Haplotype analysis of SNAP-25 suggests a role in the aetiology of ADHD

Mill, Jonathan; Richards, Sandra; Knight, Jo; Curran, Sarah; Taylor, Eugene; Asherson, Philip

doi:10.1038/sj.mp.4001482

Cited by 92 publications

(82 citation statements)

References 19 publications

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“…MAOA is an interesting gene involved in the catabolism of catecholamine neurotransmitters with evidence of extensive LD across the gene locus; we obtained evidence for association consistent with one previous report. For SNAP-25 we were not able to replicate the associations reported to be present at the 3 0 end of the gene, but did detect an association signal in the 5 0 UTR, consistent with findings reported by Mill et al 50 Finally, we detected several novel associations with the strongest evidence coming from PNMT and SLC9A9, in addition to evidence for association with two genes in the circadian rhythm system.…”

Section: Discussionsupporting

confidence: 85%

“…[47][48][49][50] Interpretation of these data has been difficult with various combinations of alleles found to be significant across the three studies: T-allele of rs1051312, 48 T-C haplotype of rs1051312 and rs3746544 49,50 and the T-T haplotype of the two SNPs. 50 We were unable to genotype these two markers for technical reasons. We did however investigate two alternative SNPs in the 3 0 UTR and did not detect an association signal.…”

Section: Snap-25mentioning

confidence: 99%

“…Other SNAP25 markers reported to be associated with ADHD include a SNP in the 5 0 flanking region (A-2015T), 50 a microsatellite marker in intron 1 51 and the G-allele of a SNP in intron 7 (G-80609A). 50 More recently SNP associations were reported with several SNPs in introns 2 and 4 and exon 5.…”

Section: Snap-25mentioning

confidence: 99%

“…50 More recently SNP associations were reported with several SNPs in introns 2 and 4 and exon 5. We included two of the four associated SNPs reported in this study, neither of which gave an association signal.…”

Section: Snap-25mentioning

confidence: 99%

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The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes

et al. 2006

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Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples. Molecular Psychiatry (2006) 11, 934-953.

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Section: Discussionsupporting

confidence: 85%

Section: Snap-25mentioning

confidence: 99%

Section: Snap-25mentioning

confidence: 99%

Section: Snap-25mentioning

confidence: 99%

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The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes

et al. 2006

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“…Given previous findings of preferential paternal transmission bias with other candidate genes in ADHD, [23][24][25][26] TDTPHASE 27 was used to test transmissions from fathers and mothers separately. The proportions of transmitted vs nontransmitted alleles between ADHD subtypes and comorbid groups were compared using w 2 tests.…”

Section: Methodsmentioning

confidence: 99%

Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD

et al. 2005

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Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable, neurodevelopmental disorder with onset in early childhood. Genes involved in neuronal development and growth are, thus, important etiological candidates and brain-derived neurotrophic factor (BDNF), has been hypothesized to play a role in the pathogenesis of ADHD. BDNF is a member of the neurotrophin family and is involved in the survival and differentiation of dopaminergic neurons in the developing brain (of relevance because drugs that block the dopamine transporter can be effective therapeutically). The common Val66Met functional polymorphism in the human BDNF gene (rs 6265) was genotyped in a collaborative family-based sample of 341 white UK or Irish ADHD probands and their parents. We found evidence for preferential transmission of the valine (G) allele of BDNF (odds ratio, OR ¼ 1.6, P ¼ 0.02) with a strong paternal effect (paternal transmissions: OR ¼ 3.2, P ¼ 0.0005; maternal transmissions: OR ¼ 1.00; P ¼ 1.00). Our findings support the hypothesis that BDNF is involved in the pathogenesis of ADHD. The transmission difference between parents raises the possibility that an epigenetic process may be involved. Keywords: attention deficit hyperactivity disorder; association study; neurotrophic factor; polymorphism Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects 2-5% of school-aged children with more boys diagnosed than girls. 1 It is characterized by marked and pervasive inattention, overactivity and impulsiveness and causes significant social, educational and psychological problems. Quantitative genetic research over the last decade, from family, twin and adoption studies has firmly established that ADHD has a significant genetic contribution. 2 The medications most often used for ADHD are psychostimulants including methylphenidate and dexamphetamine. Precise therapeutic mechanisms of these drugs in ADHD remain unclear, although methylphenidate is known to inhibit the dopamine transporter. As a result, most candidate gene studies to date have focused on the dopamine system. 3 Positive findings have been successfully replicated for variants in the D4 dopamine receptor (DRD4), 4 D5 dopamine receptor (DRD5) 5 and the dopamine transporter (DAT1). 6 These family-based meta-analyses each report small effect sizes with odds ratios of less than 1.5, indicating that if they are true susceptibility variants for ADHD their contribution to the overall phenotype is small. Given that ADHD is a neurodevelopmental disorder, genes involved in neuronal development and growth represent an important set of candidates for involvement in the pathogenesis. One such candidate that has been postulated to play a role in ADHD is BDNF (MIM 113505). 7 The gene encoding BDNF is located at 11p13 and codes for a precursor peptide (proBDNF), which is proteolytically cleaved to form the mature protein. Only one nonsynonymous polymorphism in the human BDNF gene (rs 6265) has been identified, a single nucleotide polymorph...

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Molecular genetic studies of ADHD: 1991 to 2004

Bobb¹,

Castellanos

Addington³

et al. 2004

American J of Med Genetics Pt B

117

108

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Attention deficit hyperactivity disorder (ADHD) is highly heritable but is likely a complex disorder involving multiple genes of moderate effect (Smalley [1997: Am J Hum Genet 60:1276-1282). Over 100 studies have examined the genetics of ADHD by linkage or association, though no article has presented a comprehensive overview of all published reports. We reviewed all ADHD studies, including 3 genome-wide linkage studies, and association studies of 94 polymorphisms in 33 candidate genes. To simplify comparisons across heterogeneous articles, demographics and comorbidity were ignored; analyses of subtype and haplotypes were excluded; and only the most positive finding for each polymorphism in a study was reported. Thirty-six percent of all findings were positive (P 0.05), 17% were trends (0.05 < P 0.15), and 47% were negative (P > 0.15). Studies utilizing dimensional measures of ADHD tended to result in higher rates of positive findings than those using categorical diagnoses (x 2 ¼ 5.6, P ¼ 0.018), and case-control studies tended to result in higher rates of positive findings than family-based studies (x 2 ¼ 18.8, P < 0.001). However, for either dichotomy, no significant difference remained when analyzing only studies using both methods within the same population and polymorphism. Evidence for association exists for four genes in ADHD: the dopamine D4 and D5 receptors, and the dopamine and serotonin transporters; others are promising but need further replication, including the dopamine D2 and serotonin 2A receptors. All candidate gene approaches continue to face the problem of relatively low power, given modest odds ratios for even the best replicated genes.

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Haplotype analysis of SNAP-25 suggests a role in the aetiology of ADHD

Cited by 92 publications

References 19 publications

The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes

The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes

Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD

Molecular genetic studies of ADHD: 1991 to 2004

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