Since variation in CNS serotonin (5-HT) levels has been associated with alcohol use disorder (AUD), aggression and violent behavior including suicidality we have analyzed variants in serotonergic genes including SLC6A4, HTR3B and MAOA. 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. We have 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 childhood trauma (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, 2016). The GABAergic system is strongly implicated in addiction. Animal and human studies indicate that GABBR1, encoding the GABAB1 receptor subunit, and SLC6A1, encoding the neuronal GABA transporter GAT1, play a role in addiction by modulating synaptic GABA. In an earlier RNA-Seq study of GABAergic gene expression in human postmortem hippocampus we found that GABBR1 was down-regulated in alcoholics and cocaine addicts relative to controls, potentially resulting in increased synaptic GABA (Enoch et al., 2012). Therefore we investigated GABBR1 and SLC6A1 variants as predictors for risk/resilience for AUD. We found a significant and congruent association between AUD and GABBR1 rs29220 in three populations: African Americans, Plains Indians and Finnish Caucasians, and between AUD and a uniquely African SLC6A1 insertion/deletion polymorphism. Our results showed that with both GABBR1 and SLC6A1, the minor genotypes/alleles were protective against risk for AUD (Enoch et al, 2016). Our findings suggest that GABBR1 rs29220 might predict treatment response/adverse effects for baclofen, a GABAB receptor agonist. Further work with GABAergic genes, including GPHN, GAD1 and GAD2, is ongoing. 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 common functional polymorphisms 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 were 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 at all time-points (p < 0.0001). 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 (Enoch et al, 2016). Externalizing behaviors in childhood have been associated with increased risk of psychopathology in adulthood, including alcohol and drug addiction. The strength of this study is that a large cohort of pregnant women was recruited and their children were assessed at regular intervals from ages 2 to 18 years. Therefore it was possible to track across development genetic and environmental influences on behaviors that predict addiction. The findings of this study have implications for early preventive measures against the development of addiction.
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