Gene-Environment Interactions Underlying Alcoholism Vulnerability Disorders

在非裔美国人寻求治疗的物质依赖者和对照组的样本中，我们发现，童年创伤(CT)的暴露预示着物质依赖和自杀行为。由于中枢神经系统5-羟色胺(5-HT)水平的变化与酒精使用障碍、攻击性和包括自杀在内的暴力行为有关，我们最近分析了5-羟色胺能基因的变异，包括SLC6A4、HTR3B和MAOA。5-羟色胺作用于多种受体，但只有5-HT3受体(由HTR3B和HTR3A基因编码)负责快速突触传递。5-羟色胺转运体在5-羟色胺从突触间隙重新摄取的过程中起作用。5-羟色胺转运体基因SLC6A4在其调控区有一个功能可变数目串联重复序列(5-HTTLPR)多态，在远端区域有两个连锁功能单核苷酸多态(SNPs)。在早期的一项研究中，我们表明低活性的5-HTTLPR变体与功能性HTR3B SNP在酒精+药物依赖方面具有相加(但不是交互)效应(Enoch等人，2011年)。我们最近发现，5-HTTLPR和SLC6A4两个SNP双倍型对自杀行为有独立的GE交互作用，因此在低活性5-HTTLPR变异体和主要ATAT双倍型携带者中自杀企图的风险更大，在这两个变异体的携带者中最大，但仅在接触高CT的个体中(Enoch等人，2013)。相比之下，在我们与俄克拉荷马州家庭健康模式数据库的Lovallo博士对健康年轻人的合作研究中，我们发现只有在有酗酒家族史(FH+)的个人中，高活动5-HTTLPR变体的携带者在负面情绪中得分更高，而情感调节(神经质、伤害回避、抑郁症状)较差(Lovallo等人，2014)。因此，在FH+个体中，高活性的5-HTTLPR变体可能是饮酒模式的一个危险因素，这种饮酒模式是对这种情感倾向的补偿。 X连锁的MAOA基因编码MAOA酶，在5-羟色胺和其他神经递质的降解中起作用，在启动子区域(MAOA-LPR)具有功能上的VNTR，已被证明影响攻击性。我们研究了MAOA-LPR基因和童年创伤史在预测男性囚犯群体攻击行为方面的交互作用。我们的发现表明，早期生活、身体忽视和MAOA-LPR可能会特别增加公开攻击行为的风险，但不会增加冲动或敌意。此外，MAOA-LPR低活动变体可能对低应激条件下攻击行为的发展具有保护作用，至少在这个囚犯群体中是这样(GoroDetsky等人，2014年)。相反，在美国西南部印第安人的女性样本中，我们先前证明MAOA-LPR低活性等位基因与酒精中毒，特别是反社会酒精中毒显著相关，但仅在儿童期性虐待暴露过的女性中(Ducci等人，2008年)。 目前，我们与奥兹博士合作，对600名非洲裔美国人第一个出生的孩子及其母亲进行了纵向研究，从出生前到18年，我们已经有了初步的结果。我们最初分析了rs279858，这是GABRA2基因(编码GABAA2受体亚单位)中的一个标签SNP，它与成年后的酒精中毒和青春期的外部性疾病密切相关。我们发现，两岁时外化障碍(ED)和内化障碍(ID)得分的独立预测因素包括性别、母性掌握、母体心理健康、母体心理健康×GABRA2 rs279858交互作用和母体自我效能×护士家访(NHV)交互作用。在后一种情况下，母亲高自我效能感和接受过NHV的儿童的ED和ID得分均显著低于其他3组。GABRA2 rs279858的影响在18岁时再次出现，对ED和ID都有主要影响。此外，GABRA2 rs279858基因与12岁的青少年ED之间存在交互作用-报告18岁时的酒精和药物使用障碍。进一步的分析正在使用其他压力基因功能变体，包括5-HTTLPR，MAOA-LPR和FKBP5 rs1360780。

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.