In the Southwestern American Indian sample we found that the low activity allele of the monoamine oxidase A functional polymorphism MAOA-LPR was significantly associated with alcoholism, particularly antisocial alcoholism, only in women who had been exposed to childhood sexual abuse. In contrast, there was no relationship between alcoholism/antisocial behavior and MAOA-LPR genotype among non-abused women (Ducci et al, 2008). In the African American men we found that exposure to childhood trauma predicted substance dependence. Severe childhood trauma predicted polysubstance dependence. The African Americans had four common haplotypes within the distal GABRA2 haplotype block: two that correspond to the Caucasian and Asian yin-yang haplotypes and two not found in other ethnic groups. One of the unique GABRA2 haplotypes predicted heroin addiction whereas the other haplotype was more common in controls and appeared to confer resilience to addiction after exposure to severe childhood trauma. Furthermore, variation in an intronic GABRA2 SNP (rs11503014) that is putatively implicated in exon splicing interacted with childhood trauma to influence addiction vulnerability, particularly to cocaine (Enoch et al, 2010). Childhood trauma is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Both factors increase risk for suicidal behavior. Alcohol and drug addiction are also associated with an increased risk of suicidality. FKBP5 is an HPA axis regulating gene at the level of the glucocorticoid receptor. Corticotropin releasing hormone (CRH) is a key regulator of the HPA axis through the CRH1 receptor. The actions of CRH are moderated by a high-affinity binding protein (CRHBP). In the group of Italian male prisoners we observed a significant influence of FKBP5 gene variation on both a lifetime history of aggressive behavior and on violent behavior in jail but only in individuals exposed to childhood trauma, in particular to physical abuse (Bevilacqua et al, 2012). In a study in African American men and women, we found that haplotypes of FKBP5 interacted with childhood trauma to predict suicide attempts: in the group exposed to high childhood trauma, 51% with two copies of the risk haplotype , 36% with one copy, and 20% with no copies had attempted suicide. In contrast, this haplotype conferred no suicide risk to individuals not exposed to childhood trauma (Roy et al, 2010). Three distal CRHBP SNPs (that we had previously associated with alcohol use disorders and anxiety disorders (Enoch et al, PLoS ONE, 2008) showed a significant interaction with childhood trauma to predict suicide attempt. In addition, there was an additive effect with FKBP5: in the group exposed to high trauma, the prevalence of suicide attempt was 0.35-0.30 in carriers of either the FKBP5 rs3800373 major homozygote or the CRHBP rs7728378 major homozygote and 0.58 in carriers of both major homozygotes. Individuals without either major homozygote were resilient to the effects of childhood trauma (suicide attempt prevalence 0.24)(Roy et al, 2012). The results of these studies suggest that, at least in individuals with substance dependence, FKBP5 and CRHBP variation may predispose, independently and additively, to suicidal behavior in individuals who have experienced significant childhood trauma. CRHR1 haplotype tagging SNPs were derived from the GWAS in the SAGE dataset. Logistic regression analyses identified significant genotype and haplotype interactive effects with traumatic stress on the likelihood of developing alcoholism. These findings are consistent with the hypothesized role of HPA axis dysregulation in the initiation and maintenance of alcoholism (Ray et al, submitted).

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2012
Total Cost
$44,098
Indirect Cost
Name
National Institute on Alcohol Abuse and Alcoholism
Department
Type
DUNS #
City
State
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Lovallo, William R; Enoch, Mary-Anne; Acheson, Ashley et al. (2016) Early-Life Adversity Interacts with FKBP5 Genotypes: Altered Working Memory and Cardiac Stress Reactivity in the Oklahoma Family Health Patterns Project. Neuropsychopharmacology 41:1724-32
Gorodetsky, E; Carli, V; Sarchiapone, M et al. (2016) Predictors for self-directed aggression in Italian prisoners include externalizing behaviors, childhood trauma and the serotonin transporter gene polymorphism 5-HTTLPR. Genes Brain Behav 15:465-73
Enoch, Mary-Anne; Hodgkinson, Colin A; Shen, Pei-Hong et al. (2016) GABBR1 and SLC6A1, Two Genes Involved in Modulation of GABA Synaptic Transmission, Influence Risk for Alcoholism: Results from Three Ethnically Diverse Populations. Alcohol Clin Exp Res 40:93-101
Enoch, Mary-Anne; Kitzman, Harriet; Smith, Joyce A et al. (2016) A Prospective Cohort Study of Influences on Externalizing Behaviors Across Childhood: Results From a Nurse Home Visiting Randomized Controlled Trial. J Am Acad Child Adolesc Psychiatry 55:376-82
Yang, J; Wang, S; Yang, Z et al. (2015) The contribution of rare and common variants in 30 genes to risk nicotine dependence. Mol Psychiatry 20:1467-78
Lovallo, William R; Enoch, Mary-Anne; Acheson, Ashley et al. (2015) Cortisol Stress Response in Men and Women Modulated Differentially by the Mu-Opioid Receptor Gene Polymorphism OPRM1 A118G. Neuropsychopharmacology 40:2546-54
Enoch, Mary-Anne (2014) Genetic influences on response to alcohol and response to pharmacotherapies for alcoholism. Pharmacol Biochem Behav 123:17-24
Heitzeg, Mary M; Villafuerte, Sandra; Weiland, Barbara J et al. (2014) Effect of GABRA2 genotype on development of incentive-motivation circuitry in a sample enriched for alcoholism risk. Neuropsychopharmacology 39:3077-86
Pecina, M; Martinez-Jauand, M; Hodgkinson, C et al. (2014) FAAH selectively influences placebo effects. Mol Psychiatry 19:385-91
Lovallo, William R; Enoch, Mary-Anne; Yechiam, Eldad et al. (2014) Differential impact of serotonin transporter activity on temperament and behavior in persons with a family history of alcoholism in the Oklahoma Family Health Patterns Project. Alcohol Clin Exp Res 38:1575-81

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