Gene-Environment Interations Underlying Alcoholism Vulnerability Disorders

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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.