title: Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder.
abstract: OBJECTIVE
  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 (χ(2) = 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.
authors.affiliation: a School of Psychological Sciences, Monash University , Melbourne , Australia.
authors.forename: Janette
authors.initials: J
authors.lastname: Tong
authors.affiliation: a School of Psychological Sciences, Monash University , Melbourne , Australia.
authors.forename: Leigh-Anne
authors.initials: LA
authors.lastname: McKinley
authors.affiliation: a School of Psychological Sciences, Monash University , Melbourne , Australia.
authors.forename: Tarrant D R
authors.initials: TD
authors.lastname: Cummins
authors.affiliation: a School of Psychological Sciences, Monash University , Melbourne , Australia.
authors.forename: Beth
authors.initials: B
authors.lastname: Johnson
authors.affiliation: b Queensland Brain Institute, University of Queensland , Brisbane , Australia.
authors.forename: Natasha
authors.initials: N
authors.lastname: Matthews
authors.affiliation: c Academic Child Psychiatry Unit, Department of Paediatrics , University of Melbourne, Royal Children's Hospital, Murdoch Children's Research Institute , Parkville, Vic , Australia.
authors.forename: Alasdair
authors.initials: A
authors.lastname: Vance
authors.affiliation: d Department of Respiratory and Sleep Medicine , Mater Children's Hospital, Mater Health Services , South Brisbane , Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Heussler
authors.affiliation: e Department of Psychiatry , Trinity College , Dublin , Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.affiliation: f School of Medicine, University of St Andrews, St Andrews , Scotland , UK.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Kent
authors.affiliation: a School of Psychological Sciences, Monash University , Melbourne , Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bellgrove
authors.affiliation: a School of Psychological Sciences, Monash University , Melbourne , Australia.
authors.forename: Ziarih
authors.initials: Z
authors.lastname: Hawi
mesh_terms: D000483:Alleles; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D001315:Australia; D002648:Child; D004299:Dopamine beta-Hydroxylase / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007494:Ireland; D008297:Male; D011110:Polymorphism, Genetic; D006113:United Kingdom
chemical_list: D004299:Dopamine beta-Hydroxylase
keywords: DBH; attention deficit hyperactivity disorder; gene expression; genetics; polymorphism