Exclusion of close linkage between the synaptic vesicular monoamine transporter locus and schizophrenia spectrum disorders

Persico, Antonio M.; Wang, Zhe Wu; Black, Donald W.; Andreasen, Nancy C.; Uhl, George R.; Crowe, Raymond R.

doi:10.1002/ajmg.1320600616

Cited by 21 publications

(19 citation statements)

References 11 publications

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“…DAT1 gene variants do not appear to provide widespread contributions to the etiology of schizophrenia spectrum disorders, according to linkage studies. 18,25 Most of the previous studies on the VNTR polymorphism of the DAT1 gene showed no positive evidence of allelic association between DAT1 alleles and schizophrenia, however, one of the studies showed that the DAT1 genotype distribution in schizophrenic patients did display a statistically significant departure from the genotype distribution found in controls. 26 There was no significant difference between controls and schizophrenic patients in the present study in both allelic and genotypic distributions of the novel polymorphism of the DAT1 gene, nor in the haplotype analysis.…”

Section: Discussionmentioning

confidence: 94%

Identification of a novel polymorphism of the human dopamine transporter (DAT1) gene and the significant association with alcoholism

et al. 1999

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Human dopamine transporter gene (DAT1) has a variable number of tandem repeats (VNTR) in its 3Ј-untranslated region (UTR).The association between the VNTR polymorphism and neuropsychiatric disorders has been studied, but their relationship is still unclear. Here we identified a novel polymorphism in the 3Ј-UTR of the DAT1 gene, G2319A, and a significant association between the polymorphism and alcoholism was observed in both genotypic and allelic frequencies (P = 0.040 and 0.019, extended Fisher's exact test, respectively). There was a significant gene dose effect on the risk for alcoholism associated with the 2319-A allele ( 2 = 6.16, df = 2, P = 0.046, linearity tendency test: Cochranq-Armitage analysis). Moreover, in the haplotype analysis with G2319A-and VNTR-polymorphisms, a positive gene dose efffect on the risk with the A10 allele (P = 0.044, linearity tendency test) and a negative gene dose effect with the G10 allele (P = 0.010, linearity tendency test) for alcoholism were significantly detected. Odds ratio for alcoholism with the A10 and G10 alleles were 1.76 (1.12-2.76) and 0.53 (0.32-0.79), respectively. These results indicate that the DAT1 gene may confer vulnerability to alcoholism.

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Section: Discussionmentioning

confidence: 94%

Identification of a novel polymorphism of the human dopamine transporter (DAT1) gene and the significant association with alcoholism

et al. 1999

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“…Nine-repeat allele carriers have also be found to be less likely to be tobacco smokers (Lerman et al 1999;Sabol et al 1999). On the other hand, this VNTR polymorphism is not associated with polysubstance abuse (Persico et al 1993), cocaine dependence (Gelernter et al 1994), delusional disorder (Persico and Catalano 1998), schizophrenia (Byerley et al 1993;Persico et al 1995), Tourette's syndrome (Gelernter et al 1995;Vandenbergh et al 2000), or alcoholism itself (Sander et al 1997;Vandenbergh et al 2000).…”

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confidence: 99%

The Variable Number of Tandem Repeats Polymorphism of the Dopamine Transporter Gene Is Not Associated with Significant Change in Dopamine Transporter Phenotype in Humans

Martínez

Gelernter

Abi‐Dargham

et al. 2001

Neuropsychopharmacology

176

110

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“…Persico et al 16 examined the TaqI RFLP polymorphism of the SVMT gene 13 for linkage analysis in 16 multiplex pedigrees with schizophrenia spectrum disorders. They obtained results excluding close linkage between the SVMT gene and schizophrenia spectrum disorders in their pedigrees.…”

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confidence: 99%

Exon/intron boundaries, novel polymorphisms, and association analysis with schizophrenia of the human synaptic vesicle monoamine transporter (SVMT) gene

et al. 2001

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Keywords: synaptic vesicle monoamine transporter (SVMT); polymorphism; exon/intron boundaries; schizophrenia; association studyThe synaptic vesicular monoamine transporter (SVMT), alternatively vesicular monoamine transporter 2 (VMAT2), pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles. Altered functions of SVMT have been implicated in the pathogensis of several neuropsychiatric diseases. We determined exon/intron boundaries of the human SVMT gene and performed mutational analysis for the exonic and neighboring intronic regions of the gene. Detected polymorphisms were subject to association analysis with schizophrenia in a familybased design. The human SVMT gene consists, of 16 exons and 15 introns, which is consistent with the murine SVMT gene. When mutational analysis was performed by the single strand conformational polymorphism (SSCP) analysis, we found two and four single nucleotide polymorphisms (SNPs) in exons and neighboring introns, respectively. Neither exonic SNP results in an amino acid change. In family-based association analyses in a sample of 50 Japanese schizophrenics and their parents, no significant association was found for the intronic polymorphisms. Our data suggest that there is no common polymorphism in the SVMT gene affecting the primary structure of the human SVMT protein. Furthermore, we obtained no evidence for the major effect of the novel polymorphisms on susceptibility to schizophrenia. Molecular Psychiatry (2001) 6, 456-460.The synaptic vesicular monoamine transporter (SVMT), alternatively vesicular monoamine transporter 2 (VMAT2), pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles, using the proton gradient maintained across the synaptic vesicular membrane. 1-3 It plays a central role in determining the amount of monoaminergic neurotransmitters packaged in a vesicle to be available for exocytotic release. 4 The transporter is a site of action of important drugs such as reserpine and tetrabenazine, both of which inhibit vesicular amine transport. Reserpine is a useful drug in the treatment of hypertension and schizophrenia; however, high dosages of reserpine frequently produce a syndrome resembling depressive disorder. 5 Several lines of evidence suggest the involvement of the SVMT in the psychostimulant action of amphetamines which induce monoamine efflux from vesicles, 6 resulting in an increased amount of cytoplasmic neurotransmitter, although the mechanism of action remains to be elucidated. The SVMT is also important for sequestering toxins. It modulates susceptibility to N-methyl-4-phenylpyridinium (MPP + ), the active metabolite of the neurotoxin N-methyl-1,2,3,6-tetrahydropyridine (MPTP) that induces Parkinsonism. 7,8 Recent studies on mutant mice lacking the SVMT gene have provided interesting findings. Although homozygotes for the mutated type die shortly after birth, heterozygous mice are viable into adult life and display reduced amphetamine-condition...

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Exclusion of close linkage between the synaptic vesicular monoamine transporter locus and schizophrenia spectrum disorders

Cited by 21 publications

References 11 publications

Identification of a novel polymorphism of the human dopamine transporter (DAT1) gene and the significant association with alcoholism

Identification of a novel polymorphism of the human dopamine transporter (DAT1) gene and the significant association with alcoholism

The Variable Number of Tandem Repeats Polymorphism of the Dopamine Transporter Gene Is Not Associated with Significant Change in Dopamine Transporter Phenotype in Humans

Exon/intron boundaries, novel polymorphisms, and association analysis with schizophrenia of the human synaptic vesicle monoamine transporter (SVMT) gene

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