Nader Perroud

Increased methylation of glucocorticoid receptor gene ( NR3C1 ) in adults with a history of childhood maltreatment: a link with the severity and type of trauma

Childhood maltreatment, through epigenetic modification of the glucocorticoid receptor gene (NR3C1), influences the hypothalamic–pituitary–adrenal axis (HPA axis). We investigated whether childhood maltreatment and its severity were associated with increased methylation of the exon 1F NR3C1 promoter, in 101 borderline personality disorder (BPD) and 99 major depressive disorder (MDD) subjects with, respectively, a high and low rate of childhood maltreatment, and 15 MDD subjects with comorbid post-traumatic stress disorder (PTSD). Childhood sexual abuse, its severity and the number of type of maltreatments positively correlated with NR3C1 methylation (P=6.16 × 10−8, 5.18 × 10−7 and 1.25 × 10−9, respectively). In BPD, repetition of abuses and sexual abuse with penetration correlated with a higher methylation percentage. Peripheral blood might therefore serve as a proxy for environmental effects on epigenetic processes. These findings suggest that early life events may permanently impact on the HPA axis though epigenetic modifications of the NR3C1. This is a mechanism by which childhood maltreatment may lead to adulthood psychopathology.

Response to psychotherapy in borderline personality disorder and methylation status of the BDNF gene

Downregulation of brain-derived neurotrophic factor (BDNF) gene expression with corresponding increased methylation at specific promoters has been associated with stressful experiences in early life and may explain later adulthood psychopathology. We measured the percentage of methylation at BDNF CpG exons I and IV as well as plasma BDNF protein levels in 115 subjects with borderline personality disorder (BPD) and 52 controls. BPD subjects then underwent a 4-week course of intensive dialectical behavior therapy (I-DBT). BDNF methylation status and protein levels were re-assessed at the end of treatment. BPD subjects had significantly higher methylation status in both CpG regions than controls. In addition, the higher the number of childhood trauma, the higher was the methylation status. In BPD subjects, BDNF methylation significantly increased after I-DBT. Nonresponders accounted for the majority of this increase, whereas responders showed a decrease in methylation status over time. Accordingly, the changes in methylation status over time were significantly associated with changes in depression scores, hopelessness scores and impulsivity. No association was found between protein levels and BDNF methylation status. We here found a relationship between child maltreatment and higher DNA methylation of BDNF. These results moreover support the idea that these epigenetic marks may be changed through psychotherapeutic approaches and that these changes underline changes in cognitive functions.

Prevalence and Heritability of Compulsive Hoarding: A Twin Study

OBJECTIVE Compulsive hoarding is a serious health problem for the sufferers, their families, and the community at large. It appears to be highly prevalent and to run in families. However, this familiality could be due to genetic or environmental factors. This study examined the prevalence and heritability of compulsive hoarding in a large sample of twins. METHOD A total of 5,022 twins completed a validated measure of compulsive hoarding. The prevalence of severe hoarding was determined using empirically derived cutoffs. Genetic and environmental influences on compulsive hoarding were estimated using liability threshold models, and maximum-likelihood univariate model-fitting analyses were employed to decompose the variance in the liability to compulsive hoarding into additive genetic and shared and nonshared environmental factors (female twins only; N=4,355). RESULTS A total of 2.3% of twins met criteria for caseness, with significantly higher rates observed for male (4.1%) than for female (2.1%) twins. Model-fitting analyses in female twins showed that genetic factors accounted for approximately 50% of the variance in compulsive hoarding, with nonshared environmental factors and measurement error accounting for the other half. CONCLUSIONS Compulsive hoarding is highly prevalent and heritable, at least in women, with nonshared environmental factors also likely to play an important role.

Impulsivity, aggression and suicidal behavior in unipolar and bipolar disorders

BACKGROUND Predictors of suicidal behaviors (SB) in bipolar (BD) and major depressive disorder (MDD) patients are poorly understood. It has been recognized that behavioral dysregulation characterizes SB with traits of impulsivity and aggression being particularly salient. However, little is known about how these traits are segregated among mood disorder patients with and without a history of suicide attempt (SA). METHODS This article aims to compare impulsivity and aggression between 143 controls, 138 BD and 186 MDD subjects with or without a history of SA. RESULTS BD and MDD patients showed higher impulsivity scores (BIS-10 = 57.9 vs. 44.7, p < 0.0001) and more severe lifetime aggression than controls (Lifetime History of Aggression = 7.3 vs. 3.9, p < 0.0001). Whereas impulsivity helped to distinguish MDD subjects without a history of SA from those with such a history, this was not the case in BD subjects where no difference in impulsive traits was observed between BD without and with history of SA (57.2 vs. 63.2 for BIS-10; p = 0.259). Impulsive and aggressive traits were strongly correlated in suicide attempters (independently of the diagnosis) but not in non-suicide attempters. LIMITATIONS Dimensional traits were not characterized at different stages of illness. CONCLUSIONS Impulsivity, as a single trait, may be a reliable suicide risk marker in MDD but not in BD patients, and its strong correlation with aggressive traits seems specifically related to SB. Our study therefore suggests that the specific dimension of impulsive aggression should be systematically assessed in mood disorder patients to address properly their suicidal risk.

Is it valid to measure suicidal ideation by depression rating scales

OBJECTIVE To date, most researchers rely on suicidal items of scales primarily designed to measure depression severity to capture suicidal ideation (SI). This study aims at investigating how well the suicide item of the clinician rated Hamilton Scale for Depression (HAM-D) and principal factors derived from this scale correlate with SI scores derived from a well validated measure of SI: the Becks scale for SI (SSI). METHOD 281 suicide attempters consecutively hospitalized between 2007 and 2009 were assessed by using the SSI, the HAM-D and the self-report Beck Depression Inventory (BDI). Principal Component Analysis (PCA) was computed to extract main factors. Correlations between these factors, BDIs and HAM-Ds suicide items and the SSI scores were then computed. RESULTS Three components were derived from the PCA. Factor 2 showed a major loading for the HAM-D suicide item. Both the HAM-D suicide item and Factor 2 positively correlated with the SSI total score (both p<0.00001). Moreover, the BDI suicide item highly correlated with the Factor 2 (p<0.001) and the SSI total score (p<0.00001). Finally, the HAM-D suicide item correlated significantly with the number of suicide attempts (p=0.0001) and the age at the first attempt (p=0.002). LIMITATIONS Our sample was heterogeneous and future studies should refine the taxonomy of the suicidal behavior in specific sub-populations. The study design was cross-sectional and replication in a prospective study is needed. CONCLUSION These findings suggest that the use of a single suicide item or a dimensional factor derived from a depression scale might be a valid approach to assess the suicidal ideations. Moreover, the results suggest that clinician rated scales as well as self-report questionnaires are equally valid to do so.

Interaction between BDNF Val66Met and childhood trauma on adult's violent suicide attempt.

Genetic factors, specially those related to serotoninergic activities, and childhood maltreatment have both been implicated in suicidal behaviour (SB). However, little attention has been paid to the possible interaction between genes and childhood maltreatment in the comprehension of SB. Brain‐derived neurotrophic factor (BDNF) plays an important role in the growth of serotoninergic neurons during childhood and therefore is a good candidate for studies on SB. Moreover, decreased levels of BDNF have been found in the prefrontal cortex of suicide victims. In our study we wanted to see if Val66Met (a BDNF functional single‐nucleotide polymorphism) could moderate the effect of childhood maltreatment on the onset, number and violence of SB in a sample of 813 Caucasian suicide attempters. Childhood maltreatment was evaluated using the Childhood Trauma Questionnaire. We used a regression framework to test the interaction between Val66Met and childhood maltreatment. Childhood sexual abuse was associated with violent suicide attempts (SA) in adulthood only among Val/Val individuals and not among Val/Met or Met/Met individuals (P = 0.05). The severity of childhood maltreatment was significantly associated with a higher number of SA and with a younger age at onset of suicide attempt. This result suggests that Val66Met modulates the effect of childhood sexual abuse on the violence of SB. It is proposed that childhood sexual abuse elicits brain structural modifications through BDNF dysfunction and enhances the risk of violent SB in adulthood.

The Tutsi genocide and transgenerational transmission of maternal stress: epigenetics and biology of the HPA axis

Abstract Objectives. Transmission of parental post-traumatic stress disorder (PTSD) to offspring might be explained by transmission of epigenetic processes such as methylation status of the glucocorticoid receptor (GR) gene (NR3C1). Methods. We investigated PTSD and depression severity, plasma cortisol, GR and mineralocorticoid receptor (MR) levels, and methylation status of NR3C1 and NR3C2 promoter regions in 25 women exposed to the Tutsi genocide during pregnancy and their children, and 25 women from the same ethnicity, pregnant during the same period but not exposed to the genocide, and their children. Results. Transmission of PTSD to the offspring was associated with transmission of biological alterations of the HPA axis. Mothers exposed to the genocide as well as their children had lower cortisol and GR levels and higher MR levels than non-exposed mothers and their children. Moreover, exposed mothers and their children had higher methylation of the NR3C1 exon 1F than non-exposed groups. Finally, exposed mothers showed higher methylation of CpGs located within the NR3C2 coding sequence than non-exposed mothers. Conclusions. PTSD was associated with NR3C1 epigenetic modifications that were similarly found in the mothers and their offspring, modifications that may underlie the possible transmission of biological alterations of the HPA axis.

Genetic predictors of response to serotonergic and noradrenergic antidepressants in major depressive disorder: a genome-wide analysis of individual-level data and a meta-analysis

Testing whether genetic information could inform the selection of the best drug for patients with depression, Rudolf Uher and colleagues searched for genetic variants that could predict clinically meaningful responses to two major groups of antidepressants.

Childhood maltreatment and methylation of the glucocorticoid receptor gene NR3C1 in bipolar disorder

BACKGROUND Early-life adversities represent risk factors for the development of bipolar affective disorder and are associated with higher severity of the disorder. This may be the consequence of a sustained alteration of the hypothalamic-pituitary-adrenal (HPA) axis resulting from epigenetic modifications of the gene coding for the glucocorticoid receptor (NR3C1). AIMS To investigate whether severity of childhood maltreatment is associated with increased methylation of the exon 1F NR3C1 promoter in bipolar disorder. METHOD A sample of people with bipolar disorder (n = 99) were assessed for childhood traumatic experiences. The percentage of NR3C1 methylation was measured for each participant. RESULTS The higher the number of trauma events, the higher was the percentage of NR3C1 methylation (β = 0.52, 95% CI 0.46-0.59, P<<0.0001). The severity of each type of maltreatment (sexual, physical and emotional) was also associated with NR3C1 methylation status. CONCLUSIONS Early-life adversities have a sustained effect on the HPA axis through epigenetic processes and this effect may be measured in peripheral blood. This enduring biological impact of early trauma may alter the development of the brain and lead to adult psychopathological disorder.

Genetic and epigenetic analysis of SSAT gene dysregulation in suicidal behavior.

It has recently been proposed that the SSAT gene plays a role in the predisposition to suicidal behavior. SSAT expression was found to be down‐regulated in the brain of suicide completers. In addition, a single nucleotide polymorphism (SNP) rs6526342 was associated both with variation in SSAT expression and with suicidal behavior. In this study, we aimed to characterize the relationship between SSAT dysregulation and suicide behavior. To this end, we measured SSAT expression levels in the ventral prefrontal cortex (VPFC) of suicide completers (n = 20) and controls (n = 20) and found them to be significantly down‐regulated in suicide victims (P = 0.007). To identify the basis of the regulation of SSAT expression, we performed an association analysis of 309 SNPs with SSAT transcript levels in 53 lymphoblastoid cell lines from the CEPH collection. We then examined the methylation status of the SSAT promoter region in males and females suicide completers and control subjects whose SSAT brain expression had been measured. We found no evidence to support a role for SNPs in controlling the level of SSAT expression. SSAT promoter methylation levels were not different between suicide completers and controls and did not correlate with SSAT expression levels. In addition, we found no indication of a genetic association between suicidal behavior and SNPs located within the SSAT gene. Our study provides new results which show that dysregulation of SSAT expression does play a role in suicide behavior. However, our data do not support any association between rs6526342 and variation in SSAT expression or suicidal behavior.