Glucocorticoid receptor exon 1_F methylation and the cortisol stress response in health and disease

Childhood trauma has been proposed to increase vulnerability to develop psychopathology in part through an altered cortisol stress response. Research in rats has suggested that this effect is mediated by methylation in the glucocorticoid receptor 17 region (GR-17 or GR-1F in humans), with higher methylation after poor maternal care leading to an increased cortisol stress response in adulthood. In humans, the associations between childhood trauma and GR-1F methylation or the cortisol stress response are equivocal. Remarkably, evidence for the relation between GR-1F methylation and the cortisol stress response has been conflicting as well. To further explore this, we investigated the associations of peripheral GR-1F methylation (52 CpGs) with the cortisol stress response (Trier Social Stress Test) and with childhood trauma in three independent studies (total N = 241) including healthy controls, patients with schizophrenia and bipolar disorder and unaffected siblings of patients with one of these disorders. We did not find any significant association between GR-1F methylation and the cortisol stress response (areas under the curve) or childhood trauma, nor did we observe any group differences between patients, siblings and healthy controls. Our findings do not support GR-1F methylation as a proxy for the cortisol stress response, nor its link with childhood trauma or psychopathology. These results suggest that multifactorial models for stress-related psychopathology are needed. Alternatively, future longitudinal studies may reveal GR-1F methylation to be a useful parameter at an individual level

The Role of Stressful Parenting and Mineralocorticoid Receptor Haplotypes on Social Development During Adolescence and Young Adulthood

The development of social behavior could be affected by stressful parenting. The mineralocorticoid receptor, one of the two main receptors for the stress hormone cortisol, plays a vital role in adequate responses to stress. Therefore, the effects of stressful parenting on social development (i.e., empathic concern, perspective taking and prosocial behavior) may be moderated by functional genetic variation in mineralocorticoid receptor haplotypes (a combination of alleles). A group of 343 adolescents (44.3% females) was followed from the age of 13 until 24 years. Growth curve analyses showed lower levels of prosocial behaviors and a slower increase in empathic concern and perspective taking in adolescents who reported more stressful parenting. In contrast, relatively higher levels of prosocial behavior, empathic concern and perspective taking were present in combination with stress resilient mineralocorticoid receptor haplotypes. Despite sex differences in social development with earlier social development for girls, no consistent sex differences were found with regard to mineralocorticoid receptor haplotypes. The current study showed that genetic variation in mineralocorticoid receptor impacts the social development during adolescence and young adulthood

The Role of Stress and Mineralocorticoid Receptor Haplotypes in the Development of Symptoms of Depression and Anxiety During Adolescence

Adolescence is a critical developmental period characterized by heightened levels of depressive and anxiety symptoms. Experiencing chronic or environmental stress, for example, as a result of traumatic events or insensitive parenting, increases the risk for depression and anxiety. However, not all adolescents develop depressive or anxiety symptoms following environmental stressors, due to differences in stress resilience. One of the factors involved in stress resilience is enhanced functionality of the mineralocorticoid receptor (MR), one of the two brain receptors for the stress hormone cortisol. High levels of MR functionality result in relatively lower rates of depression, particularly in women that experienced stress. However, much less is known about MR functionality in relation to the development of adolescent depression and to other internalizing behavior problems such as anxiety. We therefore examined whether the effects of a functional MR haplotype (i.e., the MR CA haplotype) on the development of depressive and anxiety symptoms are sex-dependent, as well as interact with environmental stressors. In a community sample of adolescents (N = 343, 9 waves between age 13 and 24), environmental stressors were operationalized as parental psychological control and childhood trauma. Results showed a sex-dependent effect of MR CA haplotype on the development of depressive symptoms but not for anxiety symptoms. MR CA haplotypes were protective for girls but not for boys. This study sheds more light on the sex-dependent effects of MR functionality related to the development of depressive and anxiety symptoms during adolescence

Glucocorticoid receptor exon 1F methylation and the cortisol stress response in health and disease

Childhood trauma has been proposed to increase vulnerability to develop psychopathology in part through an altered cortisol stress response. Research in rats has suggested that this effect is mediated by methylation in the glucocorticoid receptor 17 region (GR-17 or GR-1F in humans), with higher methylation after poor maternal care leading to an increased cortisol stress response in adulthood. In humans, the associations between childhood trauma and GR-1F methylation or the cortisol stress response are equivocal. Remarkably, evidence for the relation between GR-1F methylation and the cortisol stress response has been conflicting as well. To further explore this, we investigated the associations of peripheral GR-1F methylation (52 CpGs) with the cortisol stress response (Trier Social Stress Test) and with childhood trauma in three independent studies (total N = 241) including healthy controls, patients with schizophrenia and bipolar disorder and unaffected siblings of patients with one of these disorders. We did not find any significant association between GR-1F methylation and the cortisol stress response (areas under the curve) or childhood trauma, nor did we observe any group differences between patients, siblings and healthy controls. Our findings do not support GR-1F methylation as a proxy for the cortisol stress response, nor its link with childhood trauma or psychopathology. These results suggest that multifactorial models for stress-related psychopathology are needed. Alternatively, future longitudinal studies may reveal GR-1F methylation to be a useful parameter at an individual level

The Role of Stressful Parenting and Mineralocorticoid Receptor Haplotypes on Social Development During Adolescence and Young Adulthood

The development of social behavior could be affected by stressful parenting. The mineralocorticoid receptor, one of the two main receptors for the stress hormone cortisol, plays a vital role in adequate responses to stress. Therefore, the effects of stressful parenting on social development (i.e., empathic concern, perspective taking and prosocial behavior) may be moderated by functional genetic variation in mineralocorticoid receptor haplotypes (a combination of alleles). A group of 343 adolescents (44.3% females) was followed from the age of 13 until 24 years. Growth curve analyses showed lower levels of prosocial behaviors and a slower increase in empathic concern and perspective taking in adolescents who reported more stressful parenting. In contrast, relatively higher levels of prosocial behavior, empathic concern and perspective taking were present in combination with stress resilient mineralocorticoid receptor haplotypes. Despite sex differences in social development with earlier social development for girls, no consistent sex differences were found with regard to mineralocorticoid receptor haplotypes. The current study showed that genetic variation in mineralocorticoid receptor impacts the social development during adolescence and young adulthood

Development of psychopathology in deployed armed forces in relation to plasma GABA levels

The GABA system is pivotal for an adequate response to a stressful environment but has remained largely unexplored in this context. The present study investigated the relationship of prospectively measured plasma GABA levels with psychopathology symptoms in military deployed to Afghanistan at risk for developing psychopathology following trauma exposure during deployment, including posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Plasma GABA levels were measured in military personnel (N=731) one month prior to deployment (T0), and one (T1) and six months (T2) after deployment using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Mental health problems and depressive symptoms were measured with the Dutch revised Symptom Checklist (SCL-90) and PTSD symptoms with the Dutch Self-Rating Inventory for PTSD (SRIP). Six months after deployment increases in GABA concentrations were present in individuals who had developed mental health problems (T2: β=0.06, p=1.6×10(-2), T1: β=4.7×10(-2), p=0.13), depressive symptoms (T2: β=0.29, p=7.9×10(-3), T1: β=0.23, p=0.072) and PTSD symptoms at T2 (T2: β=0.12, p=4.3×10(-2), T1: β=0.11, p=0.13). Plasma GABA levels prior to and one month after deployment poorly predicted a high level of psychopathology symptoms either one or six months after deployment. The number of previous deployments, trauma experienced during deployment, childhood trauma, age and sex were not significantly associated with plasma GABA levels over time. Exclusion of subjects who either started or stopped smoking, alcohol or medication use between the three time points rendered the association of increasing GABA levels with the emergence of psychopathology symptoms more pronounced (mental health problems at T2: β=0.09, p=4.2×10(-3); depressive symptoms at T2: β=0.35, p=3.5×10(-3), PTSD symptoms at T2: β=0.17, p=1.7×10(-2)). To our knowledge, this is the first study to provide prospective evidence that the development of psychopathology after military deployment is associated with increasing plasma GABA levels. Our finding that plasma GABA rises after the emergence of psychopathology symptoms suggests that GABA increase may constitute a compensatory mechanism and warrants further exploration of the GABA system as a potential target for treatment

The Role of Stressful Parenting and Mineralocorticoid Receptor Haplotypes on Social Development During Adolescence and Young Adulthood

The development of social behavior could be affected by stressful parenting. The mineralocorticoid receptor, one of the two main receptors for the stress hormone cortisol, plays a vital role in adequate responses to stress. Therefore, the effects of stressful parenting on social development (i.e., empathic concern, perspective taking and prosocial behavior) may be moderated by functional genetic variation in mineralocorticoid receptor haplotypes (a combination of alleles). A group of 343 adolescents (44.3% females) was followed from the age of 13 until 24 years. Growth curve analyses showed lower levels of prosocial behaviors and a slower increase in empathic concern and perspective taking in adolescents who reported more stressful parenting. In contrast, relatively higher levels of prosocial behavior, empathic concern and perspective taking were present in combination with stress resilient mineralocorticoid receptor haplotypes. Despite sex differences in social development with earlier social development for girls, no consistent sex differences were found with regard to mineralocorticoid receptor haplotypes. The current study showed that genetic variation in mineralocorticoid receptor impacts the social development during adolescence and young adulthood

Development of psychopathology in deployed armed forces in relation to plasma GABA levels

The GABA system is pivotal for an adequate response to a stressful environment but has remained largely unexplored in this context. The present study investigated the relationship of prospectively measured plasma GABA levels with psychopathology symptoms in military deployed to Afghanistan at risk for developing psychopathology following trauma exposure during deployment, including posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Plasma GABA levels were measured in military personnel (N=731) one month prior to deployment (T0), and one (T1) and six months (T2) after deployment using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Mental health problems and depressive symptoms were measured with the Dutch revised Symptom Checklist (SCL-90) and PTSD symptoms with the Dutch Self-Rating Inventory for PTSD (SRIP). Six months after deployment increases in GABA concentrations were present in individuals who had developed mental health problems (T2: β=0.06, p=1.6×10(-2), T1: β=4.7×10(-2), p=0.13), depressive symptoms (T2: β=0.29, p=7.9×10(-3), T1: β=0.23, p=0.072) and PTSD symptoms at T2 (T2: β=0.12, p=4.3×10(-2), T1: β=0.11, p=0.13). Plasma GABA levels prior to and one month after deployment poorly predicted a high level of psychopathology symptoms either one or six months after deployment. The number of previous deployments, trauma experienced during deployment, childhood trauma, age and sex were not significantly associated with plasma GABA levels over time. Exclusion of subjects who either started or stopped smoking, alcohol or medication use between the three time points rendered the association of increasing GABA levels with the emergence of psychopathology symptoms more pronounced (mental health problems at T2: β=0.09, p=4.2×10(-3); depressive symptoms at T2: β=0.35, p=3.5×10(-3), PTSD symptoms at T2: β=0.17, p=1.7×10(-2)). To our knowledge, this is the first study to provide prospective evidence that the development of psychopathology after military deployment is associated with increasing plasma GABA levels. Our finding that plasma GABA rises after the emergence of psychopathology symptoms suggests that GABA increase may constitute a compensatory mechanism and warrants further exploration of the GABA system as a potential target for treatment

Brain GABA levels across psychiatric disorders : A systematic literature review and meta-analysis of 1H-MRS studies

The inhibitory gamma-aminobutyric acid (GABA) system is involved in the etiology of most psychiatric disorders, including schizophrenia, autism spectrum disorder (ASD) and major depressive disorder (MDD). It is therefore not surprising that proton magnetic resonance spectroscopy (1H-MRS) is increasingly used to investigate in vivo brain GABA levels. However, integration of the evidence for altered in vivo GABA levels across psychiatric disorders is lacking. We therefore systematically searched the clinical 1H-MRS literature and performed a meta-analysis. A total of 40 studies (N = 1,591) in seven different psychiatric disorders were included in the meta-analysis: MDD (N = 437), schizophrenia (N = 517), ASD (N = 150), bipolar disorder (N = 129), panic disorder (N = 81), posttraumatic stress disorder (PTSD) (N = 104), and attention deficit/hyperactivity disorder (ADHD) (N = 173). Brain GABA levels were lower in ASD (standardized mean difference [SMD] = −0.74, P = 0.001) and in depressed MDD patients (SMD = −0.52, P = 0.005), but not in remitted MDD patients (SMD = −0.24, P = 0.310) compared with controls. In schizophrenia this finding did not reach statistical significance (SMD = −0.23, P = 0.089). No significant differences in GABA levels were found in bipolar disorder, panic disorder, PTSD, and ADHD compared with controls. In conclusion, this meta-analysis provided evidence for lower brain GABA levels in ASD and in depressed (but not remitted) MDD patients compared with healthy controls. Findings in schizophrenia were more equivocal. Even though future 1H-MRS studies could greatly benefit from a longitudinal design and consensus on the preferred analytical approach, it is apparent that 1H-MRS studies have great potential in advancing our understanding of the role of the GABA system in the pathogenesis of psychiatric disorders

The Role of Stress and Mineralocorticoid Receptor Haplotypes in the Development of Symptoms of Depression and Anxiety During Adolescence

Adolescence is a critical developmental period characterized by heightened levels of depressive and anxiety symptoms. Experiencing chronic or environmental stress, for example, as a result of traumatic events or insensitive parenting, increases the risk for depression and anxiety. However, not all adolescents develop depressive or anxiety symptoms following environmental stressors, due to differences in stress resilience. One of the factors involved in stress resilience is enhanced functionality of the mineralocorticoid receptor (MR), one of the two brain receptors for the stress hormone cortisol. High levels of MR functionality result in relatively lower rates of depression, particularly in women that experienced stress. However, much less is known about MR functionality in relation to the development of adolescent depression and to other internalizing behavior problems such as anxiety. We therefore examined whether the effects of a functional MR haplotype (i.e., the MR CA haplotype) on the development of depressive and anxiety symptoms are sex-dependent, as well as interact with environmental stressors. In a community sample of adolescents (N = 343, 9 waves between age 13 and 24), environmental stressors were operationalized as parental psychological control and childhood trauma. Results showed a sex-dependent effect of MR CA haplotype on the development of depressive symptoms but not for anxiety symptoms. MR CA haplotypes were protective for girls but not for boys. This study sheds more light on the sex-dependent effects of MR functionality related to the development of depressive and anxiety symptoms during adolescence