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双倍型对自杀行为具有独立的G x E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未遂的风险更大，在这两个变异体的携带者中最大，但仅在暴露于高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。此外，我们最近已经表明，在意大利男性囚禁数据集中，高活动变体预测自我定向攻击行为(GoroDetsky等人，提交)。 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)。 我们一直在与奥兹博士合作，对田纳西州孟菲斯的600名以非裔美国人为主、经济贫困的母亲和她们的第一个孩子进行产前/婴儿期护士家访(NHV)的随机对照试验。对孕期母亲的评估包括心理健康(MH)、自我效能感和掌握能力。母亲们纵向报告吸烟和酗酒/吸毒的情况。SLC6A4 5-HTTLPR、FKBP5 rs1360780和DRD2/ANKK1 rs1800497与186个AIMS一起进行基因分型。母亲报告Achenbach儿童行为量表中的综合内在性(ID)和外在性(ED)障碍得分被纳入2、6、12和18岁时间点的因变量回归分析。我们发现ID和ED分数在所有时间点都是相关的(p&lt；0.0001)。年轻时的行为强烈预示着以后的行为(p&lt；0.0001)。母亲自我效能感高的儿童在2岁时表现较好。母亲较差的MH在12岁时对ID/ED有负面影响，但在18岁时，母亲的掌握对ID/ED有较强的正向影响(p=0.0001)。母亲吸烟与6岁和18岁较差的ID/ED相关。儿童时期的遗传预测因子各不相同：FKBP5 rs1360780至6岁，5-HTTLPR从6至12岁，DRD2/ANKK1 rs1800497从2岁至18岁。我们的研究表明，母亲的MH、韧性和吸烟对儿童行为有长期的影响，遗传因素也起到了作用。NHV对早期行为有积极影响。我们的发现对预防成年期的病理行为有一定的意义(Enoch等人提交)。 &#8195；

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 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 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. Moreover, we have recently shown that the high activity variant predicts self-directed aggressive behavior in the male Italian prisoned dataset (Gorodetsky et al, submitted). 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 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 functional polymorphisms SLC6A4 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 wwere 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 (p<0.0001) at all time-points. 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. Our findings have implications for prevention of pathological behaviors in adulthood (Enoch et al, submitted). &#8195;