Preliminary evidence for association between schizophrenia and polymorphisms in the regulatory Regions of the ADRA2A, DRD3 and SNAP-25 Genes

Lochman, Jan; Balcar, Vladimír J.; Šťastný, F; Šerý, Omar

doi:10.1016/j.psychres.2012.08.003

Cited by 35 publications

(20 citation statements)

References 47 publications

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“…Human and animal studies indicate that SNAP25 is a risk factor for mental illness, such as SCZ (38,39). For the SNAP25 rs3746544 polymorphism, there have been two previous studies with positive results (47,48) in Europeans (Czechs and British populations) and one negative result (49) in Asians (Japanese). The present meta-analysis of rs3746544 found a strong association with SCZ on the allelic level (P=0.006), and under the dominant (P=0.001) and additive models (P=0.02).…”

Section: Discussionmentioning

confidence: 99%

Meta-analyses of 10 polymorphisms associated with the risk of schizophrenia

Dai

Wang²,

Yuan

et al. 2014

Biomedical Reports

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Abstract. Schizophrenia (SCZ) is a severe complex psychiatric disorder that generates problems for the associated family and society and causes disability with regards to work for patients. The aim of the present study was to assess the contribution of 10 genetic polymorphisms to SCZ susceptibility. Meta-analyses were conducted using the data without a limitation for time or language. A total of 27 studies with 7 genes and 10 polymorphisms were selected for the meta-analyses. Two polymorphisms were found to be significantly associated with SCZ. SNAP25 rs3746544 was shown to increase the SCZ risk by 18% [P=0.01; odds ratio (OR), 1.18; 95% confidence interval (CI), 1.05-1.34] and GRIK3 rs6691840 was found to increase the risk by 30% (P=0.008; OR, 1.30; 95% CI, 1.07-1.58). Significant results were found under the dominant (P=0.001; OR, 1.36; 95% CI, 1.13-1.65) and additive (P=0.02; OR, 1.45; 95% CI, 1.06-1.98) model for the SNAP25 rs3746544 polymorphism and under the additive model for the GRIK3 rs6691840 polymorphism (P=0.03; OR, 1.73; 95% CI, 1.04-2.85). There were no significant results observed for the other eight polymorphisms, which were CCKAR rs1800857, CHRNA7 rs904952, CHRNA7 rs6494223, CHRNA7 rs2337506, DBH Ins>Del, FEZ1 rs559668, FEZ1 rs597570 and GCLM rs2301022. In conclusion, the present meta-analyses indicated that the SNAP25 rs3746544 and GRIK3 rs6691840 polymorphisms were risk factors of SCZ, which may provide valuable information for the clinical diagnosis of SCZ.

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Section: Discussionmentioning

confidence: 99%

Meta-analyses of 10 polymorphisms associated with the risk of schizophrenia

Dai

Wang²,

Yuan

et al. 2014

Biomedical Reports

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“…SNAP25 occurs on chromosome 20p12.2, which has been linked to schizophrenia in some samples, [55–59]. No identified studies have examined the levels of SNAP25 mRNA transcripts in Schizophrenia, but a preponderance of the studies that looked at the protein levels have shown a decrease in the expression levels of SNAP25 protein in key brain areas affected by schizophrenia.…”

Section: Introduction/backgroundmentioning

confidence: 99%

Dysregulations of Synaptic Vesicle Trafficking in Schizophrenia

Egbujo

Sinclair

Hahn

2016

Curr Psychiatry Rep

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Schizophrenia is a serious psychiatric illness which is experienced by about 1% of individuals worldwide and has a debilitating impact on perception, cognition and social function. Over the years, several models/hypotheses have been developed which link schizophrenia to dysregulations of the dopamine, glutamate and serotonin receptor pathways. An important segment of these pathways that have been extensively studied for the pathophysiology of schizophrenia is the presynaptic neurotransmitter release mechanism. This set of molecular events is an evolutionarily well-conserved process that involves vesicle recruitment, docking, membrane fusion and recycling, leading to efficient neurotransmitter delivery at the synapse. Accumulated evidence indicate dysregulation of this mechanism impacting post-synaptic signal transduction via different neurotransmitters in key brain regions implicated in schizophrenia. In recent years, after ground-breaking work that elucidated the operations of this mechanism, research efforts have focused on the alterations in the mRNA and protein expression of pre-synaptic neurotransmitter release molecules in schizophrenia and other neuropsychiatric conditions. In this review article, we present recent evidence from schizophrenia human post-mortem studies that key proteins involved in the pre-synaptic release mechanism are dysregulated in the disorder. We also discuss the potential impact of dysfunctional pre-synaptic neurotransmitter release on the various neurotransmitter systems implicated in schizophrenia.

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“…Postmortem brain and gene association studies in schizophrenia consistently report abnormalities of individual components of the SNARE machinery (26-33), although there is no obvious convergence of findings across studies (26-30; 34-36). Compensatory in vivo effects related to SNARE functional efficiency (with or without altered expression of protein amounts) could be part of the pathological substrate of schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Increased SNARE Protein-Protein Interactions in Orbitofrontal and Anterior Cingulate Cortices in Schizophrenia

Ramos-Miguel

Beasley

Dwork

et al. 2015

Biological Psychiatry

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Background Synaptic dysfunction in schizophrenia may be associated with abnormal expression or function of SNARE proteins (syntaxin, SNAP25, VAMP), forming the molecular complex underlying neurosecretion. The impact of such abnormalities on efficient SNARE heterotrimer formation is poorly understood. We investigated putative SNARE dysfunction, along with possible roles for the SNARE binding partners Munc18-1, complexins (Cplx) 1/2 and synaptotagmin, in brains from autopsies of individuals with and without schizophrenia. Methods Postmortem samples were obtained from orbitofrontal (OFC) and/or anterior cingulate (ACC) cortices from two separate cohorts (n = 15+15 schizophrenia cases, n = 13+15 controls). SNARE interactions were studied by immunoprecipitation and one- or two-dimensional blue native electrophoresis (BN-PAGE). Results In the first cohort, syntaxin, Munc18-1 and Cplx1, but not VAMP, Cplx2 or synaptotagmin, were two-fold enriched in SNAP25-immunoprecipitated products from schizophrenia OFC in the absence of any alterations in total tissue homogenate levels of these proteins. In BN-PAGE, the SNARE heterotrimer was identified as a 150-kDa complex, increased in schizophrenia samples from Cohort 1 (OFC: +45%; ACC: +44%) and Cohort 2 (OFC: +40%), with lower 70-kDa SNAP25-VAMP dimer (−37%) in the OFC. Upregulated 200-kDa SNARE-Cplx1 (+65%), and downregulated 550-kDa Cplx1-containing oligomers (−24%) in schizophrenia OFC were identified by BN-PAGE. These findings were not explained by postmortem interval, antipsychotic medication, or other potentially confounding variables. Conclusions The findings support the hypothesis of upregulated SNARE complex formation in schizophrenia OFC, possibly favored by enhanced affinity for Munc18-1 and/or Cplx1. These alterations offer new therapeutic targets for schizophrenia.

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Preliminary evidence for association between schizophrenia and polymorphisms in the regulatory Regions of the ADRA2A, DRD3 and SNAP-25 Genes

Cited by 35 publications

References 47 publications

Meta-analyses of 10 polymorphisms associated with the risk of schizophrenia

Meta-analyses of 10 polymorphisms associated with the risk of schizophrenia

Dysregulations of Synaptic Vesicle Trafficking in Schizophrenia

Increased SNARE Protein-Protein Interactions in Orbitofrontal and Anterior Cingulate Cortices in Schizophrenia

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