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

Abstract

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.

Key words::

• attention deficit hyperactivity disorder
• genetics
• gene expression
• DBH
• polymorphism

Acknowledgments

This work would not have been possible without the generous support provided by the NHMRC to ZH, TDRC and MAB (APP569636, APP1002458, APP1065677). MAB is supported by a Future Fellowship from the Australian Research Council of Australia (FT130101488).

Statement of Interest

MAB received remuneration for speaking and travel expenses from Lilly Pharmaceuticals, MAB reports no further conflicts of interest. JT, LM, TDRC, BPJ, NM, AV, HH, MG, LK, ZH report no conflicts of interest. The material presented in the accompanying manuscript is original research, it has not been previously published and has not been submitted for publication elsewhere while under consideration.

Supplementary material available online

Supplementary Table 1. Observed and expected heterozygosity, genotyping success rate and minor allele frequency of the examined DBH markers