Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder
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Objectives. Dysregulation in neurotransmitter signalling has been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Polymorphisms of the gene encoding dopamine beta hydroxylase (DBH) have been reported to be associated with ADHD; however, small sample sizes have led to inconsistency. Methods. We conducted transmission disequilibrium test analysis in 794 nuclear families to examine the relationship between DBH 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. Results. A SNP within the 3' untranslated region of DBH rs129882 showed a significant association with ADHD (χ2 = 9.71, p = 0.0018, OR = 1.37). This association remained significant after Bonferroni correction for multiple testing (p = 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 (p <0.001) in luciferase activity. Conclusions. These data demonstrate for the first time that a DBH gene variant, rs129882, which confers risk to ADHD is also associated with reduced in vitro gene expression. Reduced DBH expression would be consistent with decreased conversion of dopamine to noradrenaline and thus with a relative hypo-noradrenergic state in ADHD.
Tong , J , Mckinley , L-A , Cummins , T D R , Johnson , B , Matthews , N , Vance , A , Heussler , H , Gill , M , Kent , L , Bellgrove , M A & Hawi , Z 2015 , ' Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder ' World Journal of Biological Psychiatry , vol 16 , no. 8 , pp. 610-618 . DOI: 10.3109/15622975.2015.1036771
World Journal of Biological Psychiatry
© 2015, Publisher / the Author(s). This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at www.tandfonlnie.com / https://dx.doi.org/10.3109/15622975.2015.1036771