In the sample of African American treatment-seeking substance dependent individuals and controls, we found that exposure to childhood trauma (CT) predicted substance dependence and suicidal behavior. Since variation in CNS serotonin (5-HT) levels has been associated with alcohol use disorder, aggression and violent behavior including suicidality we have recently analyzed variants in serotonergic genes including SLC6A4, HTR3B and MAOA. 5-HT acts on numerous receptors but only the 5-HT3 receptors (encoded by the HTR3B and HTR3A genes) are responsible for fast synaptic transmission. The 5-HT transporter plays a role in re-uptake of 5-HT from the synaptic cleft. SLC6A4, the gene encoding the serotonin transporter has a functional variable number of tandem repeats (VNTR) polymorphism, 5-HTTLPR, in its regulatory region and two linked functional single nucleotide polymorphisms (SNPs) in the distal region. In an earlier study we showed that the low activity 5-HTTLPR variant had an additive (but not an interactive) effect with a functional HTR3B SNP on alcohol + drug dependence (Enoch et al, 2011). We have recently found independent G x E interactive effects of 5-HTTLPR and the SLC6A4 two-SNP diplotype on suicidal behavior such that the risk of suicide attempt was greater in carriers of the low activity 5-HTTLPR variant and the major ATAT diplotype and was greatest in carriers of both variants but only in individuals exposed to high CT (Enoch et al, 2013). In contrast, in our collaborative study with Dr Lovallo of the Oklahoma Family Health Patterns dataset of healthy young adults we found that only in individuals with a family history of alcoholism (FH+), carriers of the high activity 5-HTTLPR variant scored higher in negative moods and poorer affect regulation (neuroticism, harm avoidance, depressive symptoms) (Lovallo et al, 2014). Thus in FH+ individuals, the high activity 5-HTTLPR variant may be a risk factor for a drinking pattern that is compensatory for such affective tendencies. Moreover, we have recently shown that the high activity variant predicts self-directed aggressive behavior in the male Italian prisoned dataset (Gorodetsky et al, submitted). The X-linked MAOA gene, encoding the MAOA enzyme that plays a role in the degradation of serotonin and other neurotransmitters, has a functional VNTR in the promoter region (MAOA-LPR) that has been shown to influence aggression. We investigated the interactive effect of MAOA-LPR genotype and a history of childhood trauma in predicting aggressive behaviors in a male prisoner population. Our findings suggest that early life physical neglect and MAOA-LPR may interact to specifically increase risk for overt aggressive behavior but not impulsivity or hostility. Moreover, 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 (Gorodetsky et al, 2014). In contrast, in the Southwestern American Indian female sample we previously demonstrated that the MAOA-LPR low activity allele was significantly associated with alcoholism, particularly antisocial alcoholism, but only in women who had been exposed to childhood sexual abuse (Ducci et al, 2008). We have been collaborating with Dr. Olds on a randomized controlled trial of prenatal/infancy nurse home visits (NHV) conducted in 600 predominantly African American, economically deprived mothers and their firstborn children from Memphis, TN. Assessments of mothers in pregnancy included mental health (MH), self-efficacy and mastery. Mothers reported longitudinally on smoking and alcohol/drug use. The functional polymorphisms SLC6A4 5-HTTLPR, FKBP5 rs1360780 and DRD2/ANKK1 rs1800497 were genotyped together with 186 AIMs. Composite internalizing (ID) and externalizing (ED) disorders scores from the mother-report Achenbach Child Behavior Checklist wwere included as dependent variables in regression analyses for time-points 2, 6, 12 and 18 years. We found that ID and ED scores were correlated (p<0.0001) at all time-points. Behaviors at younger ages strongly predicted later behaviors (p<0.0001). Children whose mothers had high self-efficacy and had received NHV were better behaved at age 2. Poorer maternal MH adversely influenced ID/ED up to 12 years but at age 18, maternal mastery exerted a strong, positive effect (p=0.0001). Maternal smoking was associated with worse ID/ED at 6 and 18. Genetic predictors varied across childhood: FKBP5 rs1360780 up to age 6, 5-HTTLPR from 6 to 12 and DRD2/ANKK1 rs1800497 from 2 to 18 years. Our study suggests that there are long-lasting effects of maternal MH, resilience and smoking on childhood behavior and that genetic factors play a role. NHV had a positive effect on early behavior. Our findings have implications for prevention of pathological behaviors in adulthood (Enoch et al, submitted).
Showing the most recent 10 out of 53 publications
