Attention Deficit Hyperactivity Disorder (ADHD) is a common, extremely disabling disorder that has major adverse sequelae in childhood and later life. Despite being such an important clinical problem, the aetiology and pathogenesis of ADHD is poorly understood. The available evidence shows that genetic factors are of major importance and that genes co-act and interact with environmental risk factors. The presence of antisocial behaviour in children with ADHD is an important marker of heterogeneity, indexing greater clinical severity, poorer outcome, persistent problems in adult life, a stronger association with neurocognitive deficits, especially affecting prefrontal cortical functioning and higher genetic loading.

Previous evidence had suggested that prefrontal cortical function is influenced by a valine/methionine variant in the catechol-O-methyltransferase (COMT) gene and indeed this was recently found in the ALSPAC sample (Barnett et al., 2007). We tested for association between this functional COMT gene variant and antisocial behaviour in ADHD in our well characterised sample of 240 clinic children with ADHD. We found evidence of association with the same COMT val/val genotype (Thapar et al, 2005). Since this publication, the finding has been replicated in two independent population-based samples (Caspi et al, 2008). There was significant evidence of association between the COMT val/val genotype and 1) childhood antisocial behaviour in those with ADHD in one sample, and 2) adult criminality in those with ADHD in the other. A pooled analysis of 4 published studies, showed significant association (Caspi et al, 2008).

The aim of this first stage proposal is to identify a potential mediating mechanism. Specifically we wish to test the hypothesis that

1). the COMT val/val genotype is associatied with antisocial behaviour in ADHD and

2). these effects are mediated through prefrontal cortical functioning.

The aim at this stage is to undertake analysis on existing data, develop research links with Bristol under the auspices of the Neurosciences Centres, publish findings and provide the basis for a subsequent grant /fellowship application.

The future application would aim to integrate the research we are undertaking on a clinical sample through Wellcome Trust programme funding on the genetics of ADHD with ALSPAC data. The key aims would be to test associated gene variants (gene discovery in other samples-notably our own clinical study and collaborative whole genome association studies) in a population-based sample a)for links with ADHD and antisocial behaviour in ADHD and b)investigate potential mediating mechanisms-specifically cognitive vs. emotion-based pathways.