Attention deficit hyperactivity disorder (ADHD) is a common, extremely disabling disorder which has major adverse squalae in childhood and later life. Despite being such an important clinical problem, the aetiology and pathogenesis of ADHD is poorly understood. Available evidence suggests that both genetic and environmental risk factors are important.

Association studies have suggested that maternal smoking during pregnancy may be an environmental risk factor for ADHD. However, there is a growing body of evidence to suggest that these associations are due to shared genetic liability between smoking and ADHD, rather than there being a causal environmental effect.

Using a novel design looking at children born through IVF, we have shown that where mothers are not genetically related to the child they carry in pregnancy (e.g. children conceived following egg donation) no significant association is observed between maternal smoking during pregnancy and ADHD symptoms. Conversely when the mother is genetically related to the child she carries (e.g. children conceived following sperm donation) a significant association between smoking during pregnancy and ADHD is observed. This suggests that the association may arise because of shared genetic liability for maternal smoking and child ADHD. Similarly, studies looking at the children of twins and discordant sibling pairs where the mother smokes during one pregnancy but not the other, also indicate that there is a genetic or familial influence on the links between maternal smoking during pregnancy and child behaviour.

Although these studies are suggestive of shared genetic liability, the evidence is still incomplete.

The aim of this proposal is to further explore the causal pathways for association between maternal smoking during pregnancy and childhood ADHD and the possibility that this is due to shared genetic liability.

1). Firstly, we propose to compare the risk for child ADHD when mothers and fathers smoked during the pregnancy; any true environmental effect (taking into account passive smoking effects) would be observed only in those who are exposed to smoke in utero via their mother whilst an equal risk from the father would be indicative of shared genetic liability.

2). We also propose to look at a specific gene variant in the CHRNA3 gene (rs1051730) which has been shown across a number of studies to be associated with increased risk of cigarette smoking and in the ALSPAC sample with smoking during pregnancy, again comparing differential risk passed from the mother and father.

3). Using this genetic information, we aim to look at the child's genotype: If there is shared genetic liability for this particular variant-then we would expect to find association between this SNP and childhood ADHD symptoms. In the future this pilot work could lead to applying for funding to test other variants in relation to the shared genetic liability between smoking and ADHD.

4). Stan Zammit to lead:

Although there have been fewer studies that have examined the relationship between maternal substance use and psychosis, effects on psychosis are equally plausible given the diverse detrimental effects of in-utero exposure to tobacco on cerebral development and function, and also given the evidence that such exposure can lead to cognitive deficits that are an established risk factor for psychosis. In fact, within ALSPAC, we observed that maternal smoking during pregnancy was associated with increased risk of child psychotic experiences, whereas paternal smoking during pregnancy was not associated (although confidence intervals for maternal and paternal smoking overlapped). High levels of maternal alcohol use during pregnancy were also associated with child psychotic symptoms. We would therefore like to examine whether maternal and child genetic variants associated with smoking behaviour are associated with risk of child psychotic experiences.