Hypothalamic-pituitary-adrenal Axis Genes Research Articles

Gene‒environment interaction effect of hypothalamic‒pituitary‒adrenal axis gene polymorphisms and job stress on the risk of sleep disturbances.

Studies have shown that chronic exposure to job stress may increase the risk of sleep disturbances and that hypothalamic‒pituitary‒adrenal (HPA) axis gene polymorphisms may play an important role in the psychopathologic mechanisms of sleep disturbances. However, the interactions among job stress, gene polymorphisms and sleep disturbances have not been examined from the perspective of the HPA axis. This study aimed to know whether job stress is a risk factor for sleep disturbances and to further explore the effect of the HPA axis gene × job stress interaction on sleep disturbances among railway workers. In this cross-sectional study, 671 participants (363 males and 308 females) from the China Railway Fuzhou Branch were included. Sleep disturbances were evaluated with the Pittsburgh Sleep Quality Index (PSQI), and job stress was measured with the Effort-Reward Imbalance scale (ERI). Generalized multivariate dimensionality reduction (GMDR) models were used to assess gene‒environment interactions. We found a significant positive correlation between job stress and sleep disturbances (P < 0.01). The FKBP5 rs1360780-T and rs4713916-A alleles and the CRHR1 rs110402-G allele were associated with increased sleep disturbance risk, with adjusted ORs (95% CIs) of 1.75 [1.38-2.22], 1.68 [1.30-2.18] and 1.43 [1.09-1.87], respectively. However, the FKBP5 rs9470080-T allele was a protective factor against sleep disturbances, with an OR (95% CI) of 0.65 [0.51-0.83]. GMDR analysis indicated that under job stress, individuals with the FKBP5 rs1368780-CT, rs4713916-GG, and rs9470080-CT genotypes and the CRHR1 rs110402-AA genotype had the greatest risk of sleep disturbances. Individuals carrying risk alleles who experience job stress may be at increased risk of sleep disturbances. These findings may provide new insights into stress-related sleep disturbances in occupational populations.

Epigenetic associations in HPA axis genes related to bronchopulmonary dysplasia and antenatal steroids.

Bronchopulmonary dysplasia (BPD), a common morbidity among very preterm infants, is associated with chronic disease and neurodevelopmental impairments. A hypothesized mechanism for these outcomes lies in altered glucocorticoid (GC) activity. We hypothesized that BPD and its treatments may result in epigenetic differences in the hypothalamic-pituitary-adrenal (HPA) axis, which is modulated by GC, and could be ascertained using an established GC risk score and DNA methylation (DNAm) of HPA axis genes. DNAm was quantified from buccal tissue (ECHO-NOVI) and from neonatal blood spots (ELGAN ECHO) via the EPIC microarray. Prenatal maternal characteristics, pregnancy complication, and neonatal medical complication data were collected from medical record review and maternal interviews. The GC score was not associated with steroid exposure or BPD. However, six HPA genes involved in stress response regulation demonstrated differential methylation with antenatal steroid exposure; two CpGs within FKBP5 and POMC were differentially methylated with BPD severity. These findings were sex-specific in both cohorts; males had greater magnitude of differential methylation within these genes. These findings suggest that BPD severity and antenatal steroids are associated with DNAm at some HPA genes in very preterm infants and the effects appear to be sex-, tissue-, and age-specific. This study addresses bronchopulmonary dysplasia (BPD), an important health outcome among preterm neonates, and interrogates a commonly studied pathway, the hypothalamic-pituitary-adrenal (HPA) axis. The combination of BPD, the HPA axis, and epigenetic markers has not been previously reported. In this study, we found that BPD itself was not associated with epigenetic responses in the HPA axis in infants born very preterm; however, antenatal treatment with steroids was associated with epigenetic responses.

The impact of parental and developmental stress on DNA methylation in the avian hypothalamic-pituitary-adrenal axis.

The hypothalamic-pituitary-adrenal (HPA) axis coordinates an organism's response to environmental stress. The responsiveness and sensitivity of an offspring's stress response may be shaped not only by stressors encountered in their early post-natal environment but also by stressors in their parent's environment. Yet, few studies have considered how stressors encountered in both of these early life environments may function together to impact the developing HPA axis. Here, we manipulated stressors in the parental and post-natal environments in a population of house sparrows (Passer domesticus) to assess their impact on changes in DNA methylation (and corresponding gene expression) in a suite of genes within the HPA axis. We found that nestlings that experienced early life stress across both life-history periods had higher DNA methylation in a critical HPA axis gene, the glucocorticoid receptor (NR3C1). In addition, we found that the life-history stage when stress was encountered impacted some genes (HSD11B1, NR3C1 and NR3C2) differently. We also found evidence for the mitigation of parental stress by post-natal stress (in HSD11B1 and NR3C2). Finally, by assessing DNA methylation in both the brain and blood, we were able to evaluate cross-tissue patterns. While some differentially methylated regions were tissue-specific, we found cross-tissue changes in NR3C2 and NR3C1, suggesting that blood is a suitable tissue for assessing DNA methylation as a biomarker of early life stress. Our results provide a crucial first step in understanding the mechanisms by which early life stress in different life-history periods contributes to changes in the epigenome of the HPA axis.

CpG Methylation Levels in HPA Axis Genes Predict Chronic Pain Outcomes Following Trauma Exposure

Chronic post-traumatic musculoskeletal pain (CPTP) is a common outcome of traumatic stress exposure. Biological factors that influence the development of CPTP are poorly understood, though current evidence indicates that the hypothalamic-pituitary-adrenal (HPA) axis plays a critical role in its development. Little is known about molecular mechanisms underlying this association, including epigenetic mechanisms. Here, we assessed whether peritraumatic DNA methylation levels at 248 5′—C—phosphate—G—3′ (CpG) sites in HPA axis genes (FKBP5, NR3C1, CRH, CRHR1, CRHR2, CRHBP, POMC) predict CPTP and whether identified CPTP-associated methylation levels influence expression of those genes. Using participant samples and data collected from trauma survivors enrolled into longitudinal cohort studies (n = 290), we used linear mixed modeling to assess the relationship between peritraumatic blood-based CpG methylation levels and CPTP. A total of 66 (27%) of the 248 CpG sites assessed in these models statistically significantly predicted CPTP, with the three most significantly associated CpG sites originating from the POMC gene region (ie, cg22900229 [β = .124, P < .001], cg16302441 [β = .443, P < .001], cg01926269 [β = .130, P < .001]). Among the genes analyzed, both POMC (z = 2.36, P = .018) and CRHBP (z = 4.89, P < .001) were enriched in CpG sites significantly associated with CPTP. Further, POMC expression was inversely correlated with methylation levels in a CPTP-dependent manner (6-months NRS<4: r = -.59, P < .001; 6-months NRS ≥ 4: r = -.18, P = .2312). Our results suggest that methylation of HPA axis genes including POMC and CRHBP predict risk for and may contribute to vulnerability to CPTP. PerspectivePeritraumatic blood levels of CpG methylation sites in HPA axis genes, particularly CpG sites in the POMC gene, predict CPTP development. This data substantially advances our understanding of epigenetic predictors and potential mediators of CPTP, a highly common, morbid, and hard-to-treat form of chronic pain.

High-Fat Diet Exacerbates Stress Responsivity in Juvenile Traumatic Brain Injury.

Abstract Traumatic brain injury (TBI) is one of the leading causes of death for children in the United States. Juveniles are more likely to sustain TBIs than most other age groups, and TBI has been shown to result in increased anxiety and stress behaviors. In addition, the hypothalamic-pituitary-adrenal (HPA) axis has previously been shown to become dysregulated after a TBI. Further, many children consume diets high in saturated fats and refined sugars, which are also connected to alterations in HPA axis function and behavior disorders. The goal of the current study was to identify a potential relationship between high-fat diet (HFD) consumption and TBI on HPA axis function in juvenile rats. In the present study, male juvenile Long-Evans rats were fed either a combination of an HFD with a high-fructose corn syrup solution or a standard chow diet. On post-natal Day 30, subjects sustained either a sham TBI or a TBI via the Closed-Head Injury Model of Engineered Rotational Acceleration (CHIMERA). Subjects participated in a trial of the open field test (OFT) following injury. In addition, some rats performed in an acute restraint stress test. All subjects were euthanized 7 days post-injury. Brain and blood plasma samples were collected for use in real-time polymerase chain reaction (RT-PCR), immunohistochemistry, and corticosterone or adrenocorticotropic hormone (ACTH) assays. Immediately following TBI, injured juveniles had increased time to righting and walking, with HFD-fed TBI rats having increased time to walking over Chow-fed TBI rats. HFD-fed TBI rats had a reduced number of entries to the center of the OFT, in addition to reduced time spent in the center compared with HFD Sham controls and Chow TBI rats. During the acute restraint stress test, HFD-fed TBI rats had elevated pre-stress ACTH and corticosterone and post-stress ACTH levels. Pre-stress ACTH levels were significantly elevated in HFD TBI compared with Chow TBI. Further, pre-stress ACTH:corticosterone ratios were elevated in HFD TBI compared with Chow TBI. cFos immunoreactivity in the paraventricular nucleus (PVN) of the hypothalamus following the acute restraint stress test was elevated in HFD-fed TBI rats. HFD TBI rats had greater activation of cFos in the PVN compared with Chow TBI. In addition, RT-PCR showed significantly reduced expression of relevant HPA axis genes, NR3C1, NR3C2, and CRHR2, in the hypothalamus of TBI subjects compared with Sham subjects. Further, AVP and CRHR2 in the hypothalamus were significantly reduced in HFD TBI compared with Chow TBI. These results offer evidence that TBI paired with high-fat diet consumption can cause HPA axis dysfunction, resulting in more anxiety-like behaviors.

Pilot study suggests DNA methylation of the glucocorticoid receptor gene (NR3C1) is associated with MDMA-assisted therapy treatment response for severe PTSD.

Previous research has demonstrated that epigenetic changes in specific hypothalamic-pituitary-adrenal (HPA) genes may predict successful psychotherapy in post-traumatic stress disorder (PTSD). A recent Phase 3 clinical trial reported high efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for treating patients with severe PTSD compared to a therapy with placebo group (NCT03537014). This raises important questions regarding potential mechanisms of MDMA-assisted therapy. In the present study, we examined epigenetic changes in three key HPA axis genes before and after MDMA and placebo with therapy. As a pilot sub-study to the parent clinical trial, we assessed potential HPA epigenetic predictors for treatment response with genomic DNA derived from saliva (MDMA, n = 16; placebo, n = 7). Methylation levels at all 259 CpG sites annotated to three HPA genes (CRHR1, FKBP5, and NR3C1) were assessed in relation to treatment response as measured by the Clinician-Administered PTSD Scale (CAPS-5; Total Severity Score). Second, group (MDMA vs. placebo) differences in methylation change were assessed for sites that predicted treatment response. Methylation change across groups significantly predicted symptom reduction on 37 of 259 CpG sites tested, with two sites surviving false discovery rate (FDR) correction. Further, the MDMA-treatment group showed more methylation change compared to placebo on one site of the NR3C1 gene. The findings of this study suggest that therapy-related PTSD symptom improvements may be related to DNA methylation changes in HPA genes and such changes may be greater in those receiving MDMA-assisted therapy. These findings can be used to generate hypothesis driven analyses for future studies with larger cohorts.

DNA Methylation Levels in Hypothalamic-pituitary-adrenal Axis Genes Predict Chronic Pain Outcomes Following Trauma Exposure

Chronic posttraumatic musculoskeletal pain (CPTP) is a common outcome of traumatic stress exposure. Biological factors that predict risk for and mediate the development of CPTP are poorly understood. Current evidence indicates that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis plays a substantial role in the development of CPTP. However, little is known about the molecular mechanisms that drive the association between HPA axis genes and CPTP, such as epigenetic regulatory mechanisms. In the current study, we assessed whether peritraumatic DNA methylation levels at 248 CG dinucleotides (CpG sites) in seven HPA axis genes (FKBP5, NR3C1, CRH, CRHR1, CRHR2, CRHBP, POMC) predicted CPTP and whether identified CPTP-associated methylation levels influenced mRNA expression of those genes. Using participant samples and data collected from multi-ethnic women and men enrolled into four longitudinal cohort studies of trauma survivors (n=290), we used repeated measures mixed modeling to assess the relationship between peritraumatic CpG levels and CPTP (assessed via 0-10 NRS six weeks, six months, and one year following trauma exposure). Sixty-six (27%) of the CpG sites assessed in these models were statistically significantly associated with CPTP. Both POMC (z = 2.36, p = 0.018) and CRHBP (z = 4.89, p < 0.001) were enriched in CpG sites significantly associated with CPTP. The three CpG sites that were most statistically significantly associated with CPTP originated from the POMC gene region (i.e. cg22900229 [β=0.124, p<0.001,], cg16302441 [β=0.443, p<0.001], cg01926269[β=0.130, p<0.001]). Further, mRNA expression in the POMC gene was inversely correlated with CpG methylation levels in a CPTP dependent manner (six-month NRS<4: r=-0.590959, p<0.001; six-month NRS≥4: r=-0.1780231, p=0.2312). Altogether our results suggest that CpG methylation of HPA axis genes such as POMC and CRHBP might contribute to vulnerability to CPTP. Further studies are needed to validate these findings. Grant support from National Institute of General Medical Sciences 1T32GM135128 R01NS118563 Rita Allen Award in Pain K01AR071504.

Effects of Galp and alarin peptides on HPA axis gene expression and adrenal function: In vivo experiments.

Many experimental data indicate interactions between peptides involved in the control of food intake, energy homeostasis and adrenocortical hormone release. Glucocorticoids stimulate or inhibit the secretion of orexigenic and anorexigenic peptides, which in turn are involved in the regulation of adrenal growth, structure and function. Galanin-like peptide (Galp) and alarin (Ala) are involved in the regulation of food intake. Galp and Ala mRNAs have already been shown to be present in the arcuate nucleus (ARC) of the hypothalamus in both rats and mice. To investigate the expression of Ala, Galp and their receptors in the hypothalamus and pituitary and adrenal glands of the rat hypothalamic-pituitary-adrenal (HPA) axis after intraperitoneal administration of peptides in vivo. Experimental in vivo models were used: acute and long-term exposure to peptides. The expression of Galp, Ala, their receptors, and steroidogenesis enzymes was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). Statistically significant expression changes were found in the hypothalamus and pituitary after 1-hour exposure to the peptides, such as a decrease in corticotropin-releasing hormone (CRH) expression after Ala, Galp and adrenocorticotropic hormone (ACTH) administration, and a decrease in the expression of receptors for galanin (Gal) (Galr1 and Galr2). In the pituitary, there was a statistically significant increase in the expression of Ala, Galr1, Galr2, and Galr3 receptors 1 h after Galp administration. In the adrenal glands, only a statistically significant decrease in Galr2 expression was observed after 1 h of Ala 0.5 administration. The mRNA expression of steroidogenesis enzymes also changed: for example, the expression of cholesterol desmolase increased 24 h after Ala peptide administration. The results indicate that the peptides tested under in vivo conditions can alter the expression of the peptides tested, as well as of Galp, Ala and Gal receptors and steroidogenesis enzymes - Cyp11a1 (cholesterol desmolase), Cyp11b1 (11β-hydroxylase) and Cyp11b2 (aldosterone synthase).

DNA methylation in blood cells is associated with cortisol levels in offspring of mothers who had prenatal post-traumatic stress disorder.

Maternal stress during pregnancy is associated with differential DNA methylation in offspring and disrupted cortisol secretion. This study aimed to determine methylation signatures of cortisol levels in children, and whether associations differ based on maternal post-traumatic stress disorder (PTSD). Blood epigenome-wide methylation and fasting cortisol levels were measured in 118 offspring of mothers recruited from the Kosovo Rehabilitation Centre for Torture Victims. Mothers underwent clinically administered assessment for PTSD using Diagnostic and Statistical Manual of Mental Disorders. Correlations between offspring methylation and cortisol levels were examined using epigenome-wide analysis, adjusting for covariates. Subsequent analysis focussed on a priori selected genes involved in the hypothalamic-pituitary-adrenal (HPA) axis stress signalling. Methylation at four sites were correlated with cortisol levels (cg15321696, r=-0.33, cg18105800, r=+0.33, cg00986889, r=-0.25, and cg15920527, r=-0.27). In adjusted multivariable regression, when stratifying based on prenatal PTSD status, significant associations were only found for children born to mothers with prenatal PTSD (p<0.001). Several sites within HPA axis genes were also associated with cortisol levels in the maternal PTSD group specifically. There is evidence that methylation is associated with cortisol levels, particularly in offspring born to mothers with prenatal PTSD. However, larger studies need to be carried out to independently validate these findings.

A variant in the 3'-untranslated region of the MC2R gene decreases the risk of schizophrenia in a female Han Chinese population.

ObjectiveSchizophrenia is a complex mental disorder with high heritability. The hypothalamic–pituitary–adrenal (HPA) axis, which is the stress system of the neuroendocrine system, is considered to impact psychotic disorders. We hypothesized that polymorphisms of HPA axis genes might be involved in the development of schizophrenia.MethodsA case–control study comprising 234 patients with schizophrenia and 399 matched healthy controls was conducted to investigate the association between the human melanocortin 2 receptor (MC2R) gene and schizophrenia risk. Seven tag single nucleotide polymorphisms (SNPs) (rs16941303, rs16941314, rs2186944, rs28926188, rs7230126, rs948322, and rs948331) of MC2R were genotyped by direct sequencing.ResultsNo significant associations were observed between any of the alleles, genotypes, or haplotypes examined within the MC2R gene and the risk of schizophrenia in the total group or in subgroups stratified by smoking or alcoholism. However, a subgroup analysis stratified by sex revealed that under the additive model, the C allele of the MC2R rs948331 SNP significantly decreased the risk of schizophrenia in females (odds ratio=0.18).ConclusionThe C allele of the MC2R rs948331 locus may be a protective factor, reducing the risk of schizophrenia in the female Han Chinese population.

The ADCYAP1R1 Gene Is Correlated With Posttraumatic Stress Disorder Symptoms Through Diverse Epistases in a Traumatized Chinese Population.

The adenylate cyclase activating polypeptide 1 (pituitary) receptor (ADCYAP1R1) gene is associated with the hypothalamic-pituitary-adrenal (HPA) axis, which controls stress responses. The single-nucleotide polymorphism of ADCYAP1R1, rs2267735, has been investigated in many studies to test its association with posttraumatic stress disorder (PTSD), but the results have not been consistent. It is worth systematically exploring the role of rs2267735 in PTSD development. In this study, we analyzed rs2267735 in 1,132 trauma-exposed Chinese individuals (772 females and 360 males). We utilized the PTSD checklist for DSM-5 (PCL-5) to measure the PTSD symptoms. Then, we analyzed the main, G × E (rs2267735 × trauma exposure), and G × G (with other HPA axis gene polymorphisms) effects of rs2267735 on PTSD severity (total symptoms). There were no significant main or G × E effects (P > 0.05). The G × G ADCYAP1R1-FKBP5 interaction (rs2267735 × rs1360780) was associated with PTSD severity (beta = −1.31 and P = 0.049) based on all subjects, and the G × G ADCYAP1R1-CRHR1 interaction (rs2267735 × rs242924) was correlated with PTSD severity in men (beta = −4.72 and P = 0.023). Our study indicated that the ADCYAP1R1 polymorphism rs2267735 may affect PTSD development through diverse gene-gene interactions.

Harsh Parenting Predicts Novel HPA Receptor Gene Methylation and NR3C1 Methylation Predicts Cortisol Daily Slope in Middle Childhood.

Adverse experiences in childhood are associated with altered hypothalamic-pituitary-adrenal (HPA) axis function and negative health outcomes throughout life. It is now commonly accepted that abuse and neglect can alter epigenetic regulation of HPA genes. Accumulated evidence suggests harsh parenting practices such as spanking are also strong predictors of negative health outcomes. We predicted harsh parenting at 2.5years old would predict HPA gene DNA methylation similarly to abuse and neglect, and cortisol output at 8.5years old. Saliva samples were collected three times a day across 3 days to estimate cortisol diurnal slopes. Methylation was quantified using the Illumina Infinium MethylationEPIC array BeadChip (850K) with DNA collected from buccal cells. We used principal components analysis to compute a summary statistic for CpG sites across candidate genes. The first and second components were used as outcome variables in mixed linear regression analyses with harsh parenting as a predictor variable. We found harsh parenting significantly predicted methylation of several HPA axis genes, including novel gene associations with AVPRB1, CRHR1, CRHR2, and MC2R (FDR corrected p < 0.05). Further, we found NR3C1 methylation predicted a steeper diurnal cortisol slope. Our results extend the current literature by demonstrating harsh parenting may influence DNA methylation similarly to more extreme early life experiences such as abuse and neglect. Further, we show NR3C1 methylation is associated with diurnal HPA function. Elucidating the molecular consequences of harsh parenting on health can inform best parenting practices and provide potential treatment targets for common complex disorders.

Correlation between hypothalamic-pituitary-adrenal axis gene polymorphisms and posttraumatic stress disorder symptoms

BackgroundThe hypothalamic-pituitary-adrenal (HPA) axis is the main neuroendocrine system that controls stress responses, including fear learning. To further understand the correlation between the HPA axis and stress- and fear-related symptoms in humans, the current study investigated the relationship between HPA axis gene polymorphisms and a stress- and fear-related disorder, posttraumatic stress disorder (PTSD). This is the first study that systematically investigates the correlations between HPA axis genes and distinct PTSD symptom clusters. MethodsParticipants included 1132 Chinese earthquake survivors (772 women and 360 men). PTSD symptoms were measured by the PTSD Checklist for DSM-5 (PCL-5), and the severity (total symptoms) and symptom clusters were calculated according to the hybrid seven-factor model of DSM-5 PTSD. We genotyped eight single nucleotide polymorphisms (SNPs) of three HPA axis genes, including FKBP5, CRHR1 and CRHR2. ResultsThe main effects of the CRHR2 SNP rs2267715 were associated with PTSD severity (P = 0.0035) and all PTSD symptom clusters except dysphoric arousal (P ranging from 0.0011 to 0.048). In women, a gene–environment interaction (G × E) effect of FKBP5 (rs3800373 × trauma exposure) was correlated with PTSD severity (P = 0.038), externalizing behaviors, anxious arousal and dysphoric arousal symptoms (P ranging from 0.014 to 0.028); the G × E effect of CRHR1 (rs4458044 × trauma exposure) was associated with anxious arousal symptoms (P = 0.016). In men, a gene–gene interaction (G × G) effect of FKBP5–CRHR1 (rs9470080 × rs4458044) was associated with PTSD severity (P = 0.0091), intrusion, negative affect, externalizing behaviors and anxious arousal (P ranging 0.012–0.049). ConclusionOur results systematically revealed that the main effects and G × E and G × G effects of some genetic polymorphisms of HPA axis genes are involved in the severity and distinct symptom clusters of PTSD.

Association of childhood trauma and genetic variability of CRH-BP and FKBP5 genes with suicidal behavior in bipolar patients

BackgroundAround 8% of bipolar disorder (BD) patients die by suicide every year, accounting for the highest rate among the psychiatric population. Suicidal behavior (SB) is mediated by an intertwining system of extrinsic and intrinsic factors. Childhood trauma (CT) and gene variants of the stress-management hypothalamic-pituitary-adrenal (HPA) axis have been reported as risk factors for SB. The aim of this study was to elucidate the association of CT and HPA axis genetic variants with SB. Methods135 BD patients were recruited for clinical assessment of CT and SB by means of the Childhood Trauma Questionnaire (CTQ) and the Columbia Suicide Severity Rating Scale (C-SSRS), respectively. A total of 28 single nucleotide polymorphisms (SNPs) from 8 HPA axis genes (POMC, NR3C2, CRH-BP, NR3C1, FKBP5, CRHR2, CRHR1, and MC2R) were genotyped. ResultsThe analyses showed an association of total CTQ score (p = 0.003), emotional abuse (p = 0.001), sexual abuse (p = 0.005) and emotional neglect (p = 0.005) with SB. CRH-BP rs7728378-C carriers (p = 0.004; OR = 3.05), FKBP5 rs3777747-AA (p = 0.039; OR = 0.34) and FKBP5 rs2766533-GG genotypes (p = 0.001; OR = 2.93) were associated with SB although only rs2766533 survived multiple test correction. No gene-environment interaction was found. LimitationsThe relatively small sample size limits the statistical power to detect smaller environmental and genetic effects. Cross-sectional data collection in psychometric assessments can yield biased data. ConclusionsThe present study characterizes novel SB risk factors and replicates previous findings in BD patients. CT and variability in CRH-BP and FKBP5 genes should be further studied for a better understanding of SB and ultimately help in suicide prevention.

HPA-axis genes as potential risk variants for neurocognitive decline in trauma-exposed, HIV-positive females.

PurposePrevious studies have independently provided evidence for the effects of HIV infection, hypothalamic–pituitary–adrenal (HPA) axis dysfunction and early life trauma on neurocognitive impairment (NCI). This study examined the interaction between single-nucleotide polymorphisms (SNPs) of two HPA axis genes, corticotrophin-releasing hormone receptor 1 (CRHR1; rs110402, rs242924, rs7209436, and rs4792888) and corticotrophin-releasing hormone-binding protein (CRHBP; rs32897, rs10062367, and rs1053989), childhood trauma, and HIV-associated NCI.Patients and methodsThe sample comprised 128 HIV-positive Xhosa females of whom 88 (69%) had a history of childhood trauma. NCI was assessed using a battery of 17 measures sensitive to the effects of HIV, and the history of childhood trauma was assessed using the validated retrospective Childhood Trauma Questionnaire-Short Form. Generalized linear regression models were used to compare allelic distribution by trauma status and global NCI. The association between genotype, childhood trauma, and cognitive scores was also evaluated using generalized linear regression models, assuming additive models for the SNPs, and ANOVA.ResultsOf the seven polymorphisms assessed, only the rs10062367 variant of CRHBP was significantly associated with global NCI (P=0.034), independent of childhood trauma. This polymorphism was not significantly associated with z-scores on any specific cognitive domain. The interaction of childhood trauma and variants of CRHR1 was associated with poorer learning (rs110402) and/or recall (rs110402 and rs4792888).ConclusionThese findings suggest that CRHBP rs10062367 A allele is a possible risk variant for NCI in HIV, independent of childhood trauma. Furthermore, results show that the interaction of childhood trauma with variants of CRHR1, rs110402 and rs4792888, confer added vulnerability to NCI in HIV-infected individuals in cognitive domains that are known to be impacted by HIV. While these findings need independent replication in larger samples, it adds CRHBP and CRHR1 to the list of known genes linked to HIV- and childhood trauma-associated neurocognitive phenotypes.

Role of HPA and the HPG Axis Interaction in Testosterone-Mediated Learned Helpless Behavior.

Affective disorders show sex-specific differences in prevalence, symptoms, and complications. One hypothesis for this discrepancy is the interaction between the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis. The present study investigates the influence of androgen on the behavioral phenotype and explores how it interacts with HPA axis genes. Gonadectomized (GDX) and GDX rats treated with testosterone propionate (T) were tested for learned helplessness (LH) behavior and compared with tested controls (TC). Prefrontal cortex was used for analyses of HPG- axis-related genes (androgen receptor, (Ar); estrogen receptor-β (Er-β)) and HPA axis-related genes (corticotropin-releasing hormone, (Crh); glucocorticoid receptor, (Nr3c1); corticotropin-releasing hormone receptor 1, (Crhr1); corticotropin-releasing hormone receptor 2, (Crhr2); FK506 binding protein 5, (Fkbp5)). Promoter-specific CpG methylation in the Crh gene was determined by bisulfite sequencing. Chromatin immunoprecipitation (ChIP) assay was used for determining ER-β binding on the proximal promoter region of Crh gene. Serum testosterone levels confirmed a testosterone-depleted GDX group, a group with supraphysiological levels of testosterone (T) and another group with physiological levels of testosterone (control (C)). Unlike GDX rats, T group exhibited significantly higher LH score when compared with any other group. Crh and Fkbp5 genes were significantly upregulated in GDX group compared with controls, whereas Er-β showed a significant downregulation in the same group. Methylation analysis showed no significant differences in-between groups. ChIP assay was unable to determine a significant change in ER-β binding but revealed a notable contrast in Crh promoter occupancy between T and GDX groups. Altogether, the present study reveals an increased susceptibility to depression-like behavior due to chronic supraphysiological level of androgen via HPA axis inhibition.

Antidepressant Outcomes Predicted by Genetic Variation in Corticotropin-Releasing Hormone Binding Protein.

Genetic variation within the hypothalamic-pituitary-adrenal (HPA) axis has been linked to risk for depression and antidepressant response. However, these associations have yet to produce clinical gains that inform treatment decisions. The authors investigated whether variation within HPA axis genes predicts antidepressant outcomes within two large clinical trials. The test sample comprised 636 patients from the International Study to Predict Optimized Treatment in Depression (iSPOT-D) who completed baseline and 8-week follow-up visits and for whom complete genotyping data were available. The authors tested the relationship between genotype at 16 candidate HPA axis single-nucleotide polymorphisms (SNPs) and treatment outcomes for three commonly used antidepressants (escitalopram, sertraline, and extended-release venlafaxine), using multivariable linear and logistic regression with Bonferroni correction. Response and remission were defined using the Hamilton Depression Rating Scale. Findings were then validated using the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study of outcome predictors in treatment-naive patients with major depression. The authors found that the rs28365143 variant within the corticotropin-releasing hormone binding protein (CRHBP) gene predicted antidepressant outcomes for remission, response, and symptom change. Patients homozygous for the G allele of rs28365143 had greater remission rates, response rates, and symptom reductions. These effects were specific to drug class. Patients homozygous for the G allele responded significantly better to the selective serotonin reuptake inhibitors escitalopram and sertraline than did A allele carriers. In contrast, rs28365143 genotype was not associated with treatment outcomes for the serotonin norepinephrine reuptake inhibitor venlafaxine. When patients were stratified by race, the overall effect of genotype on treatment response remained. In the validation sample, the GG genotype was again associated with favorable antidepressant outcomes, with comparable effect sizes. These findings suggest that a specific CRHBP SNP, rs28365143, may have a role in predicting which patients will improve with antidepressants and which type of antidepressant may be most effective. The results add to the foundational knowledge needed to advance a precision approach to personalized antidepressant choices.

FKBP5 DNA methylation does not mediate the association between childhood maltreatment and depression symptom severity in the Detroit Neighborhood Health Study

Exposure to childhood maltreatment increases the risk of developing mental illness later in life. Childhood maltreatment and depression have both been associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis—a key regulator of the body's stress response. Additionally, HPA axis dysregulation has been implicated in the etiology of a range of mental illnesses. A substantial body of work has shown history of childhood maltreatment alters DNA methylation levels within key HPA axis genes. We therefore investigated whether one of these key genes, FKBP5 mediates the relationship between childhood maltreatment and depression, and assessed FKBP5 DNA methylation and gene expression within 112 adults from the Detroit Neighborhood Health Study (DNHS). DNA methylation was assessed in 4 regions, including the upstream promoter, downstream promoter, and two glucocorticoid response elements (GREs) via pyrosequencing using whole blood derived DNA; Taqman assays measured relative RNA expression from leukocytes. Mediation analyses were conducted using sequential linear regression. Childhood maltreatment was significantly associated with depression symptom severity (FDR < 0.006), but was not a significant predictor of DNA methylation in any of the four loci examined. FKBP5 showed elevated expression levels in participants with vs. without a history of depression (p < 0.001); no significant difference in gene expression levels was observed in relation to childhood maltreatment (p > 0.05). Our results suggest DNA methylation does not mediate the childhood maltreatment-depression association in the DNHS.

Single-nucleotide polymorphisms in genes related to the hypothalamic-pituitary-adrenal axis as risk factors for posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a common psychiatric disorder. The etiology of PTSD is multifactorial, depending on many environmental and genetic risk factors, and the exposure to life or physical integrity-threatening events. Several studies have shown significant correlations of many neurobiological findings with PTSD. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is strongly correlated with this disorder. One hypothesis is that HPA axis dysfunction may precede the traumatic event, suggesting that genes expressed in the HPA axis may be involved in the development of PTSD. This article reviews molecular genetic studies related to PTSD collected through a literature search performed in PubMed, MEDLINE, ScienceDirect, and Scientific Electronic Library Online (SciELO). The results of these studies suggest that several polymorphisms in the HPA axis genes, including FKBP5, NR3C1, CRHR1, and CRHR2, may be risk factors for PTSD development or may be associated with the severity of PTSD symptoms.

Glucocorticoid receptor DNA methylation, childhood maltreatment and major depression

IntroductionAltered DNA methylation (DNAm) levels of hypothalamic-pituitary-adrenal (HPA) axis genes has been associated with exposure to childhood maltreatment (CM) and depression; however, it is unknown whether CM and depression have joint and potentially interacting effects on the glucocorticoid receptor (NR3C1) DNAm. We investigated the impact of CM and lifetime major depressive disorder (MDD) on NR3C1 DNAm and gene expression (GE) in 147 adult participants from the Detroit Neighborhood Health Study. MethodsNR3C1 promoter region DNAm was assessed via pyrosequencing using whole blood-derived DNA. Quantitative RT-PCR assays measured GE from leukocyte-derived RNA. Linear regression models were used to examine the relationship among CM, MDD, and DNAm. ResultsBoth CM and MDD were significant predictors of NR3C1 DNAm: CM was associated with an increase in DNAm in an EGR1 transcription factor binding site (TFBS), whereas MDD was associated with a decrease in DNAm downstream of the TFBS. No significant CM-MDD interactions were observed. CM alone was associated with significantly lower NR3C1 GE. LimitationsOur report of CM is a retrospective self-report of abuse, which may introduce recall bias. DNAm was measured in whole blood and may not reflect brain-derived DNAm levels. ConclusionsCM and MDD are both associated with altered DNAm levels in the NR3C1 promoter region, however the location and direction of effects differ between the two exposures, and the functional effects, as measured by GE, appear to be limited to CM exposure alone. CM exposure may be biologically embedded in this key HPA axis gene.