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

• Published in: PloS one Vol. 8; no. 4; p. e60274
• Main Authors: Hawi, Ziarih, Matthews, Natasha, Wagner, Joseph, Wallace, Robyn H, Butler, Tim J, Vance, Alasdair, Kent, Lindsey, Gill, Michael, Bellgrove, Mark A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12-04-2013; Public Library of Science (PLoS)
• Subjects: Active control; Adult; Adults; Alleles; Animals; Association analysis; Attention Deficit Disorder with Hyperactivity - genetics; Attention deficit hyperactivity disorder; Binding sites; Biology; Brain; Child; Children & youth; Cortex (frontal); Deoxyribonucleic acid; DNA; DNA - genetics; Dopamine; Families & family life; Frontal gyrus; Gene deletion; Gene expression; Genes; Genetic aspects; Genetic Association Studies; Genetic Predisposition to Disease; Genetic research; Genomes; Haplotypes; Haplotypes - genetics; Humans; Hyperactivity; Linkage Disequilibrium - genetics; Male; Medicine; Mice; Mutation; Polymorphism, Single Nucleotide - genetics; Prefrontal cortex; Prefrontal Cortex - metabolism; Prefrontal Cortex - pathology; Proteins; Psychiatry; Risk; Risk Factors; Single nucleotide polymorphisms; Single-nucleotide polymorphism; SNAP-25 protein; Social and Behavioral Sciences; Synaptosomal-Associated Protein 25 - genetics; Synaptosomal-Associated Protein 25 - metabolism; Transcription; Melbourne Victoria Australia; Queensland Australia; Australia; Ireland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0060274

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.
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.
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.