In our longitudinal study of a large U.K. population sample, ALSPAC, we found that childhood stressful life events and family adversity, in particular maternal psychopathology and social deprivation experienced in the first few years of life, were associated with behavioral disinhibition detectable as early as age four years. The components of overall adversity and the timing had differing effects on behavior and no one component adequately explained all the variation (Tables , ). In girls, the interaction of MAOA-LPR with stressful life events experienced from ages 6 months to 3 ½ years predicted hyperactivity at ages 4 and 7 years. In boys, the interaction of MAOA-LPR with stressful life events experienced between ages 1 ½ and 2 ½ years predicted hyperactivity at 7 years. Although early-life family adversity was a strong predictor of behavioral disinhibition there was no interaction with MAOA-LPR genotype. It may well be that different stressors interact with different genes at different time-points during development to influence behavior.
In line with earlier G × E studies (Caspi et al, 2002
; Ducci et al, 2008
; Foley et al, 2004
; Kim-Cohen et al, 2006
; Widom and Brzustowicz, 2006
) we found that in both sexes, the low activity MAOA-LPR
allele imparted risk for hyperactivity in the context of early life stress. Moreover, our results indicate a crossover of risk whereby in the 25% of girls who had been exposed to the greatest stress (≥ 9 life events from 6 months to 3.5 years), the low activity allele was associated with increased hyperactivity. In contrast, in the 75% of girls who had been exposed to less or no stress, the low activity allele was associated with lower hyperactivity. Based on our results it is tempting to speculate that the MAOA-LPR
low activity allele confers risk for behavioral inhibition in the absence of stress and behavioral disinhibition in the presence of significant stress whereas modest early life stress exposure is beneficial to all genotypes (the crossover point of graphs in ). Childhood inhibited and disinhibited behaviors both predict psychopathology in young adulthood (Caspi et al, 1996
). However, the SDQ hyperactivity scores are not diagnostic of pathology per se and therefore the terms behavioral ‘inhibition’ and ‘disinhibition’ may be inappropriate descriptors in our study. Nevertheless, similar G × E crossover effects have been reported in three community studies of boys with longitudinal measures of maltreatment (Caspi et al, 2002
; Foley et al, 2004
; Kim-Cohen et al, 2006
). Although our results are in line with earlier findings, it should be noted that apparently significant G×E interactions can actually be statistical artifacts (Eaves, 2006
The results of our longitudinal study suggest that children may be most susceptible to family adversity in the first year of life and stressful life events in the first three years of life and that this adverse influence may be persistent. Indeed, earlier studies have shown that behavioral disturbances at age three are associated with psychopathology at age 21 (Caspi et al, 1996
). Our study demonstrated that maternal psychopathology (anxiety / depression occurring in 20% of mothers), as experienced by boys and girls during the first postnatal year was a strong predictor of hyperactivity and conduct disturbances until at least the age of 7 years. This finding is in line with previous studies that have shown that children of depressed mothers have increased rates of antisocial behavior and depression (Burke, 2003
) and are often exposed to harsh discipline and poor nurturing (Caspi et al, 2004
; Kim-Cohen et al, 2005
; McLearn et al, 2006
). Moreover our study showed that social deprivation had the strongest impact in both sexes when experienced from pre-birth to age one. Nevertheless, another ALSPAC study suggests that the influence of family adversity at least on conduct disturbances may be relatively modest: family adversity in the first two years of life contributes 7.5% of the variance in persistent conduct disturbances between 4 and 11 years (CDS, personal communication).
Most studies of childhood behavioral disinhibition have focused on conduct disturbances. We chose to include hyperactivity firstly because hyperactivity and conduct disturbances both predict later-onset externalizing behaviors, for example, these behaviors in boys aged eight predict frequent drunkenness 10 years later (Niemela et al, 2006
). Secondly, these behaviors may follow divergent paths; hyperactivity at age 6-7 years is a stronger predictor than conduct disturbances of poor social adjustment and relationship problems 10 year later (Danckaerts et al, 2000
). In fact we did not detect G × E interaction effects on conduct disturbances, perhaps because this is a relatively weak phenotype in a general population sample of pre-pubertal children. Very few children had high conduct problem scores which may account for the negative G × E findings.
It is not clear why the G × E results were weaker in boys than in girls. The influence of adversity on behavior was the same in both sexes. Boys tended to be slightly more hyperactive. Conduct problem scores differed little between the sexes unlike in adulthood when the prevalence of antisocial behavior is much higher in men than women (Rutter et al, 2003
). Indeed, a recent study has shown that MAOA-LPR
interacts with CSF testosterone to predict antisocial behaviors in men (Sjoberg et al
, 2008). Thus there may be hormonal or age-related effects that complicate the relationship between MAOA-LPR
genotype and early life stress, and therefore the G × E interaction may be hard to detect in pre-pubertal boys. Only one study has detected a G × E effect in boys aged 7 years but in this case the MAOA-LPR
interaction was with severe maltreatment (Kim-Cohen et al, 2006
appears to be among the 15% of X-linked genes that escape X-inactivation (Carrel and Willard, 2005
). However, partial X inactivation could conceivably result in higher brain MAOA expression levels for female homozygotes than male hemizygotes. Furthermore, one study has shown epigenetic gene regulation in the MAOA
promoter region only in females, representing a possible dosage compensation mechanism that does not correlate with X-inactivation (Pinsonneault et al, 2006
). This may be another explanation for why our findings were more striking in pre-pubertal girls than boys.
We regard this as an exploratory study since it was not clear a priori which stressors would have the greatest effect in this population sample. Any correction for multiple testing would render most of the results non-significant. This is a general population sample and there was not much variability in hyperactivity scores and even less variability in conduct scores. Moreover, the SDQ scales are not a measure of pathological behavior. Nevertheless, the strength of this study is that because we had a very large sample we were able to detect a modest effect of MAOA-LPR × early life stress on behavioral disinhibition in a general population sample of children in which few had been exposed to severe adversity.
In conclusion, our study has shown that within a general population sample, exposure to common stressors within the first few years of life and interaction between MAOA-LPR genotype and stressful life events predicts behavioral disinhibition in pre-pubertal girls and boys.