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

Janette Tong, Leigh-Anne Mckinley, Tarrant D. R. Cummins, Beth Johnson, Natasha Matthews, Alasdair Vance, Helen Heussler, Michael Gill, Lindsey Kent, Mark A. Bellgrove, Ziarih Hawi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)
6 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)610-618
Number of pages9
JournalWorld Journal of Biological Psychiatry
Volume16
Issue number8
Early online date15 May 2015
DOIs
Publication statusPublished - 17 Nov 2015

Keywords

  • Attention Deficit Hyperactivity Disorder
  • Genetics
  • Gene expression
  • DBH
  • Polymorphism

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