Gene-Environment Interactions Underlying Alcoholism Vulnerability Disorders

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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 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. 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 currently have preliminary results from our collaboration with Dr Olds on a longitudinal study of a cohort of 600 African American firstborn children and their mothers, followed from pre-birth to 18 years. We have initially analyzed rs279858, a tag SNP in the GABRA2 gene (encoding the GABAA2 receptor subunit) that has been robustly associated with alcoholism in adulthood and externalizing disorders across adolescence. We have shown that independent predictors for both externalizing disorders (ED) and internalizing disorders (ID) scores at age two include sex, maternal mastery, maternal mental health, a maternal mental health x GABRA2 rs279858 interaction and a maternal self-efficacy x nurse home visiting (NHV) interaction. In the latter case, ED and ID scores were both significantly lower in children whose mothers had high self-efficacy and had received NHV, compared with the other 3 groups. The influence of GABRA2 rs279858 emerged again at age 18 with a main effect on both ED and ID. Moreover, there was an interactive effect between GABRA2 rs279858 genotype and youth-report ED at age 12 on alcohol and drug use disorders at age 18. Further analyses are underway using other stress-gene functional variants, including 5-HTTLPR, MAOA-LPR and FKBP5 rs1360780.