Interactive effects of corticotropin releasing hormone receptor 1, serotonin transporter linked polymorphic region, and child maltreatment on diurnal cortisol regulation and internalizing symptomatology

Within an allostatic load framework, the effect of Gene × Environment (G × E) interactions on diurnal cortisol regulation and internalizing symptomatology were investigated. Variation in the corticotropin releasing hormone receptor 1 (CRHR1) TAT haplotype and serotonin transporter linked polymorphic region (5-HTTLPR) was determined in a sample of maltreated (n = 238, 21.4% with early physical and sexual abuse) and nonmaltreated (n = 255) children (M age = 10.08) participating in a summer research camp. Internalizing and depressive symptoms were assessed by other and self-report. G × E effects for CRHR1 and maltreatment and early abuse on diurnal cortisol regulation were observed; CRHR1 variation was related to cortisol dysregulation only among maltreated children. Early abuse and high internalizing symptoms also interacted to predict atypical diurnal cortisol regulation. The interaction of CRHR1, 5-HTTLPR, and child maltreatment (G × G × E) identified a subgroup of maltreated children with high internalizing symptoms who shared the same combination of the two genes. The findings support an allostatic load perspective on the effects of the chronic stress associated with child maltreatment on cortisol regulation and internalizing symptomatology as moderated by genetic variation.     

The effects of child maltreatment on early signs of antisocial behavior: genetic moderation by tryptophan hydroxylase, serotonin transporter, and monoamine oxidase A genes

Gene-environment interaction effects in predicting antisocial behavior in late childhood were investigated among maltreated and nonmaltreated low-income children (N = 627, M age = 11.27). Variants in three genes were examined: tryptophan hydroxylase 1 (TPH1), serotonin transporter linked polymorphic region (5-HTTLPR), and monoamine oxidase A (MAOA) upstream variable number tandem repeat. In addition to child maltreatment status, we considered the impact of maltreatment subtypes, developmental timing of maltreatment, and chronicity. Indicators of antisocial behavior were obtained from self-, peer, and adult counselor reports. In a series of analyses of covariance, child maltreatment and its parameters demonstrated strong main effects on early antisocial behavior as assessed by all report forms. Genetic effects operated primarily in the context of gene-environment interactions, moderating the impact of child maltreatment on outcomes. Across the three genes, among nonmaltreated children no differences in antisocial behavior were found based on genetic variation. In contrast, among maltreated children specific polymorphisms of TPH1, 5-HTTLPR, and MAOA were each related to heightened self-report of antisocial behavior; the interaction of 5-HTTLPR and developmental timing of maltreatment also indicated more severe antisocial outcomes for children with early onset and recurrent maltreatment based on genotype. TPH1 and 5-HTTLPR interacted with maltreatment subtype to predict peer reports of antisocial behavior; genetic variation contributed to larger differences in antisocial behavior among abused children. The TPH1 and 5-HTTLPR polymorphisms also moderated the effects of maltreatment subtype on adult reports of antisocial behavior; again, the genetic effects were strongest for children who were abused. In addition, TPH1 moderated the effect of developmental timing of maltreatment and chronicity on adult reports of antisocial behavior. The findings elucidate how genetic variation contributes to identifying which maltreated children are most vulnerable to antisocial development.     

An association between a polymorphism of the tryptophan hydroxylase gene and aggression in schizophrenia and schizoaffective disorder

Serotonergic pathways have been implicated in impulsive and aggressive behavior. Polymorphisms in the regulatory region of the serotonin transporter (5-HTT), in intron 7 of the tryptophan hydroxylase (TPH) gene and in the MAOA gene were previously reported to be associated with mood and anxiety disorders, impulsivity and aggression. In this study, we analyzed these polymorphisms in men and women with schizophrenia or schizoaffective disorder (n = 84) who met our criteria for violence (history of two or more assaults on others) or nonviolence (no history of either assaultive or threatening behavior). In males, a modest association between TPH genotype and history of violence (chi-square test = 6.703, degrees of freedom = 2, P = 0.035) was not statistically significant after correction for multiple comparisons (corrected P = 0.21). The TPH L allele was more frequent in violent males (chi-square = 5.323, degrees of freedom = 1, P = 0.021) but this difference also failed to withstand correction (corrected P = 0.126). No significant associations were found for either the 5-HTT or MAOA polymorphisms in males or females. These results tend to support previous reports by New et al. (1996; 1998) of an association between the TPH L allele and impulsive aggression in males with personality disorder, but larger studies are needed.     

Harsh Discipline,Childhood Sexual Assault,and MAOA Genotype: An Investigation of Main and Interactive Effects on Diverse Clinical Externalizing Outcomes

We studied the impact of MAOA genotype, childhood sexual assault, and harsh discipline on clinical externalizing symptoms (substance problems, adult antisocial behavior, and conduct disorder). Participants were 841 individual twins from the Minnesota Twin Family Study assessed through age 25. MAOA genotype was not associated with differences in any phenotype, nor was there a significant interaction between MAOA and harsh discipline for any phenotype or a significant interaction between MAOA and childhood sexual assault for substance problems. We found evidence that childhood sexual assault interacted with MAOA genotype to predict antisocial behavior and conduct disorder symptoms. Individuals with the low MAOA activity genotype who reported childhood sexual assault had more symptoms than individuals with either the high MAOA activity genotype and/or no history of childhood sexual assault. These findings suggest that the previously reported interaction between MAOA and childhood maltreatment may be specific to the antisocial subset of externalizing disorders.     

Child maltreatment and allostatic load: consequences for physical and mental health in children from low-income families

Child maltreatment and biomarkers of allostatic load were investigated in relation to child health problems and psychological symptomatology. Participants attended a summer research day camp and included 137 maltreated and 110 nonmaltreated low-income children, who were aged 8 to 10 years (M = 9.42) and racially and ethnically diverse; 52% were male. Measurements obtained included salivary cortisol and dehydroepiandosterone, body mass index, waist-hip ratio, and blood pressure; these indicators provided a composite index of allostatic load. Child self-report and camp adult-rater reports of child symptomatology were obtained; mothers provided information on health problems. The results indicated that higher allostatic load and child maltreatment status independently predicted poorer health outcomes and greater behavior problems. Moderation effects indicated that allostatic load was related to somatic complaints, attention problems, and thought problems only among maltreated children. Risks associated with high waist-hip ratio, low morning cortisol, and high morning dehydroepiandosterone also were related to depressive symptoms only for maltreated children. The results support an allostatic load conceptualization of the impact of high environmental stress and child abuse and neglect on child health and behavioral outcomes and have important implications for long-term physical and mental health.     

Aberrant accumulation of serotonin in dopaminergic neurons

Gene targeting approaches greatly facilitate insight into the functioning of monoamine transporters, the targets of potent antidepressants. The serotonin transporter (5-HTT) is the molecular target of a large number of antidepressants. To assess the clearance of serotonin (5-HT) in the absence of the 5-HTT, we have generated double knockout mice lacking both the 5-HTT and the catabolizing enzyme monoamine oxidase A (MAOA). We found aberrant 5-HT accumulation in the striatum of these MAOA/5-HTT double knockout mice. By additional ablation of the dopamine transporter (DAT), this aberrant 5-HT accumulation was abolished in MAOA/5-HTT/DAT triple knockout mice. Thus, aberrant uptake of 5-HT occurs in dopaminergic terminals under conditions of elevated 5-HT levels, and this aberrant uptake is mediated by the DAT. These findings have important consequences for antidepressant therapy, since during treatment of depression with selective serotonin reuptake inhibitors, clearance of 5-HT by dopaminergic neurons may reduce the desired therapeutic elevation of extracellular 5-HT levels. This provides a molecular rationale for improving antidepressant efficacy by additional pharmacological inhibition of the DAT.     

Monoamine oxidase A (MAOA) and antisocial behaviors in the presence of childhood and adolescent maltreatment.

There is a robust relationship between the experience of maltreatment in childhood and later antisocial behaviors amongst adolescents and adults. Animal and human studies suggest that variation in monoamine oxidase A (MAOA) genotype may moderate the effects of maltreatment. Self-reported conduct problems and criminal convictions amongst sibling-pairs from the National Longitudinal Study of Adolescent Health were tested for association with reports of maltreatment before and after the age of 12. MAOA promoter polymorphisms were tested for possible moderation effects. Maltreatment predicted conduct problems and criminal convictions. MAOA genotype did not have a significant moderating effect in any of the six analyses that were conducted. We did not replicate a previous report that MAOA polymorphisms moderated the relationship between maltreatment and conduct problems. There was, however, a non-significant trend in the predicted direction. Additional studies will be needed before firm conclusions can be drawn about this hypothesized genotype-environment interaction.     

Trajectories of resting frontal brain activity and psychopathology in female adolescents exposed to child maltreatment

Resting frontal electroencephalogram (EEG) alpha asymmetry patterns reflecting different affective and motivational tendencies have been proposed as a putative mechanism underlying resilience among maltreated youth. This 2‐year prospective study examined whether developmental stability of resting frontal alpha asymmetry moderated the relation between child maltreatment severity and psychopathology in female adolescents (n = 43; ages 12–16) recruited from child protection agencies. Results identified two trajectories of resting frontal asymmetry: 60.5% displayed stable right and 39.5% displayed stable left frontal alpha asymmetry. Although individuals with these alpha asymmetry profiles experienced comparable childhood trauma severity, adolescents with stable left alpha asymmetry and lower levels of trauma were less likely to present symptoms or an episode of posttraumatic stress disorder (PTSD) and depression over 2 years than those with stable right alpha asymmetry and lower levels of trauma. These findings suggest that developmental patterns of resting left frontal brain activity may buffer against psychopathology in maltreated female youth.     

School contextual experiences and longitudinal changes in depressive symptoms from adolescence to young adulthood

The current study examined the direct and multiplicative influences by adolescent school context experiences (disengagement and maltreatment) and contextual characteristics (school minority concentration and school aggregated family poverty) on changes in depressive symptoms from adolescence to young adulthood. Adolescent experiences with maltreatment and school disengagement were positively associated with changes in depressive symptoms over time. In addition, the school disengagement effect was larger among Hispanic youth than African American or European American adolescents. The influence by maltreatment was significantly greater in minority‐concentrated school contexts. Final models that included cross‐level interaction terms explained approximately 10.54% of level 1 variance and 17.10% of level 2 variance (ICC=2%). Adolescent school experiences and being of Hispanic ethnic background exert continued developmental influences on changes in young adult depressive symptoms. Thus, school‐based health promotion programs need to consider school contextual effects on the subsequent development and wellbeing of youth. © 2011 Wiley Periodicals, Inc.     

Adult attachment and gene polymorphisms of the dopamine D4 receptor and serotonin transporter (5-HTT)

Recently, the Dopamine D4 Receptor Gene (DRD4) and the Serotonin Transporter Gene (5-HTT) have been found to be candidate genes for infant attachment disorganization. The present study aimed to explore the relationship of these genes to adult attachment representations. The Adult Attachment Interview was used to assess attachment representations in 167 German adults. DNA from buccal cells was genotyped for the DRD4 VNTR Exon III and 5-HTT LPR polymorphisms with respect to the presence of the 7repeat allele and the short allele, respectively. DRD4 7repeat allele carriers were significantly more likely to be securely attached than those without 7repeat but only for subjects with unloving caregiver recollections. No association between the 5-HTT LPR polymorphism and adult attachment was found. These findings encourage further investigations to explore endophenotypical and mediating psychological processes between the DRD4 Gene and secure attachment patterns.     

Telomeric length varies with age and polymorphisms of the MAOA gene promoter in peripheral blood cells obtained from a community in Taiwan

OBJECTIVE: Telomere shortening and increased MAOA gene activity both occur with aging. We undertook to develop a predictive model of telomere shortening and to investigate the possible association between MAOA gene promoter polymorphisms and telomere length as influenced by age and gender. METHODS: A stratified random household sample was selected from a community in southern Taiwan. Of 1231 subjects attending our health-screening program, 441 agreed to have additional venous blood withdrawn for DNA extraction and genetic study. Exactly 433 subjects completed the questionnaires and genetic analysis. Their telomere lengths were distributed (6.4-11.63 kb). RESULTS: The rate of shortening per year was 69 base pairs, and the gender difference in length was not statistically significant (F = 0.091, P = 0.763). The lognormal distribution of telomere lengths was linear. The polynomial regression analysis showed Ln (telomere length) = -2.57-0.007 x age - 0.34 MAOA (adjusted R-square = 0.60). The gender effect on telomere length was not statistically significant (P = 0.52). No interaction effects were found between age, gender and MAOA gene polymorphisms. The high-activity allele of the MAOA promoter polymorphisms were negatively associated with telomere length (P = 0.013). Structural equation modeling confirmed the null model structure. The present data suggest that high-activity MAOA promoter gene polymorphisms, as in aging, are a risk factor for telomeric shortening. CONCLUSIONS: Central nervous system serotonergic activity correlates with human aggressive behavior and depression in many studies, and the MAOA promoter gene may also serve as a clinical marker in the treatment of cardiovascular disease. The predictive model and table of telomere length presented in this study will provide a quick reference for future studies.     

The effect of childhood maltreatment on suicidal ideation through cognitive emotion regulation strategies and specific obsessive–compulsive symptoms in obsessive–compulsive disorder

Childhood maltreatment is thought to be associated with suicidality in patients with obsessive–compulsive disorder (OCD). Although the underlying mechanism of this relationship is not clear, cognitive emotion regulation strategies (CERSs) and the specific OC symptoms including unacceptable obsessional thoughts (UOTs) and responsibility for harm (RFH) may underlie this link. Accordingly, the study aimed to assess the effect of childhood maltreatment on suicidal ideation through UOTs, RFH and adaptive and maladaptive CERSs in OCD patients. Three hundred patients meeting a DSM-5 diagnosis of OCD were selected and completed the scales measuring childhood maltreatment, OCD, suicidality and depressive symptoms. After controlling for depressive symptoms and OCD severity, childhood maltreatment was shown to affect suicidal ideation directly. Also, the indirect effect of childhood maltreatment on suicidal ideation was mediated by adaptive CERSs, UOTs and RFH. The findings show that OCD patients with a history of childhood maltreatment, less use of adaptive CERSs and the experiences of UOTs and RFH should be carefully considered regarding suicidal risk.     

Serotonin transporter promoter polymorphism and monoamine oxidase type A VNTR allelic variants together influence alcohol binge drinking risk in young women.

The short allelic variant of the serotonin transporter protein promoter polymorphism (5HTTLPR) appears to influence binge drinking in college students. Both monoamine oxidase type A (MAOA) and the serotonin transporter protein are involved in the processing of serotonin, and allelic variants are both associated with differences in the efficiency of expression. We hypothesized that a significant gene x gene interaction would further stratify the risk of binge drinking in this population. Participants were college students (n = 412) who completed the College Alcohol Study, used to measure binge drinking behaviors. Genomic DNA was extracted from saliva for PCR based genotyping. The risk function for binge drinking was modeled using logistic regression, with final model fit P < 0.0005. This model was valid only for Caucasian females (n = 223), but the power to detect sex and ethnic effects was small. Young Caucasian women carrying higher expression MAOA VNTR alleles homozygous for the short allelic variant of the 5HTTLPR demonstrated the highest rate of binge drinking by self-report, odds ratio (genotype odds: population odds) and 95% confidence intervals, 3.11 (1.14-18.10). Individuals carrying higher expression MAOA VNTR alleles carrying at least one long 5HTTLPR allelic variant had the lowest risk of binge drinking 0.46 (0.28-0.71). These results support the hypothesis that binge drinking behavior in young adulthood may be influenced by neurobiological differences in serotonergic function conferred by functional polymorphisms in genes involved in serotonin processing.     

Adapting to aging out: profiles of risk and resilience among emancipated foster youth

This investigation employed latent profile analysis to identify distinct patterns of multiform competence among 164 emancipated foster youth (Mage = 19.67 years, SD = 1.12; 64% female). Fit indices and conceptual interpretation converged on a four-profile solution. A subset of emancipated youth evidenced a maladaptive profile (16.5%; n = 27), which was characterized by low educational competence, low occupational competence, low civic engagement, problematic interpersonal relationships, low self-esteem, and high depressive symptoms. However, the largest group of emancipated youth exhibited a resilient profile in which they were faring reasonably well in all domains despite marked adversity (47%; n = 77). Two additional groups evidenced discordant adjustment patterns wherein they exhibited high levels of psychological competence despite behavioral difficulties (i.e., internally resilient; 30%; n = 49) or significant emotional difficulties despite manifest competence (i.e., externally resilient; 6.5%; n = 11). The obtained profiles were validated against independent measures of behavioral and socioemotional adjustment. Exploratory analyses examined etiological differences across profiles with respect to child welfare variables, such as age at entry into care, placement disruption, reason for placement, and severity of child maltreatment. The findings highlight the need for multidimensional models of risk and resilience and illustrate the importance of heretofore underappreciated heterogeneity in the adaptive outcomes of emancipated foster youth.     

Gene-gene interaction between MAOA and COMT in suicidal behavior

Several lines of evidence suggest that suicidal behavior is associated with altered noradrenergic neurotransmission. Noradrenaline (NA) is catabolized by monoamine oxidase A (MAOA) and cathecol-O-methyl transferase (COMT). We hypothesized that the genes encoding MAOA and COMT might contain genetic variation conferring increased risk for attempted suicide. In order to test this hypothesis, we genotyped the 941T > G and the promoter VNTR polymorphisms in the MAOA gene and the Val 108/158 Met COMT polymorphism in 305 families with at least one member having bipolar disorder (BD). No association with history of suicide attempt was found either in the MAOA polymorphisms (VNTR:LRS = 1.90, d.f. = 1, p = 0.16; 941T > G:LRS = 1.39, d.f. = 1, p = 0.23), or with the Val 158 Met polymorphism (LRS = 1.61, d.f.=1, p = 0.20). When we performed the haplotype analysis for MAOA gene, we found no association between suicide attempt and haplotype distribution (LRS = 3.07, d.f. = 2, p = 0.21). As both genes are involved in degrading noradreanline, we also tested the hypothesis of epistasis between MAOA polymorphisms and Val158Met, however, no additive effect was found in conferring risk for suicide attempt. These findings suggest that MAOA and COMT genes may not influence suicidal behavior in patients with bipolar disorder.     

Diverse patterns of neuroendocrine activity in maltreated children

Cortisol regulation was investigated in a sample of school-aged maltreated (n = 175) and demographically comparable low-income nonmaltreated (n = 209) children in the context of a day camp research program. Overall group differences between maltreated and nonmaltreated children were not found for average morning or average afternoon cortisol levels. However, significant variations were found that were based on the subtypes of maltreatment that the children had experienced. Maltreated children who had been both physically and sexually abused (as well as neglected or emotionally maltreated) exhibited substantial elevations in morning cortisol levels; children who had high (>1 SD) cortisol levels in both the morning and afternoon were also overrepresented in the multiple abuse group. Developmental timing of maltreatment did not account for these group differences, whereas the severity of sexual abuse was implicated. In contrast to the multiple abuse group, a subgroup of physically abused children showed evidence of a trend toward lower morning cortisol relative to nonmaltreated children with a significantly smaller decrease in cortisol levels from morning to afternoon. The findings are discussed in terms of the diversity of atypical cortisol regulation patterns that are exhibited among maltreated children.     

Meta-analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders.

Family, twin, and adoption studies show that psychiatric diseases including bipolar disorder (BP) and unipolar disorder (UP) have a substantial genetic component. For these illnesses, both positive and negative associations have been reported for two polymorphisms located in the serotonin transporter gene (5-HTT) on chromosome 17: a 17-base-pair (bp) variable-number tandem-repeat (VNTR) in intron 2 and a 44-bp insertion/deletion in the promoter region. Thus, associations between these 5-HTT polymorphisms and affective disorders remain unclear. The present work investigates these potential associations in meta-analyzes that maximize the power to find associations between each disease and the two 5-HTT polymorphisms. We applied meta-analysis techniques to case-control studies of two 5-HTT polymorphisms and two affective disorders (BP and UP), resulting in four meta-analyzes. For each polymorphism, we assessed the evidence for allelic associations, heterogeneity among studies, the influence of individual studies, and the potential for publication bias. The short allele(s) of the 44-bp insertion/deletion polymorphism showed a significant association for BP (odds ratio (OR) = 1.13, P = 0.001) but not UP. For the 17-bp VNTR, an increase in the number of tandem repeats had no significant association with any of the disorders. The small but significant effects of the 44-bp insertion/deletion polymorphism for BP is consistent with being one of many genes that contributes to the multi-factorial nature of these psychiatric disorders.     

Interactions Between Genotype and Depressive Symptoms on Obesity

Depression and Genetic variation in serotonin and monoamine transmission have both been associated with body mass index (BMI), but their interaction effects are not well understood. We examined the interaction between depressive symptoms and functional polymorphisms of serotonin transporter (SLC6A4) and monoamine oxidase A (MAOA) on categories of BMI. Participants were from the National Longitudinal Study of Adolescent Health. Multiple logistic regression was used to investigate interactions between candidate genes and depression on risk of obesity (BMI ≥ 30) or overweight + obese combined (BMI ≥ 25). Males with an MAOA active allele with high depressive symptoms were at decreased risk of obesity (OR 0.22; 95% CI 0.06–0.78) and overweight + obesity (OR 0.48; 95% CI 0.26–0.89). No similar effect was observed among females. These findings highlight that the obesity–depression relationship may vary as a function of gender and genetic polymorphism, and suggest the need for further study. Handling editor: Tatiana Foroud.     

Maltreated Youth Display a Blunted Blood Pressure Response to an Acute Interpersonal Stressor

Although there is much evidence of hypothalamic-pituitary-adrenal axis dysfunction among individuals who have experienced child maltreatment, dysregulation of the autonomic nervous system (ANS) has received less attention. Understanding the role of the ANS in maltreated children may help clarify how these children respond to subsequent life stress. We explored ANS reactivity among 111 youth (ages 9–14), 34 of whom had experienced verified child maltreatment. ANS activity was assessed via blood pressure—a convenient, noninvasive physiological index—while youth underwent a social stress task. Blood pressure and subjective mood ratings were obtained prior to and following the task. Nonmaltreated youth experienced an increase in systolic blood pressure following the stressor, whereas maltreated youth did not. Self-reported subjective mood worsened for both groups. The current data suggest that children who experienced early stress exposure demonstrate blunted ANS reactivity. Results are discussed in terms of children's healthy adaptations to transient social stressors. In addition, we discuss the cost-effectiveness and benefits of physiological measures such as blood pressure for understanding risk for psychopathology.