Childhood trauma is associated with hypothalamic-pituitary-adrenal axis (HPA) 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 SNPs were genotyped in a sample of African Americans: 398 treatment seeking patients with substance dependence (90% men; 120 suicide attempters) and 432 non-substance dependent individuals (40% men; 21 suicide attempters). In all, a total of 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 block, 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.

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--. Participants completed the dot-probe task, measuring attention biases toward or away from angry and happy faces. Biases for angry faces increased with the genotypepredicted neurotransmission (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.

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) Val66Met 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 Met allele carriers, 36 Val/Val homozygotes). Results Amygdala and anterior hippocampal GMVs were significantly smaller in patients than healthy 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. Additionally, insula and dorsal– anterior cingulate cortex (ACC) GMVs were modulated by BDNF genotype. In both regions, GMVs were larger in the Val/Val homozygote patients than in those 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.

The 5-HT3 receptor is rapidly potentiated by ethanol and mediates fast excitatory 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 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, 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.Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: