Elena Gorodetsky

Interaction of FKBP5, a Stress-Related Gene, with Childhood Trauma Increases the Risk for Attempting Suicide

Childhood trauma is associated with hypothalamic–pituitary–adrenal (HPA) axis dysregulation and is a known risk factor for suicidal behavior. In this study we sought to determine whether the impact of childhood trauma on suicide risk might be modified by FKBP5, an HPA-axis regulating gene. Sixteen FKBP5 haplotype-tagging single nucleotide polymorphisms (SNPs) were genotyped in a sample of African Americans: 398 treatment-seeking patients with substance dependence (90% men; 120 suicide attempters) and 432 nonsubstance-dependent individuals (40% men; 21 suicide attempters). In all, 474 participants (112 suicide attempters) also completed the Childhood Trauma Questionnaire (CTQ). Primary haplotype analyses were conducted with the four SNPs implicated in earlier studies: rs3800373, rs9296158, rs1360780, and rs9470080. We found that childhood trauma was associated with suicide attempt (P<0.0001). Although there was no main effect of the two major yin yang haplotypes in the four SNP haplotype blocks, there was a haplotype influence on suicide risk (p=0.006) only in individuals exposed to high levels of childhood trauma. In this group, 51% with two copies of the risk haplotype, 36% with one copy, and 20% with no copies had attempted suicide. The total logistic regression model accounted for 13% of the variance in attempted suicide. Analyses of the 16 SNPs showed significant main effects on suicide attempt of rs3777747, rs4713902, and rs9470080 and interactive effects of rs3800373, rs9296158, and rs1360780 with CTQ score on suicide attempt. These data suggest that childhood trauma and variants of the FKBP5 gene may interact to increase the risk for attempting suicide.

Variations in the serotonin-transporter gene are associated with attention bias patterns to positive and negative emotion faces

Both attention biases to threat and a serotonin-transporter gene polymorphism (5-HTTLPR) have been linked to heightened neural activation to threat and the emergence of anxiety. The short allele of 5-HTTLPR may act via its effect on neurotransmitter availability, while attention biases shape broad patterns of cognitive processing. We examined individual differences in attention bias to emotion faces as a function of 5-HTTLPR genotype. Adolescents (N=117) were classified for presumed SLC6A4 expression based on 5-HTTLPR-low (SS, SL(G), or L(G)L(G)), intermediate (SL(A) or L(A)L(G)), or high (L(A)L(A)). Participants completed the dot-probe task, measuring attention biases toward or away from angry and happy faces. Biases for angry faces increased with the genotype-predicted neurotransmission levels (low>intermediate>high). The reverse pattern was evident for happy faces. The data indicate a linear relation between 5-HTTLPR allelic status and attention biases to emotion, demonstrating a genetic mechanism for biased attention using ecologically valid stimuli that target socioemotional adaptation.

Functional genetic variants that increase synaptic serotonin and 5-HT3 receptor sensitivity predict alcohol and drug dependence.

The 5-HT3 receptor is rapidly potentiated by ethanol and mediates fast excitatory serotonin (5-HT) transmission that modulates dopamine release in the reward circuitry. The 5-HT transporter regulates synaptic 5-HT availability. Functional polymorphisms in genes encoding the transporter and receptor may therefore influence addiction vulnerability. In this study, 360 treatment-seeking African American male patients with single and comorbid DSM-IV lifetime diagnoses of alcohol, cocaine and heroin dependence and 187 African American male controls were genotyped for the triallelic 5-HTTLPR functional polymorphism in the 5-HT transporter gene (SLC6A4) and 16 haplotype-tagging single-nucleotide polymorphisms (SNPs) across HTR3B (including the functional rs1176744 Tyr129Ser) and HTR3A, genes encoding 5-HT3 receptors. The HTR3B rs1176744 gain-of-function Ser129 allele predicted alcohol dependence (P=0.002) and low 5-HTTLPR activity predicted cocaine/heroin dependence (P=0.01). Both the HTR3B Ser129 allele (P=0.014, odds ratio (OR)=1.7 (1.1–2.6)) and low 5-HTTLPR activity (P=0.011, OR=2.5 (1.3–4.6)) were more common in men with alcohol+drug dependence compared with controls. Moreover, the HTR3B Ser129 allele and low 5-HTTLPR activity had an additive (but not an interactive) effect on alcohol+drug dependence (OR=6.0 (2.1–16.6)) that accounted for 13% of the variance. One possible explanation of our findings is that increased synaptic 5-HT coupled with increased 5-HT3 receptor responsiveness may result in enhanced dopamine transmission in the reward pathway, a predictor of increased risk for addiction. Our results may have pharmacogenetic implications for 5-HT3 therapeutic antagonists such as ondansetron.

Attention to Threats and Combat-Related Posttraumatic Stress Symptoms: Prospective Associations and Moderation by the Serotonin Transporter Gene

IMPORTANCE Combat places soldiers at risk for posttraumatic stress disorder (PTSD). The excessive rates of PTSD and other adjustment disorders in soldiers returning home make it imperative to identify risk and resilience factors that could be targeted by novel therapeutic treatments. OBJECTIVE To investigate the interplay among attention to threat, combat exposure, and other risk factors for PTSD symptoms in soldiers deployed to combat. DESIGN AND SETTING Longitudinal prospective study of Israeli Defense Force infantry soldiers carried out in 2008 through 2010. Repeated measurements during a 1-year period included baseline and predeployment data collected in training camps and deployment data collected in the combat theater. PARTICIPANTS Infantry soldiers (1085 men; mean age, 18.8 years). MAIN OUTCOME MEASURES Postcombat PTSD symptoms. RESULTS Soldiers developed threat vigilance during combat deployment, particularly when they were exposed to high-intensity combat, as indicated by faster response times to targets appearing at the location of threat relative to neutral stimuli (P < .001). Threat-related attention bias also interacted with combat exposure to predict risk for PTSD (P < .05). Bias toward threat at recruitment (P < .001) and bias away from threat just before deployment (P < .05) predicted postcombat PTSD symptoms. Moreover, these threat-related attention associations with PTSD were moderated by genetic and environmental factors, including serotonin transporter (5-HTTLPR) genotype. CONCLUSIONS AND RELEVANCE Combat exposure interacts with threat-related attention to place soldiers at risk for PTSD, and interactions with other risk factors account for considerable variance in PTSD vulnerability. Understanding these associations informs research on novel attention bias modification techniques and prevention of PTSD.

The influence of oxytocin administration on responses to infant faces and potential moderation by OXTR genotype.

RationaleOxytocin is a neuropeptide that is associated with increases in social affiliative behaviors, particularly toward infants. However, no previous study has investigated healthy adults’ responses to infant faces following oxytocin administration. In addition, given that preliminary evidence suggests that a single-nucleotide polymorphism of the oxytocin receptor (OXTR) gene, rs53576, may influence behaviors associated with parental sensitivity, we assessed whether such responses vary according to OXTR rs53576 genotype.ObjectivesThe present study assessed the effects of intranasally administered oxytocin and OXTR genotype on human adults’ preferences for infant faces.MethodsA double-blind, between-groups design was used, with 57 genotyped volunteers randomly assigned to receive intranasally administered oxytocin or placebo. Fifty minutes following the administration of oxytocin or placebo, participants viewed infants’ and adults’ faces showing neutral expressions and assessed how appealing they found each face.ResultsInfants’ faces were more strongly preferred following oxytocin inhalation relative to placebo. When participants were separated according to genotype, this effect was only observed for participants homozygous for the rs53576G allele. Parallel effects were not seen for adults’ faces.ConclusionsThe present results are consistent with the hypothesis that acute oxytocin administration increases sensitivity to reward-relevant features of infants and/or reduces sensitivity to their aversive properties. The results are also consistent with suggestions of more efficient oxytocinergic function in rs53576G homozygotes.

Serotonin polymorphisms and posttraumatic stress disorder in a trauma exposed African American population

Background: Genetic polymorphisms that influence serotonin (5‐hydroxytryptamine, 5HT) neurotransmission are candidates for contributing to susceptibility to posttraumatic stress disorder (PTSD). The objective of our study was to determine if a variable length polymorphism for the promoter regions of the 5HT transporter (5HTTLPR), and/or a substitution polymorphism in the promoter region for the 5HT2A receptor, would be associated with PTSD in a trauma exposed population of adult African‐Americans. Methods: Using a case control design, 118 participants recruited from the primary care clinics and the campus of a historically black university who met inclusion criteria including trauma exposure provided blood samples for genomic DNA. PTSD criteria were determined by the Clinician Assessment of PTSD Scale (CAPS) and criteria for other psychiatric disorders by the Structured Clinical Interview for DSM‐IV (SCID). 5HTTLPR and 5HT2A‐1438A/G were genotyped using established methods. Associations of genotypes with lifetime PTSD, and models testing associations of allele “dose”, were analyzed. Results: Fifty‐five (47%) participants met lifetime criteria for PTSD and 26 (22%) met criteria for (mostly comorbid) major depression. The 5HT2A (lower expressing) G allele was significantly associated with PTSD. We did not find significant associations with 5HTTLPR. Conclusions: Our findings suggest a relationship between genetic variation in the 5HT2A promoter region and PTSD. Depression and Anxiety 26:993–997, 2009. Published 2009 Wiley‐Liss, Inc.

Gray Matter Volume in Adolescent Anxiety: An Impact of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism?

OBJECTIVE Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val(66)Met polymorphism may modulate such brain morphometry profiles. METHOD Using voxel-based morphometry and magnetic resonance imaging, associations of BDNF and clinical anxiety with regional GMVs of anterior cingulate cortex, insula, amygdala, and hippocampus were examined in 39 affected (17 Met allele carriers, 22 Val/Val homozygotes) and 63 nonaffected adolescents (27 [corrected] Met allele carriers, 36 [corrected] Val/Val homozygotes). RESULTS Amygdala and anterior hippocampal GMVs were significantly smaller in patients than in healthy comparison adolescents, with a reverse pattern for the insula. Post-hoc regression analyses indicated a specific contribution of social phobia to the GMV reductions in the amygdala and hippocampus. In addition, insula and dorsal-anterior cingulate cortex (ACC) GMVs were modulated by BDNF genotype. In both regions, and GMVs were larger in the Val/Val homozygote patients than in individuals carrying the Met allele. CONCLUSIONS These results implicate reduced GMV in the amygdala and hippocampus in pediatric anxiety, particularly social phobia. In addition, the data suggest that genetic factors may modulate differences in the insula and dorsal ACC.

DRD4 and striatal modulation of the link between childhood behavioral inhibition and adolescent anxiety

Behavioral inhibition (BI), a temperament characterized by vigilance to novelty, sensitivity to approach-withdrawal cues and social reticence in childhood, is associated with risk for anxiety in adolescence. Independent studies link reward hyper-responsivity to BI, adolescent anxiety and dopamine gene variants. This exploratory study extends these observations by examining the impact of DRD4 genotype and reward hyper-responsivity on the BI-anxiety link. Adolescents (N = 78) completed a monetary incentive delay task in the fMRI environment. Participants were characterized based on a continuous score of BI and the 7-repeat allele (7R+) of the DRD4 functional polymorphism. Parent-report and self-report measures of anxiety were also collected. Across the entire sample, striatal activation increased systematically with increases in the magnitude of anticipated monetary gains and losses. DRD4 status moderated the relation between BI and activation in the caudate nucleus. Childhood BI was associated with parent report of adolescent anxiety among 7R+ participants with elevated levels of striatal response to incentive cues. DRD4 genotype influenced the relations among neural response to incentives, early childhood BI and anxiety. The findings help refine our understanding of the role reward-related brain systems play in the emergence of anxiety in temperamentally at-risk individuals, building a foundation for future larger scale studies.

The MAOA gene predicts happiness in women.

Psychologists, quality of life and well-being researchers have grown increasingly interested in understanding the factors that are associated with human happiness. Although twin studies estimate that genetic factors account for 35-50% of the variance in human happiness, knowledge of specific genes is limited. However, recent advances in molecular genetics can now provide a window into neurobiological markers of human happiness. This investigation examines association between happiness and monoamine oxidase A (MAOA) genotype. Data were drawn from a longitudinal study of a population-based cohort, followed for three decades. In women, low expression of MAOA (MAOA-L) was related significantly to greater happiness (0.261 SD increase with one L-allele, 0.522 SD with two L-alleles, P=0.002) after adjusting for the potential effects of age, education, household income, marital status, employment status, mental disorder, physical health, relationship quality, religiosity, abuse history, recent negative life events and self-esteem use in linear regression models. In contrast, no such association was found in men. This new finding may help explain the gender difference on happiness and provide a link between MAOA and human happiness.

The interactive effect of MAOA-LPR genotype and childhood physical neglect on aggressive behaviors in Italian male prisoners

Aggressive disorders are moderately heritable; therefore, identification of genetic influences is important. The X‐linked MAOA gene, encoding the MAOA enzyme, has a functional 30 bp repeat polymorphism in the promoter region (MAOA‐LPR) that has been shown to influence aggression. Childhood trauma is a known risk factor for numerous psychopathologies in adulthood including aggressive behaviors. We investigated the interactive effect of MAOA‐LPR genotype and a history of childhood trauma in predicting aggressive behaviors in a prisoner population. A total of 692 male prisoners were genotyped for MAOA‐LPR with genotypes grouped into high and low transcriptional activity. Participant evaluations included measures of aggression (Brown‐Goodwin Lifetime History of Aggression, BGHA), hostility (Buss–Durkee Hostility Inventory), impulsivity (Barratt Impulsiveness Scale), violence directed toward self and others, and childhood trauma [Childhood Trauma Questionnaire (CTQ)]. MAOA‐LPR interacted with CTQ physical neglect (PN), the most common (47%) form of childhood trauma in this sample, to predict BGHA aggression (P = 0.002). Within the group not exposed to PN, carriers of the MAOA‐LPR high‐activity variant were more aggressive: (tR  = 2.47, P < 0.014). We observed a crossover effect in that the increase in aggression scores with PN was greater in low‐activity individuals (tR = 5.55, P < 0.0001) than in high‐activity individuals (tR = 4.18, P < 0.0001). These findings suggest that childhood trauma and the functional MAOA‐LPR polymorphism may interact to specifically increase risk for over aggressive behavior but not impulsivity or hostility. The MAOA‐LPR low‐activity variant may be protective against the development of aggressive behavior under low stress conditions, at least in this prisoner population.