Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with ADHD

< 250 words) Dysregulation in neurotransmitter signalling has been implicated in the aetiology of ADHD. Polymorphisms of the gene encoding dopamine beta hydroxylase (DBH), a key player in catecholamine signalling, have been shown to be associated with increased risk for ADHD. Previous genetic studies of ADHD have reported associations with a range of DBH gene variants (rs2519152, rs1611115, rs1108580 and rs6271) however small sample sizes have led to inconsistency. Here we conducted TDT analysis in a large ADHD sample of 794 nuclear families to re-examine the relationship between DBH and ADHD. Although we did not replicate associations of rs2519152 and rs1611115 with ADHD, we identified a significant association with rs129882 (pcorrected = 0.02). Further, gene reporter assays of DBH rs129882 showed a significant impact of the ADHD-associated C allele on luciferase expression in a human neuroblastoma cell line, SH-SY5Y. These data demonstrate for the first time that a DBH gene variant which confers risk to ADHD is also associated with reduced in vitro gene expression.