Gene-Environment Interations Underlying Alcoholism Vulnerability Disorders

童年的逆境往往早于诸如反社会行为等外在行为和诸如抑郁症等内在行为，这两者都是问题饮酒和酗酒的风险因素。我们使用了来自英国雅芳父母和儿童纵向研究（ALSPAC）的约7000名白人女孩和男孩的出生队列中父母和教师自我报告问卷的数据。招募了怀孕早期的母亲，并提供了她们8岁以下子女的数据。我们对儿童的DNA进行了三个基因的功能多态性的基因分型：单胺氧化酶A（MAOA-LPR），5-羟色胺转运蛋白（5-HTTLPR）和儿茶酚-O-甲基转移酶（COMT Val 158 Met）。 我们发现，在两性中：（a）几乎所有压力源的最大影响都发生在0到2岁的年龄段;（B）出生后不久的压力预示着反社会行为（行为障碍，多动症和ADHD）早在4岁时就可检测到，并持续到至少8岁;（c）母亲焦虑/抑郁的影响最大（d）在同一时间段内经历的压力性生活事件具有相同的影响，尽管影响力较小;（e）MAOA-LPR和生活事件对男女行为，特别是多动症的影响之间存在相互作用，对女孩的影响最大。 我们的研究结果表明，轻度压力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，母亲的精神病理学是对幼儿行为最重要的负面影响。时机很重要：出生后不久暴露于逆境的影响最大，因此早期预防干预至关重要。MAOA-LPR基因型影响一般人群的风险弹性平衡，而不仅仅是在暴露于严重虐待的亚组中。 我们的研究还表明，母亲抑郁和压力性生活事件与6至7岁儿童的情绪增加有关。有一个紧张的生活事件和5-HTTLPR基因型的女孩之间的相互作用：这些女孩与5-羟色胺转运蛋白的低和中等表达表现出增加的情绪时，暴露于压力，而高表达基因型的女孩有弹性的压力的影响。COMT基因型对儿童情绪性无主效应或交互效应。 上述研究的结果已写成三份手稿，已提交出版。

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.