| 1 | Hum. Mol. Genet. 2008 Mar 17: 747-58 |
|---|---|
| PMID | 18045777 |
| Title | A network of dopaminergic gene variations implicated as risk factors for schizophrenia. |
| Abstract | We evaluated the hypothesis that dopaminergic polymorphisms are risk factors for schizophrenia (SZ). In stage I, we screened 18 dopamine-related genes in two independent US Caucasian samples: 150 trios and 328 cases/501 controls. The most promising associations were detected with SLC6A3 (alias DAT), DRD3, COMT and SLC18A2 (alias VMAT2). In stage II, we comprehensively evaluated these four genes by genotyping 68 SNPs in all 478 cases and 501 controls from stage I. Fifteen (23.1%) significant associations were found (p < or = 0.05). We sought epistasis between pairs of SNPs providing evidence of a main effect and observed 17 significant interactions (169 tests); 41.2% of significant interactions involved rs3756450 (5' near promoter) or rs464049 (intron 4) at SLC6A3. In stage III, we confirmed our findings by genotyping 65 SNPs among 659 Bulgarian trios. Both SLC6A3 variants implicated in the US interactions were overtransmitted in this cohort (rs3756450, p = 0.035; rs464049, p = 0.011). Joint analyses from stages II and III identified associations at all four genes (p(joint) < 0.05). We tested 29 putative interactions from stage II and detected replication between seven locus pairs (p < or = 0.05). Simulations suggested our stage II and stage III interaction results were unlikely to have occurred by chance (p = 0.008 and 0.001, respectively). In stage IV we evaluated rs464049 and rs3756450 for functional effects and found significant allele-specific differences at rs3756450 using electrophoretic mobility shift assays and dual-luciferase promoter assays. Our data suggest that a network of dopaminergic polymorphisms increase risk for SZ. |
| SCZ Keywords | schizophrenia |
| 2 | J. Hum. Genet. 2010 May 55: 285-92 |
| PMID | 20339380 |
| Title | An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes. |
| Abstract | schizophrenia is a highly complex inheritable disease characterized by numerous genetic susceptibility elements, each contributing a modest increase in risk for the disease. Although numerous linkage or association studies have identified a large set of schizophrenia-associated loci, many are controversial. In addition, only a small portion of these loci overlaps with the large cumulative pool of genes that have shown changes of expression in schizophrenia. Here, we applied a genomic gene-function approach to identify susceptibility loci that show direct effect on gene expression, leading to functional abnormalities in schizophrenia. We carried out an integrated analysis by cross-examination of the literature-based susceptibility loci with the schizophrenia-associated expression gene list obtained from our previous microarray study (Journal of Human Genetics (2009) 54: 665-75) using bioinformatic tools, followed by confirmation of gene expression changes using qPCR. We found nine genes (CHGB, SLC18A2, SLC25A27, ESD, C4A/C4B, TCP1, CHL1 and CTNNA2) demonstrate gene-function correlation involving: synapse and neurotransmission; energy metabolism and defense mechanisms; and molecular chaperone and cytoskeleton. Our findings further support the roles of these genes in genetic influence and functional consequences on the development of schizophrenia. It is interesting to note that four of the nine genes are located on chromosome 6, suggesting a special chromosomal vulnerability in schizophrenia. |
| SCZ Keywords | schizophrenia |
| 3 | Methods Mol. Biol. 2010 -1 637: 165-80 |
| PMID | 20419435 |
| Title | Genetic variants in the vesicular monoamine transporter 1 (VMAT1/SLC18A1) and neuropsychiatric disorders. |
| Abstract | Vesicular monoamine transporters (VMATs) are involved in the presynaptic packaging of monoaminergic neurotransmitters into storage granules. Upon an action potential, vesicles release their contents into the synaptic cleft via exocytosis. Since insufficient or excess release of neurotransmitter might alter neurochemical function and neurotransmission, VMATs are an important target for biological research in neuropsychiatric disorders. Two structurally related but pharmacologically distinct VMATs have been identified, encoded by separate genes, VMAT1 (SLC18A1) and VMAT2 (SLC18A2). Although it was reported initially that only VMAT2 is expressed in brain, recent studies indicate that VMAT1 is also expressed in brain, thus making both transporters plausible candidate genes for neuropsychiatric disorders. The gene encoding VMAT1 is located on chromosome 8p21, a region implicated in linkage studies of schizophrenia, bipolar disorder, and anxiety-related phenotypes. Furthermore, several recent genetic case-control studies have documented an association between common missense variations in the VMAT1 gene and susceptibility to bipolar disorder and schizophrenia. Variations in the VMAT1 gene might affect transporter function and might be involved in the etiology of neuropsychiatric disorders. This chapter describes methods for genotyping three missense polymorphisms implicated in neuropsychiatric disorders (Thr4Pro, Thr98Ser, Thr136Ile) using TaqMan-based PCR and standard PCR approaches. |
| SCZ Keywords | schizophrenia |
| 4 | Schizophr Bull 2013 Jul 39: 848-56 |
| PMID | 22532702 |
| Title | Intermediate phenotype analysis of patients, unaffected siblings, and healthy controls identifies VMAT2 as a candidate gene for psychotic disorder and neurocognition. |
| Abstract | Psychotic disorders are associated with neurocognitive alterations that aggregate in unaffected family members, suggesting that genetic vulnerability to psychotic disorder impacts neurocognition. The aim of the present study was to investigate whether selected schizophrenia candidate single nucleotide polymorphisms (SNPs) are associated with (1) neurocognitive functioning across populations at different genetic risk for psychosis (2) and psychotic disorder. The association between 152 SNPs in 43 candidate genes and a composite measure of neurocognitive functioning was examined in 718 patients with psychotic disorder. Follow-up analyses were carried out in 750 unaffected siblings and 389 healthy comparison subjects. In the patients, 13 associations between SNPs and cognitive functioning were significant at P < .05, situated in DRD1, DRD3, SLC6A3, BDNF, FGF2, SLC18A2, FKBP5, and DNMT3B. Follow-up of these SNPs revealed a significant and directionally similar association for SLC18A2 (alternatively VMAT2) rs363227 in siblings (B = -0.13, P = .04) and a trend association in control subjects (B = -0.10, P = .12). This association was accompanied by a significantly increased risk for psychotic disorder associated with the T allele (linear OR = 1.51, 95% CI 1.10-2.07, P = .01), which was reduced when covarying for cognitive performance (OR = 1.29, 95% CI 0.92-1.81, P = .14), suggesting mediation. Genetic variation in VMAT2 may be linked to alterations in cognitive functioning underlying psychotic disorder, possibly through altered transport of monoamines into synaptic vesicles. |
| SCZ Keywords | schizophrenia |
| 5 | J Psychiatr Res 2013 Nov 47: 1615-22 |
| PMID | 23932573 |
| Title | Dopaminergic gene polymorphisms and cognitive function in a north Indian schizophrenia cohort. |
| Abstract | Associations of polymorphisms from dopaminergic neurotransmitter pathway genes have mostly been reported in Caucasian ancestry schizophrenia (SZ) samples. As studies investigating single SNPs with SZ have been inconsistent, more detailed analyses utilizing multiple SNPs with the diagnostic phenotype as well as cognitive function may be more informative. Therefore, these analyses were conducted in a north Indian sample. Indian SZ case-parent trios (n = 601 families); unscreened controls (n = 468) and an independent set of 118 trio families were analyzed. Representative SNPs in the Dopamine D3 receptor (DRD3), dopamine transporter (SLC6A3), vesicular monoamine transporter 2 (SLC18A2), catechol-o-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH) were genotyped using SNaPshot/SNPlex assays (n = 59 SNPs). The Trail Making Test (TMT) was administered to a subset of the sample (n = 260 cases and n = 302 parents). Eight SNPs were nominally associated with SZ in either case-control or family based analyses (p < 0.05, rs7631540 and rs2046496 in DRD3; rs363399 and rs10082463 in SLC18A2; rs4680, rs4646315 and rs9332377 in COMT). rs6271 at DBH was associated in both analyses. Haplotypes of DRD3 SNPs incorporating rs7631540-rs2134655-rs3773678-rs324030-rs6280-rs905568 showed suggestive associations in both case-parent and trio samples. At SLC18A2, rs10082463 was nominally associated with psychomotor performance and rs363285 with executive functions using the TMT but did not withstand multiple corrections. Suggestive associations with dopaminergic genes were detected in this study, but convincing links between dopaminergic polymorphisms and SZ or cognitive function were not observed. |
| SCZ Keywords | schizophrenia |
| 6 | J Psychiatr Res 2013 Nov 47: 1760-5 |
| PMID | 24018103 |
| Title | Association study of the vesicular monoamine transporter gene SLC18A2 with tardive dyskinesia. |
| Abstract | Tardive dyskinesia (TD) is an involuntary movement disorder that can occur in up to 25% of patients receiving long-term first-generation antipsychotic treatment. Its etiology is unclear, but family studies suggest that genetic factors play an important role in contributing to risk for TD. The vesicular monoamine transporter 2 (VMAT2) is an interesting candidate for genetic studies of TD because it regulates the release of neurotransmitters implicated in TD, including dopamine, serotonin, and GABA. VMAT2 is also a target of tetrabenazine, a drug used in the treatment of hyperkinetic movement disorders, including TD. We examined nine single-nucleotide polymorphisms (SNPs) in the SLC18A2 gene that encodes VMAT2 for association with TD in our sample of chronic schizophrenia patients (n = 217). We found a number of SNPs to be nominally associated with TD occurrence and the Abnormal Involuntary Movement Scale (AIMS), including the rs2015586 marker which was previously found associated with TD in the CATIE sample (Tsai et al., 2010), as well as the rs363224 marker, with the low-expression AA genotype appearing to be protective against TD (p = 0.005). We further found the rs363224 marker to interact with the putative functional D2 receptor rs6277 (C957T) polymorphism (p = 0.001), supporting the dopamine hypothesis of TD. Pending further replication, VMAT2 may be considered a therapeutic target for the treatment and/or prevention of TD. |
| SCZ Keywords | schizophrenia |