title: DNA variation in the SNAP25 gene confers risk to ADHD and is associated with reduced expression in prefrontal cortex.
abstract: BACKGROUND
  The Coloboma mouse carries a ∼2 cM deletion encompassing the SNAP25 gene and has a hyperactive phenotype similar to that of ADHD. Such mice are 3 fold more active compared to their control littermates. Genetic association studies support a role for allelic variants of the human SNAP25 gene in predisposing to ADHD.
  
  
  RESULTS
  We performed association analysis across the SNAP25 gene in 1,107 individuals (339 ADHD trios). To assess the functional relevance of the SNAP25-ADHD associated allele, we performed quantitative PCR on post-mortem tissue derived from the inferior frontal gyrus of 89 unaffected adults. Significant associations with the A allele of SNP rs362990 (χ(2) = 10, p-corrected = 0.019, OR = 1.5) and three marker haplotypes (rs6108461, rs362990 and rs362998) were observed. Furthermore, a significant additive decrease in the expression of the SNAP25 transcript as a function of the risk allele was also observed. This effect was detected at the haplotype level, where increasing copies of the ADHD-associated haplotype reduced the expression of the transcript.
  
  
  CONCLUSIONS
  Our data show that DNA variation at SNAP25 confers risk to ADHD and reduces the expression of the transcript in a region of the brain that is critical for the regulation of attention and inhibition.
authors.affiliation: Queensland Brain Institute, the University of Queensland, Brisbane, Australia. z.hawi@uq.edu.au
authors.forename: Ziarih
authors.initials: Z
authors.lastname: Hawi
authors.forename: Natasha
authors.initials: N
authors.lastname: Matthews
authors.forename: Joseph
authors.initials: J
authors.lastname: Wagner
authors.forename: Robyn H
authors.initials: RH
authors.lastname: Wallace
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Butler
authors.forename: Alasdair
authors.initials: A
authors.lastname: Vance
authors.forename: Lindsey
authors.initials: L
authors.lastname: Kent
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bellgrove
mesh_terms: D000328:Adult; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics; D002648:Child; D004247:DNA / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D051379:Mice; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D012307:Risk Factors; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics* / Q000378:metabolism
chemical_list: C494208:SNAP25 protein, human; D050825:Synaptosomal-Associated Protein 25; D004247:DNA