DNA variation in the SNAP25 gene confers risk to ADHD and is associated with reduced expression in prefrontal cortex

Ziarih Hawi*, Natasha Matthews, Joseph Wagner, Robyn H. Wallace, Tim J. Butler, Alasdair Vance, Lindsey Kent, Michael Gill, Mark A. Bellgrove

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)
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Abstract

Background: The Coloboma mouse carries a similar to 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. Methods/Principal Findings: 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 postmortem tissue derived from the inferior frontal gyrus of 89 unaffected adults. Significant associations with the A allele of SNP rs362990 (chi(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.

Original languageEnglish
Article numbere60274
Number of pages8
JournalPLoS ONE
Volume8
Issue number4
DOIs
Publication statusPublished - 12 Apr 2013

Keywords

  • SNAP-25 gene
  • Genome-wide association
  • Candidate gene
  • Susceptibility
  • Snare complex
  • Deficit hyperactivity disorder
  • Mouse mutant coloboma
  • Polymorphisms

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