Biased paternal transmission of SNAP-25 risk alleles in attention-deficit hyperactivity disorder

Kustanovich, Vlad; Merriman, Barry; McGough, James J.; McCracken, James T.; Smalley, Susan L.; Nelson, Stanley F.

doi:10.1038/sj.mp.4001247

Cited by 105 publications

(70 citation statements)

References 32 publications

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“…[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.…”

Section: Snap-25mentioning

confidence: 99%

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: Snap-25mentioning

confidence: 99%

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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“…16,[44][45][46] A high comorbidity has been reported between ADHD and BD, more specifically with early-onset BD. 47 Therefore, our results suggest that SNAP25 might be a common susceptibility factors for these psychiatric disorders.…”

Section: Discussionmentioning

confidence: 99%

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

et al. 2009

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Bipolar disorder (BD) is one of the most common and persistent psychiatric disorders. Earlyonset BD has been shown to be the most severe and familial form. We recently carried out a whole-genome linkage analysis on sibpairs affected by early-onset BD and showed that the 20p12 region was more frequently shared in our families than expected by chance. The synaptosomal-associated protein SNAP25 is a presynaptic plasma membrane protein essential for the triggering of vesicular fusion and neurotransmitter release, and for which abnormal protein levels have been reported in postmortem studies of bipolar patients. We hypothesised that variations in the gene encoding SNAP25, located on chromosome 20p12, might influence the susceptibility to early-onset BD. We screened SNAP25 for mutations and performed a case-control association study in 197 patients with early-onset BD, 202 patients with late-onset BD and 136 unaffected subjects. In addition, we analysed the expression level of the two SNAP25 isoforms in 60 brains. We showed that one variant, located in the promoter region, was associated with early-onset BD but not with the late-onset subgroup. In addition, individuals homozygous for this variant showed a significant higher SNAP25b expression level in prefrontal cortex. These results show that variations in SNAP25, associated with an increased gene expression level in prefrontal cortex, might predispose to early-onset BD. Further analyses of this gene, as well as analysis of genes encoding for the SNAP25 protein partners, are required to understand the impact of such molecular mechanisms in BD.

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“…As mentioned above, the motivation for us undertaking analyses according to parental transmission was the prior observation that paternal preferential transmission bias has been reported in some other studies of candidate genes in ADHD, for example, variants of the synaptosomal associated protein of 25 kDa gene (SNAP 25) 23,24 and the serotonin receptor gene, 5HT1B 25,26. This raises the possibility that the pathogenesis of ADHD could involve some general epigenetic mechanism (such as abnormal imprinting-which could be developmentally-or neuroanatomically-specific) that affects multiple genes. However, the parent of origin effect observed at BDNF in our data requires confirmation in independent samples and, if replicated, the cause(s) will need to be explored further.…”

Section: Discussionmentioning

confidence: 99%

“…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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Biased paternal transmission of SNAP-25 risk alleles in attention-deficit hyperactivity disorder

Cited by 105 publications

References 32 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

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

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

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