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).
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