TY - JOUR A1 - Buchmann, Arlette F. A1 - Hellweg, Rainer A1 - Rietschel, Marcella A1 - Treutlein, Jens A1 - Witt, Stephanie H. A1 - Zimmermann, Ulrich S. A1 - Schmidt, Martin H. A1 - Esser, Günter A1 - Banaschewski, Tobias A1 - Laucht, Manfred A1 - Deuschle, Michael T1 - BDNF Val 66 Met and 5-HTTLPR genotype moderate the impact of early psychosocial adversity on plasma brain-derived neurotrophic factor and depressive symptoms - a prospective study JF - European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology N2 - Recent studies have emphasized an important role for neurotrophins, such as brain-derived neurotrophic factor (BDNF), in regulating the plasticity of neural circuits involved in the pathophysiology of stress-related diseases. The aim of the present study was to examine the interplay of the BDNF Val(66)Met and the serotonin transporter promoter (5-HTTLPR) polymorphisms in moderating the impact of early-life adversity on BDNF plasma concentration and depressive symptoms. Participants were taken from an epidemiological cohort study following the long-term outcome of early risk factors from birth into young adulthood. In 259 individuals (119 males, 140 females), genotyped for the BDNF Val(66)Met and the 5-HTTLPR polymorphisms, plasma BDNF was assessed at the age of 19 years. In addition, participants completed the Beck Depression Inventory (BDI). Early adversity was determined according to a family adversity index assessed at 3 months of age. Results indicated that individuals homozygous for both the BDNF Val and the 5-HTTLPR L allele showed significantly reduced BDNF levels following exposure to high adversity. In contrast, BDNF levels appeared to be unaffected by early psychosocial adversity in carriers of the BDNF Met or the 5-HTTLPR S allele. While the former group appeared to be most susceptible to depressive symptoms, the impact of early adversity was less pronounced in the latter group. This is the first preliminary evidence indicating that early-life adverse experiences may have lasting sequelae for plasma BDNF levels in humans, highlighting that the susceptibility to this effect is moderated by BDNF Val(66)Met and 5-HTTLPR genotype. KW - BDNF KW - 5-HTTLPR KW - Human KW - Early psychosocial adversity KW - Longitudinal study KW - Depression Y1 - 2013 U6 - https://doi.org/10.1016/j.euroneuro.2012.09.003 SN - 0924-977X VL - 23 IS - 8 SP - 902 EP - 909 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Buchmann, Arlette F. A1 - Hohm, Erika A1 - Witt, Stephanie H. A1 - Blomeyer, Dorothea A1 - Jennen-Steinmetz, Christine A1 - Schmidt, Martin H. A1 - Esser, Günter A1 - Banaschewski, Tobias A1 - Brandeis, Daniel A1 - Laucht, Manfred T1 - Role of CNR1 polymorphisms in moderating the effects of psychosocial adversity on impulsivity in adolescents JF - Journal of neural transmission N2 - Enhanced endocannabinoid signaling has been implicated in typically adolescent behavioral features such as increased risk-taking, impulsivity and novelty seeking. Research investigating the impact of genetic variants in the cannabinoid receptor 1 gene (CNR1) and of early rearing conditions has demonstrated that both factors contribute to the prediction of impulsivity-related phenotypes. The present study aimed to test the hypothesis of an interaction of the two most studied CNR1 polymorphisms rs806379 and rs1049353 with early psychosocial adversity in terms of affecting impulsivity in 15-year-olds from an epidemiological cohort sample followed since birth. In 323 adolescents (170 girls, 153 boys), problems of impulse control and novelty seeking were assessed using parent-report and self-report, respectively. Exposure to early psychosocial adversity was determined in a parent interview conducted at the age of 3 months. The results indicated that impulsivity increased following exposure to early psychosocial adversity, with this increase being dependent on CNR1 genotype. In contrast, while individuals exposed to early adversity scored higher on novelty seeking, no significant impact of genotype or the interaction thereof was detected. This is the first evidence to suggest that the interaction of CNR1 gene variants with the experience of early life adversity may play a role in determining adolescent impulsive behavior. However, given that the reported findings are obtained in a high-risk community sample, results are restricted in terms of interpretation and generalization. Future research is needed to replicate these findings and to identify the mediating mechanisms underlying this effect. KW - CNR1 KW - Impulsivity KW - Early psychosocial adversity KW - Adolescence Y1 - 2015 U6 - https://doi.org/10.1007/s00702-014-1266-3 SN - 0300-9564 SN - 1435-1463 VL - 122 IS - 3 SP - 455 EP - 463 PB - Springer CY - Wien ER - TY - JOUR A1 - Buchmann, Arlette F. A1 - Holz, Nathalie A1 - Boecker-Schlier, Regina A1 - Blomeyer, Dorothea A1 - Rietschel, Marcella A1 - Witt, Stephanie H. A1 - Schmidt, Martin H. A1 - Esser, Günter A1 - Banaschewski, Tobias A1 - Brandeis, Daniel A1 - Zimmermann, Ulrich S. A1 - Laucht, Manfred T1 - Moderating role of FKBP5 genotype in the impact of childhood adversity on cortisol stress response during adulthood JF - European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology N2 - Recent research suggests an important role of FKBP5, a glucocorticoid receptor regulating co-chaperone, in the development of stress-related diseases such as depression and anxiety disorders. The present study aimed to replicate and extend previous evidence indicating that FKBP5 polymorphisms moderate hypothalamus-pituitary-adrenal (HPA) function by examining whether FKBP5 rs1360780 genotype and different measures of childhood adversity interact to predict stress-induced cortisol secretion. At age 19 years, 195 young adults (90 males, 105 females) participating in an epidemiological cohort study completed the Trier Social Stress Test (TSST) to assess cortisol stress responsiveness and were genotyped for the FKBP5 rs1360780. Childhood adversity was assessed using the Childhood Trauma Questionnaire (CTQ) and by a standardized parent interview yielding an index of family adversity. A significant interaction between genotype and childhood adversity on cortisol response to stress was demonstrated for exposure to childhood maltreatment as assessed by retrospective self-report (CTQ), but not for prospectively ascertained objective family adversity. Severity of childhood maltreatment was significantly associated with attenuated cortisol levels among carriers of the rs1360780 CC genotype, while no such effect emerged in carriers of the T allele. These findings point towards the functional involvement of FKBP5 in long-term alterations of neuroendocrine stress regulation related to childhood maltreatment, which have been suggested to represent a premorbid risk or resilience factor in the context of stress-related disorders. (C) 2013 Elsevier B.V. and ECNR This is an open access article under the CC BY-NC-ND license. KW - FKBP5 KW - Stress KW - HPA KW - Cortisol KW - Childhood adversity Y1 - 2014 U6 - https://doi.org/10.1016/j.euroneuro.2013.12.001 SN - 0924-977X SN - 1873-7862 VL - 24 IS - 6 SP - 837 EP - 845 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Gilles, Maria A1 - Otto, Henrike A1 - Wolf, Isabell A. C. A1 - Scharnholz, Barbara A1 - Peus, Verena A1 - Schredl, Michael A1 - Suetterlin, Marc W. A1 - Witt, Stephanie H. A1 - Rietschel, Marcella A1 - Laucht, Manfred A1 - Deuschle, Michael T1 - Maternal hypothalamus-pituitary-adrenal (HPA) system activity and stress measures at birth JF - Psychoneuroendocrinology N2 - Background: Prenatal maternal stress might be a risk for the developing fetus and may have long-lasting effects on child and adult vulnerability to somatic and psychiatric disease. Over-exposure of the unborn to excess glucocorticoids and subsequent alteration of fetal development is hypothesized to be one of the key mechanisms linking prenatal stress with negative child outcome. Methods: In this prospective longitudinal study, mothers-to-be (n = 405) in late pregnancy (36.8 +/- 1.9 weeks of gestational age) and their singleton neonates were studied. We investigated the impact of different prenatal stress indices derived from six stress variables (perceived stress, specific prenatal worries, negative life events, symptoms of depression, trait anxiety, neuroticism) and diurnal maternal saliva cortisol secretion on gestational age and anthropometric measures at birth. KW - Early life stress KW - Gestational age KW - Anthropometric measures at birth KW - Cortisol KW - Prenatal distress KW - Pregnancy Y1 - 2018 U6 - https://doi.org/10.1016/j.psyneuen.2018.04.022 SN - 0306-4530 VL - 94 SP - 152 EP - 161 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Heinrich, Angela A1 - Buchmann, Arlette F. A1 - Zohsel, Katrin A1 - Dukal, Helene A1 - Frank, Josef A1 - Treutlein, Jens A1 - Nieratschker, Vanessa A1 - Witt, Stephanie H. A1 - Brandeis, Daniel A1 - Schmidt, Martin H. A1 - Esser, Günter A1 - Banaschewski, Tobias A1 - Laucht, Manfred A1 - Rietschel, Marcella T1 - Alterations of Glucocorticoid Receptor Gene Methylation in Externalizing Disorders During Childhood and Adolescence JF - Behavior genetics : an international journal devoted to research in the inheritance of behavior in animals and man N2 - Epigenetic modulations are a hypothesized link between environmental factors and the development of psychiatric disorders. Research has suggested that patients with depression or bipolar disorder exhibit higher methylation levels in the glucocorticoid receptor gene NR3C1. We aimed to investigate whether NR3C1 methylation changes are similarly associated with externalizing disorders such as aggressive behavior and conduct disorder. NR3C1 exon 1F methylation was analyzed in young adults with a lifetime diagnosis of an externalizing disorder (N = 68) or a depressive disorder (N = 27) and healthy controls (N = 124) from the Mannheim Study of Children at Risk. The externalizing disorders group had significantly lower NR3C1 methylation levels than the lifetime depressive disorder group (p = 0.009) and healthy controls (p = 0.001) This report of lower methylation levels in NR3C1 in externalizing disorders may indicate a mechanism through which the differential development of externalizing disorders as opposed to depressive disorders might occur. KW - Epigenetic KW - Glucocorticoid receptor KW - Methylation KW - Externalizing disorders KW - Adolescents Y1 - 2015 U6 - https://doi.org/10.1007/s10519-015-9721-y SN - 0001-8244 SN - 1573-3297 VL - 45 IS - 5 SP - 529 EP - 536 PB - Springer CY - New York ER - TY - JOUR A1 - Hohmann, Sarah A1 - Zohsel, Katrin A1 - Buchmann, Arlette F. A1 - Blomeyer, Dorothea A1 - Holz, Nathalie A1 - Boecker-Schlier, Regina A1 - Jennen-Steinmetz, Christine A1 - Rietschel, Marcella A1 - Witt, Stephanie H. A1 - Schmidt, Martin H. A1 - Esser, Günter A1 - Meyer-Lindenberg, Andreas A1 - Banaschewski, Tobias A1 - Brandeis, Daniel A1 - Hohm, Erika A1 - Laucht, Manfred T1 - Interacting effect of MAOA genotype and maternal prenatal smoking on aggressive behavior in young adulthood JF - Journal of neural transmission N2 - Findings on the etiology of aggressive behavior have provided evidence for an effect both of genetic factors, such as variation in the monoamine oxidase A (MAOA) gene, and adverse environmental factors. Recent studies have supported the existence of gene × environment interactions, with early experiences playing a key role. In the present study, the effects of prenatal nicotine exposure, MAOA genotype and their interaction on aggressive behavior during young adulthood were examined. In a sample of 272 young adults (129 males, 143 females) from an epidemiological cohort study, smoking during pregnancy was measured with a standardized parent interview at the offspring’s age of 3 months. Aggressive behavior was assessed between the ages of 19 and 25 years using the Young Adult Self-Report. DNA was genotyped for the MAOA 5′ untranslated region variable number of tandem repeats polymorphism (VNTR). Results revealed a significant interaction between MAOA and smoking during pregnancy, indicating higher levels of aggressive behavior in young adults carrying the MAOA low-expressing genotype who had experienced prenatal nicotine exposure (n = 8, p = .025). In contrast, in carriers of the MAOA high-expressing genotype, maternal smoking during pregnancy had no effect on aggressive behavior during young adulthood (n = 20, p = .145). This study extends earlier findings demonstrating an interaction between MAOA genotype and prenatal nicotine exposure on aggressive behavior into young adulthood. The results point to the long-term adverse effects of smoking during pregnancy on the offspring’s mental health, possibly underlining the importance of smoking cessation during pregnancy. According to the nature of the study (particularly sample size and power), analyses are exploratory and results need to be interpreted cautiously. KW - MAOA KW - Smoking during pregnancy KW - Interaction KW - Aggression KW - Longitudinal KW - Young adulthood Y1 - 2016 U6 - https://doi.org/10.1007/s00702-016-1582-x SN - 0300-9564 SN - 1435-1463 VL - 123 SP - 885 EP - 894 PB - Springer CY - Wien ER - TY - JOUR A1 - Holz, Nathalie A1 - Boecker-Schlier, Regina A1 - Buchmann, Arlette F. A1 - Blomeyer, Dorothea A1 - Baumeister, Sarah A1 - Hohmann, Sarah A1 - Jennen-Steinmetz, Christine A1 - Wolf, Isabella A1 - Rietschel, Marcella A1 - Witt, Stephanie H. A1 - Plichta, Michael M. A1 - Meyer-Lindenberg, Andreas A1 - Schmidt, Martin H. A1 - Esser, Günter A1 - Banaschewski, Tobias A1 - Brandeis, Daniel A1 - Laucht, Manfred T1 - Evidence for a Sex-Dependent MAOAx Childhood Stress Interaction in the Neural Circuitry of Aggression JF - Cerebral cortex N2 - Converging evidence emphasizes the role of an interaction between monoamine oxidase A (MAOA) genotype, environmental adversity, and sex in the pathophysiology of aggression. The present study aimed to clarify the impact of this interaction on neural activity in aggression-related brain systems. Functional magnetic resonance imaging was performed in 125 healthy adults from a high-risk community sample followed since birth. DNA was genotyped for the MAOA-VNTR (variable number of tandem repeats). Exposure to childhood life stress (CLS) between the ages of 4 and 11 years was assessed using a standardized parent interview, aggression by the Youth/Young Adult Self-Report between the ages of 15 and 25 years, and the VIRA-R (Vragenlijst Instrumentele En Reactieve Agressie) at the age of 15 years. Significant interactions were obtained between MAOA genotype, CLS, and sex relating to amygdala, hippocampus, and anterior cingulate cortex (ACC) response, respectively. Activity in the amygdala and hippocampus during emotional face-matching increased with the level of CLS in male MAOA-L, while decreasing in male MAOA-H, with the reverse pattern present in females. Findings in the opposite direction in the ACC during a flanker NoGo task suggested that increased emotional activity coincided with decreased inhibitory control. Moreover, increasing amygdala activity was associated with higher Y(A)SR aggression in male MAOA-L and female MAOA-H carriers. Likewise, a significant association between amygdala activity and reactive aggression was detected in female MAOA-H carriers. The results point to a moderating role of sex in the MAOAx CLS interaction for intermediate phenotypes of emotional and inhibitory processing, suggesting a possible mechanism in conferring susceptibility to violence-related disorders. KW - aggression KW - amygdala KW - fMRI KW - life stress KW - MAOA Y1 - 2016 U6 - https://doi.org/10.1093/cercor/bhu249 SN - 1047-3211 SN - 1460-2199 VL - 26 SP - 904 EP - 914 PB - Oxford Univ. Press CY - Cary ER - TY - JOUR A1 - Holz, Nathalie E. A1 - Buchmann, Arlette F. A1 - Boecker-Schlier, Regina A1 - Blomeyer, Dorothea A1 - Baumeister, Sarah A1 - Wolf, Isabella A1 - Rietschel, Marcella A1 - Witt, Stephanie H. A1 - Plichta, Michael M. A1 - Meyer-Lindenberg, Andreas A1 - Banaschewski, Tobias A1 - Brandeis, Daniel A1 - Laucht, Manfred T1 - Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume JF - Brain structure & function N2 - Accumulating evidence suggests a role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of depression and anxiety disorders. Based on recent findings of altered amygdala activity following childhood adversity, the present study aimed at clarifying the impact of genetic variation in FKBP5 on threat-related neural activity and coupling as well as morphometric alterations in stress-sensitive brain systems. Functional magnetic resonance imaging during an emotional face-matching task was performed in 153 healthy young adults (66 males) from a high-risk community sample followed since birth. Voxel-based morphometry was applied to study structural alterations and DNA was genotyped for FKBP5 rs1360780. Childhood adversity was measured using retrospective self-report (Childhood Trauma Questionnaire) and by a standardized parent interview assessing childhood family adversity. Depression was assessed by the Beck Depression Inventory. There was a main effect of FKBP5 on the left amygdala, with T homozygotes showing the highest activity, largest volume and increased coupling with the left hippocampus and the orbitofrontal cortex (OFC). Moreover, amygdala-OFC coupling proved to be associated with depression in this genotype. In addition, our results support previous evidence of a gene-environment interaction on right amygdala activity with respect to retrospective assessment of childhood adversity, but clarify that this does not generalize to the prospective assessment. These findings indicated that activity in T homozygotes increased with the level of adversity, whereas the opposite pattern emerged in C homozygotes, with CT individuals being intermediate. The present results point to a functional involvement of FKBP5 in intermediate phenotypes associated with emotional processing, suggesting a possible mechanism for this gene in conferring susceptibility to stress-related disorders. KW - FKBP5 KW - Childhood adversity KW - Amygdala KW - fMRI KW - Connectivity KW - Voxel-based morphometry Y1 - 2015 U6 - https://doi.org/10.1007/s00429-014-0729-5 SN - 1863-2653 SN - 1863-2661 VL - 220 IS - 3 SP - 1355 EP - 1368 PB - Springer CY - Heidelberg ER - TY - GEN A1 - Send, T. S. A1 - Gilles, M. A1 - Codd, V. A1 - Wolf, I. A. C. A1 - Bardtke, S. A1 - Streit, Fabian A1 - Strohmaier, Jana A1 - Frank, Josef A1 - Schendel, D. A1 - Sutterlin, M. W. A1 - Denniff, M. A1 - Laucht, Manfred A1 - Samani, N. J. A1 - Deuschle, Michael A1 - Rietschel, Marcella A1 - Witt, Stephanie H. T1 - Telomere length in newborns is related to maternal stress during pregnancy Response T2 - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology KW - Predictive markers KW - Risk factors Y1 - 2018 U6 - https://doi.org/10.1038/s41386-018-0079-8 SN - 0893-133X SN - 1740-634X VL - 43 IS - 11 SP - 2164 EP - 2164 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Send, Tabea A1 - Bardtke, S. A1 - Gilles, M. A1 - Wolf, I. A. C. A1 - Sütterlin, Marc Wolf A1 - Wudy, S. A. A1 - Wang, R. A1 - Laucht, Manfred A1 - Witt, Stephanie H. A1 - Rietschel, Marcella A1 - Streit, Fabian A1 - Deuschle, Michael T1 - Prenatal maternal stress is associated with lower cortisol and cortisone levels in the first morning urine of 45-month-old children JF - Psychoneuroendocrinology N2 - Prenatal stress (PS) has been related to altered hypothalamic-pituitary-adrenal (HPA) axis activity later in life. So far, studies in children assessing HPA axis functioning have focused on salivary cortisol, reflecting daytime activity. The present work is part of a prospective study and aims to extend knowledge about the association between PS and HPA axis regulation in children. To do so, we investigated cortisol, cortisone, and the ratio cortisone/(cortisone + cortisol) in the first morning urine of 45-month-old children in relation to several measures of maternal stress during pregnancy. Urinary cortisol and cortisone were measured by online turbulent flow chromatography coupled with high performance liquid chromatography-tandem mass spectrometry. PS was defined as: perceived stress for aim 1 (Perceived Stress Scale; n = 280); presence of self-reported (n = 371) and expert-rated psychopathology for aim 2 (Mini International Neuropsychiatric Interview; n = 281); continuous measures of anxiety and depression for exploratory aim 3 (State-Trait Anxiety Inventory and Edinburgh Postnatal Depression Scale; n = 280). The ratio cortisone/(cortisone + cortisol) as a global marker for the balance between the enzymes metabolizing cortisol to cortisone and vice versa (11 beta-hydroxysteroid dehydrogenases type 1 and 2; 11 beta-HSD1 and 2) was not associated with any measure of maternal PS (aims 1-3). The present study provides insight into possible programming effects of PS on nocturnal HPA axis activity and a proxy of 11 beta-HSD in a large sample. The results suggest that the nocturnal rate of cortisol production is lower in children exposed to PS, but do not support the hypothesis of divergent 11 beta-HSD activity. KW - Prenatal stress KW - Cortisol KW - Cortisone KW - HPA axis KW - Perceived stress KW - Psychopathology Y1 - 2019 U6 - https://doi.org/10.1016/j.psyneuen.2019.01.017 SN - 0306-4530 VL - 103 SP - 219 EP - 224 PB - Elsevier CY - Oxford ER -