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 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). In both sexes, exposure to family adversity and stressful life events in the first three years of life predicted behavioral disinhibition at age 4, persisting until at least age 7. In girls, MAOA-LPR interacted with stressful life events experienced from 6 months to 3.5 years to influence hyperactivity at ages 4 and 7. In boys, the interaction of MAOA-LPR with stressful life events between 1.5 and 2.5 years predicted hyperactivity at age 7 years. The low activity MAOA-LPR variant was associated with increased hyperactivity in girls and boys exposed to high stress. In contrast, there was no MAOA-LPR interaction with family adversity.(Enoch et al,in press, Genes Brain Behav). Maternal depression and stressful life events increased the odds of high emotionality in children but there were no main or interactive effects of COMT Val158Met (Evans et al, 2009) or 5-HTTLPR (Araya et al, 2009) on behavior. In the American Indian sample we found that the MAOA-LPR low activity allele was significantly associated with alcoholism, particularly antisocial alcoholism, only in women who had been exposed to childhood sexual abuse. In contrast, there was no relationship between alcoholism/antisocial behavior and MAOA-LPR genotype among non-abused women (Ducci et al, 2008). In the African American men we found that exposure to childhood trauma predicted substance dependence. Severe childhood trauma predicted polysubstance dependence. The African Americans had four common haplotypes within the distal GABRA2 haplotype block: two that correspond to the Caucasian and Asian yin-yang haplotypes and two not found in other ethnic groups. One of the unique GABRA2 haplotypes predicted heroin addiction whereas the other haplotype was more common in controls and appeared to confer resilience to addiction after exposure to severe childhood trauma. Furthermore, variation in an intronic GABRA2 SNP (rs11503014) that is putatively implicated in exon splicing interacted with childhood trauma to influence addiction vulnerability, particularly to cocaine (Enoch et al, in press, Biol Psychiatry). In another study in African American men and women, we found that haplotypes of FKBP5, a stress related gene, interacted with childhood trauma to predict suicide attempts: in the group exposed to high childhood adversity, 51% with two copies of the risk haplotype , 36% with one copy, and 20% with no copies had attempted suicide. In contrast, this haplotype conferred no suicide risk to individuals not exposed to childhood trauma (Roy et al, submitted).
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