Synaptosomal-associated protein 25 (SNAP-25) and attention deficit hyperactivity disorder (ADHD): evidence of linkage and association in the Irish population

Abstract

Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric condition characterized by hyperactive-impulsive behaviour and persistent inattention. Individuals with this condition experience social and academic dysfunction. Although the aetiology of ADHD is not known, it is postulated that a developmental failure in the brain mechanism that underlies self-control and inhibition is involved.2 ADHD affects approximately 3-6% of children and adolescents from different geographical regions worldwide.3 Boys are affected more frequently than girls, with the ratio ranging from 3:1 to 9:1. 4 Family, twin and adoption studies have indicated a strong genetic component in susceptibility to ADHD. An approximate five-to six-fold increase in the frequency of ADHD among first-degree relatives when compared with the general population was reported.5 A probandwise concordance rate of 72% monozygotic twins and 32% same-sex dizygotic twins was observed. 6 A number of twin studies have estimated the heritability of ADHD to range from 39% to 91% for various symptoms of the disorder. 7,8 Adoption studies have also supported a genetics component for ADHD. In a recent study Sprich et al 9 reported 6% of the adoptive parents of adopted ADHD probands had ADHD compared with 18% of the biological parents of non-adopted ADHD probands and 3% of the biological parents of the control.The dopaminergic neurotransmission systems have been implicated in the pathology of ADHD. Genes of the dopamine system have been linked with ADHD for a number of reasons including: (1) the reduction in symptoms brought about by pharmacological agents (such as methylphenidate) that primarily act in the dopaminergic system; 10 (2) the results from recent imaging studies of an ADHD brain implicate brain structures with rich dopamine content, such as the fronto-striatal circuitary in the aetiology of ADHD; 3 (3) animal model studies such as the mouse model lacking dopamine transporter (ie DAT1 knockout mice) demonstrate a link between the dopamine system and ADHD. Mice lacking DAT1 have high extracellular striatal dopamine levels and display increased locomotor activity, a typical characteristic of the ADHD phenotype. 11 Recently, several association studies utilizing DNA variants at DAT1, DRD4, DRD5 and DBH have suggested the involvement of these loci as susceptibility variants (genes of minor effect) for ADHD.

A high-density single-nucleotide polymorphism screen of 23 candidate genes in attention deficit hyperactivity disorder: suggesting multiple susceptibility genes among Chinese Han population

“…40 Emerging evidence from currently published association/linkage studies has further implicated SNAP25 in ADHD. 2 This work replicated previous reports of associations for the regions of 3 0 -untranslated region (UTR), introns 1 and 7, [41][42][43][44][45] although a different set of variants were included. There is, however, a lack of overlap with the associated SNPs identified in the IMAGE sample.…”

Abnormal latent inhibition and impulsivity in coloboma mice, a model of ADHD

“…This deletion causes a 50% reduction in the expression of SNAP-25, a presynaptic protein involved in calcium-triggered neurotransmitter release (Hess et al, 1992). Identification of the Snap25 gene defect in these mice provided a candidate gene for studies in humans that revealed an association between SNAP25 and ADHD (Barr et al, 2000, Brophy et al, 2002, Mill et al, 2002, Kustanovich et al, 2003. Although such studies show associations and not direct causal relationships between a genetic locus and a disorder, the association between SNAP25 and ADHD suggests that coloboma mice have etiological validity.…”

The SNAP-25 gene is associated with cognitive ability: evidence from a family-based study in two independent Dutch cohorts

“…45,48,49 Because of the observed increased hyperactivity of hemizygous Coloboma mice, the role of SNAP-25 in attention deficit hyperactivity disorder (ADHD) has been tested in several studies. [50][51][52][53][54] All, except one (Xu et al 54 ), report a significant association of SNAP-25 with ADHD in humans. The exact role of SNAP-25 in ADHD, however, remains unknown.…”