| 1 | Mol. Psychiatry 2007 Sep 12: 842-53 |
|---|---|
| PMID | 17505468 |
| Title | A region of 35 kb containing the trace amine associate receptor 6 (TAAR6) gene is associated with schizophrenia in the Irish study of high-density schizophrenia families. |
| Abstract | The TAAR6 gene has been previously associated with schizophrenia in 192 pedigrees of European and African ancestry. To replicate these findings we performed an association study of TAAR6 in 265 pedigrees of the Irish Study of High-Density schizophrenia Families (ISHDSF). Of the 24 genotyped single-nucleotide polymorphisms only rs12189813 and rs9389011 provided single-marker evidence for association (0.0094 |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Am J Psychiatry 2008 Apr 165: 497-506 |
| PMID | 18198266 |
| Title | No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. |
| Abstract | The authors carried out a genetic association study of 14 schizophrenia candidate genes (RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF). This study tested the hypothesis of association of schizophrenia with common single nucleotide polymorphisms (SNPs) in these genes using the largest sample to date that has been collected with uniform clinical methods and the most comprehensive set of SNPs in each gene. The sample included 1,870 cases (schizophrenia and schizoaffective disorder) and 2,002 screened comparison subjects (i.e. controls), all of European ancestry, with ancestral outliers excluded based on analysis of ancestry-informative markers. The authors genotyped 789 SNPs, including tags for most common SNPs in each gene, SNPs previously reported as associated, and SNPs located in functional domains of genes such as promoters, coding exons (including nonsynonymous SNPs), 3' untranslated regions, and conserved noncoding sequences. After extensive data cleaning, 648 SNPs were analyzed for association of single SNPs and of haplotypes. Neither experiment-wide nor gene-wide statistical significance was observed in the primary single-SNP analyses or in secondary analyses of haplotypes or of imputed genotypes for additional common HapMap SNPs. Results in SNPs previously reported as associated with schizophrenia were consistent with chance expectation, and four functional polymorphisms in COMT, DRD2, and HTR2A did not produce nominally significant evidence to support previous evidence for association. It is unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects cannot be ruled out. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | J. Neurosci. Res. 2008 Nov 86: 3435-46 |
| PMID | 18627029 |
| Title | Cloning, expression, and functional analysis of rhesus monkey trace amine-associated receptor 6: evidence for lack of monoaminergic association. |
| Abstract | Several recent studies report an association between trace amine-associated receptor 6 (TAAR6) and susceptibility to schizophrenia and bipolar affective disorder in humans. However, endogenous TAAR6 agonists and the receptor signaling profile and brain distribution remain unclear. Here, we clone TAAR6 from the rhesus monkey and use transfected cells to investigate whether this receptor interacts with brain monoamines and a psychostimulant drug to trigger cAMP signaling or extracellular signal-regulated kinase (ERK) phosphorylation, while investigating its expression profile in the rhesus monkey brain. Unlike TAAR1, rhesus monkey TAAR6 did not alter cAMP levels in response to 10 microM of monoamines (dopamine, norepinephrine, serotonin, beta-phenylethylamine (beta-PEA), octopamine, tryptamine, and tyramine) or methamphetamine in stably transfected cells in vitro. Real-time cell electronic sensing analysis indicated that the receptor did not alter cell impedance or change the effect of forskolin on cell impedance at exposure to 20 microM of each monoamine, suggesting a lack of either Gs or Gi-linked signaling. Whereas kappa opioid receptor activation led to ERK phosphorylation at exposure to 1 microM U69593, rhesus monkey TAAR6 had no such effect at exposure to 10 microM of monoamines or methamphetamine. Membrane and cell surface localization of TAAR6 was confirmed by immunocytochemistry, biotinylation, and Western blot testing with a TAAR6 antibody in the transfected cells. Real-time reverse transcriptase-polymerase chain reaction amplification showed that TAAR6 mRNA was undetectable in selected rhesus monkey brain regions. Together, the data reveal that TAAR6 is unresponsive to brain monoamines and is not expressed in rhesus monkey brain monoaminergic nuclei, suggesting TAAR6 lacks direct association with brain monoaminergic neuronal function. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Eur. Psychiatry 2008 Sep 23: 390-5 |
| PMID | 18583103 |
| Title | TAAR6 variation effect on clinic presentation and outcome in a sample of schizophrenic in-patients: an open label study. |
| Abstract | We recently reported an association between TAAR6 (trace amine associated receptor 6 gene) variations and schizophrenia (SZ). We now report an association of a set of TAAR6 variations and clinical presentation and outcome in a sample of 240 SZ Korean patients. Patients were selected by a Structured Clinical Interview, DSM-IV Axis I disorders - Clinical Version (SCID-CV). Other psychiatric or neurologic disorders, as well as medical diseases, were exclusion criteria. To assess symptom severity, patients were administered the CGI scale and the PANSS at baseline and at the moment of discharge, 1 month later on average. TAAR6 variations rs6903874, rs7452939, rs8192625 and rs4305745 were investigated; rs6903874, rs7452939 and rs8192625 entered the statistical investigation after LD analysis. Rs8192625 G/G homozygosis was found to be significantly associated both with a worse clinical presentation at PANSS total and positive scores and with a shorter period of illness before hospitalization. No haplotype significant findings were found. The present study stands for a role of the TAAR6 in the clinical presentation of SZ. Moreover, our results show that this genetic effect may be counteracted by a correct treatment. Haplotype analysis was not informative in our sample, probably also because of the incomplete SNPs' coverage of the gene we performed. Further studies in this direction are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Eur. Psychiatry 2008 Sep 23: 390-5 |
| PMID | 18583103 |
| Title | TAAR6 variation effect on clinic presentation and outcome in a sample of schizophrenic in-patients: an open label study. |
| Abstract | We recently reported an association between TAAR6 (trace amine associated receptor 6 gene) variations and schizophrenia (SZ). We now report an association of a set of TAAR6 variations and clinical presentation and outcome in a sample of 240 SZ Korean patients. Patients were selected by a Structured Clinical Interview, DSM-IV Axis I disorders - Clinical Version (SCID-CV). Other psychiatric or neurologic disorders, as well as medical diseases, were exclusion criteria. To assess symptom severity, patients were administered the CGI scale and the PANSS at baseline and at the moment of discharge, 1 month later on average. TAAR6 variations rs6903874, rs7452939, rs8192625 and rs4305745 were investigated; rs6903874, rs7452939 and rs8192625 entered the statistical investigation after LD analysis. Rs8192625 G/G homozygosis was found to be significantly associated both with a worse clinical presentation at PANSS total and positive scores and with a shorter period of illness before hospitalization. No haplotype significant findings were found. The present study stands for a role of the TAAR6 in the clinical presentation of SZ. Moreover, our results show that this genetic effect may be counteracted by a correct treatment. Haplotype analysis was not informative in our sample, probably also because of the incomplete SNPs' coverage of the gene we performed. Further studies in this direction are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Psychiatr. Genet. 2008 Aug 18: 208-10 |
| PMID | 18628684 |
| Title | No support for an association with TAAR6 and schizophrenia in a linked population of European ancestry. |
| Abstract | Single nucleotide polymorphisms (SNPs) in the trace amine associated receptor trace amine associated receptor 6 gene and 3' flanking region have been shown to be associated with schizophrenia. To replicate these findings, we conducted a family-based association study with the five most significant SNPs in our sample of 79 sib-pair families (56/79 sib-pair families showed linkage to 6q23) and 125 triads. No evidence for association was obtained between these SNPs and schizophrenia in our sample, even when limited to the 56 linked families (P>0.2). We conclude that trace amine associated receptor 6 is not important for the development of schizophrenia in our family samples. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | J Psychiatr Res 2008 Jan 42: 35-40 |
| PMID | 17097106 |
| Title | Association of the trace amine associated receptor 6 (TAAR6) gene with schizophrenia and bipolar disorder in a Korean case control sample. |
| Abstract | Trace amines and their receptors may be implicated in the pathogenesis of psychiatric disorders. Previous studies have reported association of the trace amine associated receptor 6 (TAAR6) gene with susceptibility to schizophrenia and bipolar disorder but results have not been consistent. The purpose of this study was to examine these associations in Korean patients and also to test for association of TAAR6 with susceptibility to major depressive disorder (MDD). A case control sample consisting of 281 patients with schizophrenia, 190 patients with bipolar disorder, 187 patients with MDD and 288 psychiatrically healthy control subjects, was examined. Patients with schizoaffective disorder were not included in any of the psychiatric samples. Five single nucleotide polymorphisms (SNPs: rs4305745; rs8192625; rs7452939; rs6903874 and rs6937506) were genotyped in the TAAR6 gene and in the 3' regulatory region, using pyrosequencing. SNP rs6903874 was significantly associated with schizophrenia (p = 0.012) and bipolar disorder (p = 0.004). A three SNP haplotype consisting of alleles GCT from SNPs rs7452939, rs6903874 and rs6937506, respectively, was significantly over-represented in patients with schizophrenia (p = 0.0003) and bipolar disorder (p = 0.00002). A second three SNP haplotype (GTT) derived from the same SNPs was significantly under-represented in patients with bipolar disorder (p = 0.001). The GTT haplotype associations withstand the most rigorous corrections for multiple testing. These findings strongly support association of the TAAR6 gene with susceptibility to both schizophrenia and bipolar disorder in Korean patients. Further studies are needed to confirm these findings in this and other populations and to identify functional variants in TAAR6 that may be implicated in pathogenesis. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Eur Neuropsychopharmacol 2009 Nov 19: 806-11 |
| PMID | 19643584 |
| Title | Epistasis between a set of variations located in the TAAR6 and HSP-70 genes toward schizophrenia and response to antipsychotic treatment. |
| Abstract | Suggestive associations have been reported between trace amines and heat shock proteins, and a disrupted pathophysiology that enhances the risk of psychosis and that modifies responses to antipsychotic treatments. Our group previously reported genetic studies on TAAR6 and HSP-70 separately in patients with schizophrenia. In the current study, we investigated possible epistasis between the same set of variations in a sample of 281 patients diagnosed with schizophrenia and 288 healthy controls. We applied the generalized multifactor dimensionality reduction (MDR) method and controlled covariates significantly associated with both diagnosis and treatment efficacy. To the best of our knowledge, epistasis between the present set of variations in schizophrenia has not been tested before. We found significant associations with both the risk of disease and response to treatment. However, the insufficiently balanced accuracy of the applied tests suggests that, despite significantly different genetic variations between cases and controls, these factors have a poor predictive value. Explanations for these findings and possible future directions are also discussed. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Schizophr. Res. 2009 Feb 107: 249-54 |
| PMID | 18973992 |
| Title | The trace amine associated receptor (TAAR6) gene is not associated with schizophrenia in the Irish Case-Control Study of Schizophrenia (ICCSS) sample. |
| Abstract | To replicate previous association between TAAR6 and schizophrenia, including our own finding in the Irish Study of High Density schizophrenia Families (ISHDSF) sample, we genotyped 12 single nucleotide polymorphisms (SNPs) in the Irish Case-Control Study of schizophrenia (ICCSS) sample. Only rs9389020 provided nominal evidence for association (p<0.0228), which did not withstand the permutation testing (p<0.2196). The combined odds ratio from ISHDSF and ICCSS samples [OR (95%CI)=1.0564 (1.0078-1.1074); p=0.02], while nominally significant, did not survive correction for multiple testing. Here we demonstrate that TAAR6 is not associated with schizophrenia in the ICCSS sample. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Aug 33: 822-6 |
| PMID | 19345712 |
| Title | Influence of TAAR6 polymorphisms on response to aripiprazole. |
| Abstract | There is some evidence suggesting a role of TAAR6 in schizophrenia. The aim of the present study is to investigate possible influences of a panel of markers in TAAR6 (rs8192625, rs4305745, rs4305746, rs6903874, rs6937506) on clinical outcomes and side effects in a sample of Korean schizophrenic aripiprazole treated patients. Efficacy was assessed at baseline and weeks 1, 2, 4, 6, 8 using CGI-S, CGI-I, BPRS and SANS. Side effects were evaluated through SAS, BAS and AIMS. Multivariate analysis of covariance (MANCOVA) was used to test possible influences of single SNPs on clinical and safety scores. Tests for associations using multi-marker haplotypes were performed using the statistics environment "R". A significant time per genotype interaction was found between rs4305746 in repeated measures of ANOVA on BPRS scores (F=2.45, df=10,365, p=0.008). In particular G/A and A/A genotype patients were more likely to improve over time as compared to carriers of the G/G genotype. Permutation analysis confirmed a significant effect of rs4305746 on course of BPRS scores over time (p=0.007). Haplotype analysis did not reveal any significant association with clinical and safety scores at any time. A possible association could exist between some genotypes in TAAR6 and response to aripiprazole. However, several limitations characterize the present work, such as small sample size, the finding related to a single scale and the possibility of false positive findings, thus further investigation is required. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Aug 33: 822-6 |
| PMID | 19345712 |
| Title | Influence of TAAR6 polymorphisms on response to aripiprazole. |
| Abstract | There is some evidence suggesting a role of TAAR6 in schizophrenia. The aim of the present study is to investigate possible influences of a panel of markers in TAAR6 (rs8192625, rs4305745, rs4305746, rs6903874, rs6937506) on clinical outcomes and side effects in a sample of Korean schizophrenic aripiprazole treated patients. Efficacy was assessed at baseline and weeks 1, 2, 4, 6, 8 using CGI-S, CGI-I, BPRS and SANS. Side effects were evaluated through SAS, BAS and AIMS. Multivariate analysis of covariance (MANCOVA) was used to test possible influences of single SNPs on clinical and safety scores. Tests for associations using multi-marker haplotypes were performed using the statistics environment "R". A significant time per genotype interaction was found between rs4305746 in repeated measures of ANOVA on BPRS scores (F=2.45, df=10,365, p=0.008). In particular G/A and A/A genotype patients were more likely to improve over time as compared to carriers of the G/G genotype. Permutation analysis confirmed a significant effect of rs4305746 on course of BPRS scores over time (p=0.007). Haplotype analysis did not reveal any significant association with clinical and safety scores at any time. A possible association could exist between some genotypes in TAAR6 and response to aripiprazole. However, several limitations characterize the present work, such as small sample size, the finding related to a single scale and the possibility of false positive findings, thus further investigation is required. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Psychiatry Res 2010 Nov 180: 20-4 |
| PMID | 20493543 |
| Title | TAAR6 variations possibly associated with antidepressant response and suicidal behavior. |
| Abstract | Trace amines are putative regulatory elements in the brain whose activity may be relevant to the pathophysiology of depressive episodes. TAAR6 is an orphan receptor probably associated with trace amines. Its genetic variations have been associated with bipolar and schizophrenic disorders. In this study we investigated for the first time the possible association between a set of TAAR6 genetic variations (rs7452939; rs4305745; rs6903874; rs6937506; and rs8192625) with clinical features of depression including antidepressant treatment response in a sample of 187 depressive patients all of Korean origins. rs6903874 T/T carriers had a statistically significant better improvement, and rs6937506 C/C genotype was found to be more frequent in patients without a history of suicide attempt (incomplete or unsuccessful suicide). Haplotype analyses confirmed the association with suicide attempt behavior being haplotype G-T at SNPs rs7452939 and rs6937506 at risk of suicide. These results suggest a possible role of TAAR6 in antidepressant response and suicide behavior in patients with depressive disorder. Heterogeneity of treatment, possible stratification bias not controlled by the statistical analyses, and the risk of false-positive finding mandate further analysis in this direction. |
| SCZ Keywords | schizophrenia, schizophrenic |