylation in peripheral blood was associated with functional differences in prefrontal-limbic circuits that modulate affective responsivity to daily stressors, which we measured using ecological momentary assessment in daily life. ConclusionsOverall, we demonstrated how FKBP5 contributes to interindividual differences in neural and real-life affect regulation via structural and functional changes in prefrontal-limbic brain circuits.

FKBP5 methylation in adrenal insufficiency: Looking at a new tool for assessing the quality of glucocorticoid replacement?

FKBP5 methylation in adrenal insufficiency: Looking at a new tool for assessing the quality of glucocorticoid replacement?

Sex-dependent association of DNA methylation of HPA axis-related gene FKBP5 with obsessive-compulsive disorder

AimsAlthough hypothalamic-pituitary-adrenal (HPA) axis dysregulation in obsessive-compulsive disorder (OCD) has been reported, epigenetic changes in HPA axis-related genes have not been well studied in OCD. The present study investigated whether the epigenetic regulation of FK506-binding protein 51 gene (FKBP5) intron 7 is associated with OCD status in each sex. In addition, relationships among the DNA methylation levels of FKBP5 intron 7, OCD status and early-life trauma were explored. MethodsA total of 267 patients with OCD and 201 controls aged between 18 and 40 years were recruited. Demographic and clinical assessment, FKBP5 rs1360780 genotyping, and pyrosequencing of FKBP5 intron 7 were conducted. DNA was extracted from peripheral blood leucocytes. First, multivariate analysis of covariance for differential DNA methylation levels between OCD patients and controls was conducted with adjustment for FKBP5 rs1360780 genotype, early-life trauma, depressive symptoms, and age as covariates in each sex. Next, path analysis was conducted to determine the mediation effects of DNA methylation levels of FKBP5 between early-life trauma and OCD status. In addition, sensitivity analyses for medication and lifetime major depression were also performed. ResultsDNA methylation at the FKBP5 intron 7 CpG site was significantly lower in men with OCD, compared to controls (mean difference −1.33%, 95% CI −2.11 to −0.55, p < 0.001). The results remained significant for drug naïve or free subjects (mean difference −1.27%, 95% CI −2.18 to −0.37, p = 0.006, in men) and for subjects without lifetime major depressive disorder (mean difference −1.60%, 95% CI −2.54 to −0.66, p < 0.001, in men). The mediation effect of DNA methylation levels was not significant between early-life trauma and OCD status. ConclusionThese findings suggest that epigenetic factors of HPA axis-related gene FKBP5 may play a role in the pathogenesis of OCD. Further studies are needed to determine how altered DNA methylation of FKBP5 intron 7 and HPA axis function are involved in OCD.

Methylation and expression of glucocorticoid receptor exon-1 variants and FKBP5 in teenage suicide-completers

A dysregulated hypothalamic-pituitary-adrenal (HPA) axis has repeatedly been demonstrated to play a fundamental role in psychiatric disorders and suicide, yet the mechanisms underlying this dysregulation are not clear. Decreased expression of the glucocorticoid receptor (GR) gene, which is also susceptible to epigenetic modulation, is a strong indicator of impaired HPA axis control. In the context of teenage suicide-completers, we have systematically analyzed the 5’UTR of the GR gene to determine the expression levels of all GR exon-1 transcript variants and their epigenetic state. We also measured the expression and the epigenetic state of the FK506-binding protein 51 (FKBP5/FKBP51), an important modulator of GR activity. Furthermore, steady-state DNA methylation levels depend upon the interplay between enzymes that promote DNA methylation and demethylation activities, thus we analyzed DNA methyltransferases (DNMTs), ten-eleven translocation enzymes (TETs), and growth arrest- and DNA-damage-inducible proteins (GADD45). Focusing on both the prefrontal cortex (PFC) and hippocampus, our results show decreased expression in specific GR exon-1 variants and a strong correlation of DNA methylation changes with gene expression in the PFC. FKBP5 expression is also increased in both areas suggesting a decreased GR sensitivity to cortisol binding. We also identified aberrant expression of DNA methylating and demethylating enzymes in both brain regions. These findings enhance our understanding of the complex transcriptional regulation of GR, providing evidence of epigenetically mediated reprogramming of the GR gene, which could lead to possible epigenetic influences that result in lasting modifications underlying an individual’s overall HPA axis response and resilience to stress.

The role of methylation of placental glucocorticoid response gene in the association between pregnancy-related anxiety in the third trimester and birth outcomes

Objective: To investigate the role of methylation of placental glucocorticoid response gene in the association between pregnancy-related anxiety in the third trimester and birth outcomes. Methods: Based on a prospective cohort study, singleton live births and their mothers from the Ma'anshan Birth Cohort Study (MABC) were included as participants in this study. The maternal pregnancy-related anxiety symptoms in the third trimester of pregnancy were evaluated by using the Pregnancy-related Anxiety Questionnaire. The neonatal birth outcomes were collected from medical records. The placental tissues from 300 pregnant women with pregnancy-related anxiety and 300 without pregnancy-related anxiety were collected to detect the methylation of FKBP5, NR3C1 and HSD11B2 genes using the Methyl Target approach. The methylation factors were extracted by exploratory factor analysis. Linear regression or logistic regression models were used to analyze the association between pregnancy-related anxiety in the third trimester, methylation factor scores, and birth outcomes. The mediating role of methylation factors in the association between pregnancy-related anxiety in the third trimester and birth outcomes was analyzed by using the Process procedure. Results: The mean age of 2 833 pregnant women was (26.60±3.60) years old. After adjusting for confounding factors, pregnancy-related anxiety in the third trimester increased the risk of small-for-gestational-age (OR=1.32, 95%CI:1.00-1.74). A total of 5 methylation factors were extracted, and the factor 5 was loaded with FKBP5 CpGs 18-21. Pregnancy-related anxiety in the third trimester was negatively correlated with the factor 5 (β=-0.24,95%CI:-0.44--0.05). The factor 5 was positively correlated with the gestational age (β=0.17, 95%CI:0.06-0.27). In addition, the factor 2 (β=0.02,95%CI:0.00-0.04) and factor 3 (β=0.03,95%CI:0.01-0.05) were positively correlated with 5-min Apgar score after delivery. However, this study did not found the mediating role of the scores of the factor characterized by FKBP5 in the relationship between pregnancy-related anxiety and birth outcomes. Conclusion: Pregnancy-related anxiety in the third trimester may reduce the methylation level of FKBP5 CpGs 18-21 in placental tissues and is associated with the risk of small-for-gestational-age.

Epigenetic differences in stress response gene FKBP5 among children with abusive vs accidental injuries.

Survivors of child abuse experience high rates of adverse physical and mental health outcomes. Epigenetic alterations in the stress response system, the FKBP5 gene specifically, have been implicated as one mechanism that may link abuse to lifelong health issues. Prior studies primarily included older individuals with a remote history of maltreatment; our objective was to test for differential methylation of FKBP5 in children with abusive vs accidental injuries at the time of diagnosis. We conducted a cross-sectional pilot study of acutely injured children <4 years old at two children's hospitals (n = 82). Research personnel collected injury histories, buccal swabs (n = 65), and blood samples (n = 25) to measure DNA methylation. An expert panel classified the injuries as abusive, accidental, or indeterminate. Children with abusive as compared to accidental injuries had lower methylation of the FKBP5 promoter in buccal and blood cells, even after controlling for injury severity, socioeconomic status, and psychosocial risk factors. These findings suggest that epigenetic variation in FKBP5 may occur at the earliest indication of abuse and may be associated with delayed resolution of the HPA axis stress response. Additional testing for epigenetic differences in larger sample sizes is needed to further verify these findings. Children (<4 years old) with abusive compared to accidental injuries showed lower methylation of the FKBP5 promoter in buccal and blood cells at the time of initial diagnosis even after controlling for injury severity, socioeconomic status, and psychosocial risk factors. Early childhood physical abuse may impact the epigenetic regulation of the stress response system, including demethylation within promoters and enhancers of the FKBP5 gene, even at the earliest indication of abuse. The findings are important because unmitigated stress is associated with adverse health outcomes throughout the life-course.

FKBP5 intron 7 methylation is associated with higher anxiety proneness and smaller right thalamus volume in adolescents.

Dysregulation of stress response systems may mediate the detrimental effects of childhood trauma (CT) on mental health. FKBP5 regulates glucocorticoid receptor sensitivity and exerts pleiotropic effects on intracellular signaling, neurobiology and behavior. We investigated whether CT, alone and in combination with rs1360780 genotype, is associated with altered FKBP5 methylation and whether CT-associated methylation profiles are associated with anxiety proneness (AP) and structural brain volumes. Ninety-four adolescents completed the Childhood Trauma Questionnaire, and a composite AP score was generated from the Childhood Anxiety Sensitivity Index and the State-Trait Anxiety Inventory-Trait measure. Mean methylation values for 12 regulatory regions and 25 individual CpG sites were determined using high-accuracy measurement via targeted bisulfite sequencing. FKBP5 rs1360780 genotype and structural MRI data were available for a subset of participants (n = 71 and n = 75, respectively). Regression models revealed an inverse association between methylation of three intron 7 CpG sites (35558438, 35558566 and 35558710) and right thalamus volume. CpG35558438 methylation was positively associated with AP scores. Our data indicate that an intron 7 methylation profile, consistent with lower FKBP5 expression and elevated high sensitivity glucocorticoid receptor levels, is associated with higher AP and smaller right thalamus volume. Research into the mechanisms underlying the intron 7 methylation-thalamus volume relationship, and whether it confers increased risk for long-term psychopathology by altering the regulatory threshold of stress responding, is required.

Potential epigenetic mechanisms in psychotherapy: a pilot study on DNA methylation and mentalization change in borderline personality disorder.

Genetic and early environmental factors are interwoven in the etiology of Borderline Personality Disorder (BPD). Epigenetic mechanisms offer the molecular machinery to adapt to environmental conditions. There are gaps in the knowledge about how epigenetic mechanisms are involved in the effects of early affective environment, development of BPD, and psychotherapy response. We reviewed the available evidence of the effects of psychotherapy on changes in DNA methylation and conducted a pilot study in a sample of 11 female adolescents diagnosed with BPD, exploring for changes in peripheral DNA methylation of FKBP5 gene, which encodes for a stress response protein, in relation to psychotherapy, on symptomatology and underlying psychological processes. For this purpose, measures of early trauma, borderline and depressive symptoms, psychotherapy outcome, mentalization, and emotional regulation were studied. A reduction in the average FKBP5 methylation levels was observed over time. Additionally, the decrease in FKBP5 methylation observed occurred only in those individuals who had early trauma and responded to psychotherapy. The results suggest an effect of psychotherapy on epigenetic mechanisms associated with the stress response. The finding that epigenetic changes were only observed in patients with early trauma suggests a specific molecular mechanism of recovery. The results should be taken with caution given the small sample size. Also, further research is needed to adjust for confounding factors and include endocrinological markers and therapeutic process variables.

A pilot investigation of genetic and epigenetic variation of FKBP5 and response to exercise intervention in African women with obesity

We investigated gluteal (GSAT) and abdominal subcutaneous adipose tissue (ASAT) DNA methylation of FKBP5 in response to a 12-week intervention in African women with obesity, as well as the effect of the rs1360780 single nucleotide polymorphism (SNP) on FKBP5 methylation, gene expression and post-exercise training adaptations in obesity and metabolic related parameters. Exercise (n = 19) participants underwent 12-weeks of supervised aerobic and resistance training while controls (n = 12) continued their usual behaviours. FKBP5 methylation was measured in GSAT and ASAT using pyrosequencing. SNP and gene expression analyses were conducted using quantitative real-time PCR. Exercise training induced FKBP5 hypermethylation at two CpG dinucleotides within intron 7. When stratified based on the rs1360780 SNP, participants with the CT genotype displayed FKBP5 hypermethylation in GSAT (p < 0.05), and ASAT displayed in both CC and CT carriers. CC allele carriers displayed improved cardiorespiratory fitness, insulin sensitivity, gynoid fat mass, and waist circumference (p < 0.05) in response to exercise training, and these parameters were attenuated in women with the CT genotype. These findings provide a basis for future studies in larger cohorts, which should assess whether FKBP5 methylation and/or genetic variants such as the rs1360780 SNP could have a significant impact on responsiveness to exercise interventions.

FKBP5 methylation in adrenal insufficiency: looking at a new tool for assessing the quality of glucocorticoid replacement?

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

P268. FKBP5 Methylation, Psychiatric Disorders and Stress: A Systematic Review and Synthesis

FKBP5 methylation levels are among the most studied epigenetic modifications related to psychiatric disorder vulnerability, however there are contradictory findings. We aimed to investigate the role of FKBP5 methylation in psychiatric disorders, in addition to its association with stress exposure (either life adversities, traumatic events or acute stress).

Associations between FKBP5 methylation, childhood trauma, anxiety proneness and structural brain volumes – a neuroimaging epigenetics study in South African adolescents

Associations between FKBP5 methylation, childhood trauma, anxiety proneness and structural brain volumes – a neuroimaging epigenetics study in South African adolescents

Associations of FKBP5 polymorphisms and methylation and parenting style with depressive symptoms among Chinese adolescents

BackgroundGenetic factors may interplay with environmental stressors to contribute to risks of depressive symptoms. This study aimed to investigate the association of FKBP5 polymorphisms and DNA methylation with depressive symptoms among Chinese adolescents, considering the role of parenting style.MethodsThis study used a nested case-control study design based on a cohort study, and the case (n = 120) and control groups (n = 118) were matched with age. Depressive symptoms, parenting style, and other demographics were measured. Fourteen potential polymorphisms and one promoter region in the FKBP5 gene were selected for genotyping and methylation analysis.ResultsIn the adjusted models, a significant association between FKBP5 rs7757037 and depressive symptoms was found in the codominant model (AG vs. GG; adjusted odds ratio [AOR] = 2.56, 95% CI = 1.13–5.78) and dominant model (AA+AG vs. GG; AOR = 2.38, 95% CI = 1.11–5.120); rs2817032 and rs2817035 polymorphisms were associated with depressive symptoms in the codominant model and dominant model. Significant interactions between rs7757037 and the father’s parenting style were found in the codominant model (P = 0.043) and dominant model (P = 0.043), but the gene-environment interactions were not significant after correcting for multiple testing. Moreover, the significant main effects of FKBP5 methylation status on depressive symptoms were not observed, and there was no significant interaction between FKBP5 methylation status and parenting style on depressive symptoms.ConclusionsFurther studies are required to confirm the effect of FKBP5 polymorphisms and methylation as well as their interactions with parenting styles in larger samples.

Gender-specific associations of pregnancy-related anxiety with placental epigenetic patterning of glucocorticoid response genes and preschooler\u2019s emotional symptoms and hyperactivity

BackgroudWe have recently reported that maternal prenatal pregnancy-related anxiety predicts preschoolers’ emotional and behavioral development in a gender-dependent manner. This study aims to test for this gender-specific effect in a different cohort and investigate whether the gender difference was specific to placental methylation of genes regulating glucocorticoids.MethodsA total of 2405 mother–child pairs from the Ma’anshan Birth Cohort Study were included in present study. The maternal pregnancy-related anxiety symptoms were evaluated with the Pregnancy-Related Anxiety Questionnaire in the third trimester of pregnancy. Child neurobehavior was assessed with the Strengths and Difficulties Questionnaire at 4 years old. Placental methylation of FKBP5, NR3C1 and HSD11B2 genes was quantified using the MethylTarget approach in 439 pregnant women. After exploratory factor analysis, the associations between methylation factor scores and pregnancy-related anxiety and child neurobehavior were examined using logistic regression analysis.ResultsAfter controlling for confounding factors, pregnancy-related anxiety in the third trimester of pregnancy increased the risk of hyperactivity only in boys and emotional symptoms only in girls. Decreased scores of the factor characterized by FKBP5 methylation were associated with maternal pregnancy-related anxiety only in boys. Furthermore, increased scores of the factors characterized by NR3C1 and HSD11B2 methylation were associated with hyperactivity (NR3C1: adjusted OR = 1.80, 95%CI = 1.15–2.83) and emotional symptoms (HSD11B2: adjusted OR = 0.53, 95%CI = 0.29–0.97; NR3C1: adjusted OR = 1.64, 95%CI = 1.03–2.59) only in boys. However, the scores of the factor characterized by FKBP5, NR3C1 and HSD11B2 did not mediate the relationship between maternal pregnancy-related anxiety and preschoolers’ emotional symptoms and hyperactivity.ConclusionsOur results suggested that pregnancy-related anxiety in the third trimester of pregnancy predicted preschoolers’ emotional symptoms and hyperactivity in a gender-dependent manner. Although we did not find the mediation role of the placental methylation of genes regulating glucocorticoids, we found it was associated with both maternal pregnancy-related anxiety and preschoolers’ emotional symptoms and hyperactivity in a gender-dependent manner.

Methylation of FKBP5 is associated with accelerated DNA methylation ageing and cardiometabolic risk: replication in young-adult and middle-aged Black Americans

ABSTRACT Methylation of FKBP5 is involved in the regulation of the stress response and is influenced by early stress exposure. Two CpG sites, cg20813374 and cg00130530, have been identified as potential reporters of early stress. We examined whether FKBP5 methylation was associated with accelerated DNA methylation ageing and indirectly predicted poorer cardiovascular health among both young adult and middle-aged Black Americans. Four hundred and forty-nine young adults, with a mean age of 28.67 and N = 469 middle-age parents and their current partners with a mean age of 57.21, provided self-reports, biometric assessments, and blood draws. Methylation values were obtained using the Illumina Epic Array. Cardiometabolic risk was calculated by summing the standardized log-transformed scores for the body mass index, mean arterial blood pressure, and HbA1c. We also used a more standard index of risk, the Framingham 10-year cardiometabolic risk index, as an alternative measure of cardiometabolic risk. To measure accelerated ageing, four widely used indices of accelerated, DNA methylation-based ageing were used controlling sex, age, other variation in FKBP5, and cell-type. Exposure to community danger was associated with demethylation of FKBP5. FKBP5 methylation was significantly associated with accelerated ageing for both young-adult and middle-aged samples, with significant indirect effects from FKBP5 methylation to cardiometabolic risk through accelerated ageing for both. Early exposure to danger may influence FKBP5 methylation. In turn, FKBP5 methylation may help explain intrinsic accelerated ageing and elevated cardiometabolic risk in adulthood for Black Americans.

Childhood trauma, the stress response and metabolic syndrome: A focus on DNA methylation.

Childhood trauma (CT) is well established as a potent risk factor for the development of mental disorders. However, the potential of adverse early experiences to exert chronic and profound effects on physical health, including aberrant metabolic phenotypes, has only been more recently explored. Among these consequences is metabolic syndrome (MetS), which is characterised by at least three of five related cardiometabolic traits: hypertension, insulin resistance/hyperglycaemia, raised triglycerides, low high-density lipoprotein and central obesity. The deleterious effects of CT on health outcomes may be partially attributable to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which coordinates the response to stress, and the consequent fostering of a pro-inflammatory environment. Epigenetic tags, such as DNA methylation, which are sensitive to environmental influences provide a means whereby the effects of CT can be biologically embedded and persist into adulthood to affect health and well-being. The methylome regulates the transcription of genes involved in the stress response, metabolism and inflammation. This narrative review examines the evidence for DNA methylation in CT and MetS in order to identify shared neuroendocrine and immune correlates that may mediate the increased risk of MetS following CT exposure. Our review specifically highlights differential methylation of FKBP5, the gene that encodes FK506-binding protein 51 and has pleiotropic effects on stress responding, inflammation and energy metabolism, as a central candidate to understand the molecular aetiology underlying CT-associated MetS risk.

The FKBP5 genotype and childhood trauma effects on FKBP5 DNA methylation in patients with psychosis, their unaffected siblings, and healthy controls

Hypothalamic–pituitary–adrenal (HPA) axis activity mediates the relationship between childhood trauma (CT) and psychosis. The FKBP5 gene, one of the key regulators of HPA axis activity after stress exposure, has been found associated with psychosis. Allele-specific and CT related FKBP5 demethylation in intron 7 was revealed in different psychiatric disorders. However, no studies have investigated FKBP5 methylation in subjects with different genetic liability for psychosis.A total of 144 participants were included in the study: 48 patients with psychotic disorders, 50 unaffected siblings, and 46 healthy controls. CT was assessed by Childhood Trauma Questionnaire. The FKBP5 rs1360780 was genotyped and FKBP5 methylation analyses were performed using bisulfite conversion followed by Sanger sequencing at three CpG sites in intron 7. Mixed linear model was used to assess group differences depending on rs1360780 T allele and CT.Results showed a significant T allele-dependent decrease of FKBP5 methylation in patients compared to unaffected siblings and controls. Effect of interaction between T allele and CT exposure on FKBP5 demethylation was found in controls. No effect of both risk factors (T allele and CT) on FKBP5 methylation level was found in unaffected siblings.We confirmed previous evidence of the association between the FKBP5 rs1360780 T allele, CT, and decreased FKBP5 methylation in intron 7. Allele-specific FKBP5 demethylation found in patients could shed a light on altered HPA axis activity in a subgroup of patients related to stress-induced psychosis. FKBP5 methylation and potential protective mechanisms in unaffected siblings after trauma exposure require further investigation.