Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder

<p><i>Objectives.</i> Dysregulation in neurotransmitter signalling has been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Polymorphisms of the gene encoding dopamine beta hydroxylase (<i>DBH</i>) have been reported to be associated with ADHD; however, small sample sizes have led to inconsistency. <i>Methods.</i> We conducted transmission disequilibrium test analysis in 794 nuclear families to examine the relationship between <i>DBH</i> and ADHD. The effects of the ADHD-associated polymorphisms on gene expression were assessed by luciferase reporter assays in a human neuroblastoma cell line, SH-SY5Y. <i>Results.</i> A SNP within the 3′ untranslated region of <i>DBH</i> rs129882 showed a significant association with ADHD (χ<i>2 = </i>9.71, <i>p = </i>0.0018, <i>OR = </i>1.37). This association remained significant after Bonferroni correction for multiple testing (<i>p = </i>0.02). Further, allelic variation in rs129882 significantly impacted luciferase expression. Specifically, the C allele of the ADHD-associated rs129882 SNP produced a 2-fold decrease (<i>p < </i>0.001) in luciferase activity. <i>Conclusions.</i> These data demonstrate for the first time that a <i>DBH</i> gene variant, rs129882, which confers risk to ADHD is also associated with reduced in vitro gene expression. Reduced <i>DBH</i> expression would be consistent with decreased conversion of dopamine to noradrenaline and thus with a relative hypo-noradrenergic state in ADHD.</p>