Gene-Environment Interations Underlying Alcoholism Vulnerability Disorders

儿童时期的逆境往往早于反社会行为等外化行为和抑郁等内化行为，这两者都是问题饮酒和酗酒的危险因素。我们使用了来自父母和儿童的雅芳纵向研究(ALSPAC)的大约7000名高加索女孩和男孩的出生队列中来自父母和教师自我报告问卷的数据。英国母亲在怀孕早期招募，他们的孩子直到8岁的数据都是可用的。我们对儿童的DNA进行了单胺氧化酶A(MAOA-LPR)、5-羟色胺转运体(5-HTTLPR)和儿茶酚-O-甲基转移酶(COMT Val158Met)三个基因功能多态性的基因分型。 我们发现，在两性中：(A)几乎所有应激源的影响最大是在0至2岁；(B)出生后不久的应激预测反社会行为(行为障碍、多动症和多动症)最早可以在4岁时检测到，并至少持续到8岁；(C)母亲的焦虑/抑郁对行为的影响最大；(D)在同一时间段经历的应激生活事件的影响相同，但影响较小；(E)在两性中，MAOA-LPR和生活事件对行为，尤其是多动症的影响是相互作用的，对女孩的影响最强。 我们的结果表明，轻微的应激源可以对成人精神病理学的行为预测产生长期影响。在一般人群中，母亲的精神病态是对幼儿行为最重要的负面影响。时机很重要：出生后不久暴露在逆境中的影响最大，因此早期预防干预至关重要。MAOA-LPR基因在普通人群中影响风险-恢复力平衡，而不只是在暴露于严重虐待的亚组中。 我们的研究还表明，母亲的抑郁和紧张的生活事件与6至7岁儿童的情绪性增加有关。女孩的应激性生活事件与5-HTTLPR基因型之间存在交互作用：5-羟色胺转运体低和中等表达的女孩在暴露于压力时表现出更高的情绪性，而高表达基因型的女孩对压力的影响具有弹性。COMT基因对儿童情绪性没有主效应或交互效应。 上述研究的结果已写成三份已提交出版的手稿。

Childhood adversity often pre-dates externalizing behaviors such as antisocial behavior and internalizing behaviors such as depression, both of which are risk factors for problem drinking and alcoholism. We have used data derived from parental and teacher self-report questionnaires in a birth cohort of approximately 7000 Caucasian girls and boys from the Avon Longitudinal Study of Parents and Children (ALSPAC), U.K. Mothers were recruited in early pregnancy and data is available on their children up to age 8 years. We have genotyped the children's DNA for functional polymorphisms in three genes: monoamine oxidase A (MAOA-LPR), serotonin transporter (5-HTTLPR) and catechol-O-methyltransferase (COMT Val158Met). We have found that in both sexes: (a) the maximum impact of nearly all stressors was at ages 0 to 2 years; (b) stress soon after birth predicted antisocial behavior (conduct disturbances, hyperactivity and ADHD) detectable as early as age 4 and persisting until at least age 8 years; (c) maternal anxiety / depression had the greatest influence (d) stressful life events experienced during the same time frame has the same, although less powerful, influence; (e) There was an interaction between MAOA-LPR and life events on behavior, particularly hyperactivity, in both sexes, with the effects strongest in girls. Our results have shown that mild stressors can have long-term effects on behavior predictive of adult psychopathology. Maternal psychopathology is the most important negative influence on young childrens behavior in the general population. Timing is important: exposure to adversity soon after birth has a maximal effect therefore early preventive intervention is critical. MAOA-LPR genotype influences the risk-resilience balance in the general population and not only in subgroups exposed to severe maltreatment. Our studies have also shown that maternal depression and stressful life events were associated with increased emotionality in children aged 6 to 7 years. There was an interaction between stressful life events and 5-HTTLPR genotype in girls: those girls with low and intermediate expression of the serotonin transporter exhibited increased emotionality when exposed to stress whereas the girls with high expression genotypes were resilient to the effects of stress. There was no main or interactive effect of COMT genotype on childhood emotionality. The results of the studies described above have been written up in three manuscripts that have been submitted for publication.