Identification of two risk haplotypes for schizophrenia and bipolar disorder in the synaptic vesicle monoamine transporter gene (SVMT)

Abstract

The synaptic vesicular monoamine transporter (SVMT) plays a key role in monoaminergic neurotransmission determining the size of neurotransmitter vesicular pools available for exocytotic release. Recently, several lines of evidence have suggested that altered functions of SVMT may be involved in the pathogenesis of certain neuropsychiatric diseases, including psychotic and mood disorders. In the present study, we tested the potential involvement of SVMT gene variants in the etiology of schizophrenia and bipolar disorder. Five different SNPs (T440G, C1368T, T2666C, A2683C, and A745G) were included in the analysis covering a region of about 35 kb along the SVMT gene. Analyses were performed in a case-control sample consisting of 88 bipolar patients, 107 subjects with schizophrenia, and 164 controls. Two risk haplotypes for both schizophrenia and bipolar disorder in SVMT gene were identified. Particularly, 2666T-2683A-745G (TAG) and 2666C-2683C-745A (CCA) combinations were significantly more frequent in both bipolar and schizophrenic patients than in controls. UNPHASED package estimated haplotype effects for all patients yielded relative risks of 4.1 (95%CI: 1.83-9.21) for TAG combination and 2.336 (95%CI: 1.28-4.26) for CCA haplotype. Conversely, 2666T-2683C-745A (TCA) and 2666C-2683A-745G (CAG) haplotypes seemed to protect against these mental disorders, since the estimated frequency in control chromosomes was 12% whilst such haplotypes were not observed in any bipolar or schizophrenic subject (P < 0.0000). Our results strongly suggest that SVMT gene or certain regions of it may constitute a genetic substrate of susceptibility for both schizophrenia and bipolar disorder.

An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes

“…47 Two risk haplo- types of SLC18A2 were reported for both SZ and bipolar mood disorder in a case-control study of Spanish population. 48 This leads to support an arguable concept that these two psychiatric disorders share common genetic determinants, 49 which is strongly supported by a recent large population study in Swedish families. 50 Energy metabolism and defense mechanisms The gene product of SLC25A27, UCP4 is a member of mitochondrial uncoupling proteins that create proton leaks across the inner mitochrondrial membranes, thus uncoupling oxidative phosphorylation from ATP synthesis in a form of exchange of energy with heat.…”

Plasma total homocysteine is associated with DNA methylation in patients with schizophrenia

“…SLC18A2 encodes the vesicular transporter type2 ( VMAT2 ), which transports monoamines into the synaptic vesicles 37 . Genetic variations of this gene have been associated with SCZ and cognitive functioning in patients with psychotic disorder 34 , 36 , 38 33 .…”

SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine

“…In addition, VMAT2 promoter haplotypes that confer increased expression of VMAT2 in vitro may provide some protection against the development of Parkinson’s disease in women with high exposure to pesticides (Fei and Krantz, 2009). To date, the results of human genetic studies attempting to link VMAT2 polymorphisms with psychiatric illness have yielded mostly negative results ((Fei and Krantz, 2009) but see (Gutierrez et al, 2007)). Additional human genetic studies investigating a possible association of VMAT1 polymorphisms with schizophrenia or bipolar disorder have also yielded mixed results (Eiden and Weihe, 2011; Wimalasena, 2010).…”