| 1 | Mol. Psychiatry 2002 -1 7: 954-61 |
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| PMID | 12399948 |
| Title | Association between serotonin 4 receptor gene polymorphisms and bipolar disorder in Japanese case-control samples and the NIMH Genetics Initiative Bipolar Pedigrees. |
| Abstract | Possible irregularities in serotonergic neurotransmission have been suggested as causes of a variety of neuropsychiatric diseases. We performed mutation and association analyses of the HTR4 gene, on 5q32, encoding the serotonin 4 receptor in mood disorders and schizophrenia. Mutation analysis was performed on the HTR4 exons and exon/intron boundaries in 48 Japanese patients with mood disorders and 48 patients with schizophrenia. Eight polymorphisms and four rare variants were identified. Of these, four polymorphisms at or in close proximity to exon d, g.83097C/T (HTR4-SVR (splice variant region) SNP1), g.83159G/A (HTR4-SVRSNP2), g.83164 (T)9-10 (HTR4-SVRSNP3), and g.83198A/G (HTR4-SVRSNP4), showed significant association with bipolar disorder with odds ratios of 1.5 to 2. These polymorphisms were in linkage disequilibrium, and only three common haplotypes were observed. One of the haplotypes showed significant association with bipolar disorder (P = 0.002). The genotypic and haplotypic associations with bipolar disorder were confirmed by transmission disequilibrium test in the NIMH Genetics Initiative Bipolar Pedigrees with ratios of transmitted to not transmitted alleles of 1.5 to 2.0 (P = 0.01). The same haplotype that showed association with bipolar disorder was suggested to be associated with schizophrenia in the case-control analysis (P = 0.003) but was not confirmed when Japanese schizophrenia families were tested. The polymorphisms associated with mood disorder were located within the region that encodes the divergent C-terminal tails of the 5-HT(4) receptor. These findings suggest that genomic variations in the HTR4 gene may confer susceptibility to mood disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Aug 121B: 7-13 |
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| PMID | 12898568 |
| Title | Association of a haplotype in the serotonin 5-HT4 receptor gene (HTR4) with Japanese schizophrenia. |
| Abstract | The serotonin 5-HT(4) receptor (5-HT(4)) is implicated in cognitive function, of which impairment is hypothesized as one of the core disturbances of schizophrenia. Linkage analysis shows that 5q33.2, in which HTR4 is located, is schizophrenia-susceptibility loci. We therefore hypothesized that variation in the 5-HT(4) receptor gene (HTR4) modifies genetic susceptibility to schizophrenia. HTR4 coding regions and introns that include the branch sites of HTR4 were investigated in 96 unrelated Japanese schizophrenics using denaturing high-performance liquid chromatography analysis. One silent single nucleotide polymorphism (SNP) within the coding region and six intronic SNPs were detected. 353 + 6G > A was located in the branch site that could be effect to RNA splicing. None of the four SNPs, in which rare-allele frequencies were more than 10% was associated with 189 schizophrenics, in comparison to 299 controls. However, a highly significant association between schizophrenia and haplotype A-T (OR = 0.13 [0.03-0.58]) was detected. These findings suggest that haplotype A-T itself may inhibit the occurrence of schizophrenia, or that another susceptible genetic variants may exist within linkage disequilibrium. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Aug 121B: 7-13 |
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| PMID | 12898568 |
| Title | Association of a haplotype in the serotonin 5-HT4 receptor gene (HTR4) with Japanese schizophrenia. |
| Abstract | The serotonin 5-HT(4) receptor (5-HT(4)) is implicated in cognitive function, of which impairment is hypothesized as one of the core disturbances of schizophrenia. Linkage analysis shows that 5q33.2, in which HTR4 is located, is schizophrenia-susceptibility loci. We therefore hypothesized that variation in the 5-HT(4) receptor gene (HTR4) modifies genetic susceptibility to schizophrenia. HTR4 coding regions and introns that include the branch sites of HTR4 were investigated in 96 unrelated Japanese schizophrenics using denaturing high-performance liquid chromatography analysis. One silent single nucleotide polymorphism (SNP) within the coding region and six intronic SNPs were detected. 353 + 6G > A was located in the branch site that could be effect to RNA splicing. None of the four SNPs, in which rare-allele frequencies were more than 10% was associated with 189 schizophrenics, in comparison to 299 controls. However, a highly significant association between schizophrenia and haplotype A-T (OR = 0.13 [0.03-0.58]) was detected. These findings suggest that haplotype A-T itself may inhibit the occurrence of schizophrenia, or that another susceptible genetic variants may exist within linkage disequilibrium. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Neurosci. Lett. 2008 Apr 435: 95-8 |
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| PMID | 18359159 |
| Title | Relationship between three serotonin receptor subtypes (HTR3A, HTR2A and HTR4) and treatment-resistant schizophrenia in the Japanese population. |
| Abstract | The proportion of treatment-resistant schizophrenia (TRS) has been estimated as 20-40% in the schizophrenic patients. Genetic factors are considered to be involved in the development of this condition. Serotonin subtypes are hypothesized to be the candidate genes. In the present study, single marker and haplotype analyses between several mutations of serotonin receptor subtypes (HTR2A, HTR3A and HTR4) and TRS (TRS=101, NON-TRS=239) were performed to determine a possible relationship with the development of TRS. Additionally, we also compared the daily neuroleptic dosage among each genotype. No significant association was observed between TRS and each allele, genotype, and haplotype. However, the daily neuroleptic dosage that patients had been receiving during their maintenance therapy was significantly higher in patients with the T/T genotype of HTR3A polymorphism (rs1062613, p=0.041). The present results support further research to examine the relationship between HTR3A polymorphism and the development of TRS in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Neurosci. Lett. 2008 Apr 435: 95-8 |
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| PMID | 18359159 |
| Title | Relationship between three serotonin receptor subtypes (HTR3A, HTR2A and HTR4) and treatment-resistant schizophrenia in the Japanese population. |
| Abstract | The proportion of treatment-resistant schizophrenia (TRS) has been estimated as 20-40% in the schizophrenic patients. Genetic factors are considered to be involved in the development of this condition. Serotonin subtypes are hypothesized to be the candidate genes. In the present study, single marker and haplotype analyses between several mutations of serotonin receptor subtypes (HTR2A, HTR3A and HTR4) and TRS (TRS=101, NON-TRS=239) were performed to determine a possible relationship with the development of TRS. Additionally, we also compared the daily neuroleptic dosage among each genotype. No significant association was observed between TRS and each allele, genotype, and haplotype. However, the daily neuroleptic dosage that patients had been receiving during their maintenance therapy was significantly higher in patients with the T/T genotype of HTR3A polymorphism (rs1062613, p=0.041). The present results support further research to examine the relationship between HTR3A polymorphism and the development of TRS in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | RNA 2010 Apr 16: 839-51 |
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| PMID | 20197377 |
| Title | Four exons of the serotonin receptor 4 gene are associated with multiple distant branch points. |
| Abstract | Splicing of vertebrate introns involves recognition of three consensus elements at the 3' end. The branch point (BP) and polypyrimidine tract (PPT) are usually located within 40 nucleotides (nt) of the 3' splice site (3' ss), AG, but can be much more distant. A characteristic of the region between distant BPs (dBPs) and the 3' ss is the absence of intervening AG dinucleotides, leading to its designation as the "AG exclusion zone" (AGEZ). The human HTR4 gene, which encodes serotonin receptor 4 and has been associated with schizophrenia, bipolar disease, and gastrointestinal disorders, has four exons with extensive AGEZs. We have mapped the BPs for HTR4 exons 3, 4, 5, and g generated by in vitro splicing, and validated them by mutagenesis in exon-trapping vectors. All exons used dBPs up to 273 nt upstream of the exon. Strikingly, exons 4 and 5 used combinations of both distant and conventionally located BPs, suggesting that successful splicing of these exons can occur by distinct pathways. Our results emphasize the importance for single nucleotide polymorphism resequencing projects to take account of potential dBPs, as the extended AGEZs are vulnerable to mutations that could affect splicing itself or regulation of alternative splicing. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Psychiatry Res 2010 Jan 175: 176-8 |
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| PMID | 19892407 |
| Title | Lack of association between HTR4 gene polymorphisms and schizophrenia in case-control and family-based samples. |
| Abstract | Previous studies have found haplotypic association of HTR4 variants and schizophrenia. Examining case-control pairs, G-G of rs7713886 was associated with schizophrenia risk. The A-A-G-G-G-A-A rs9325104-rs1422636-rs7715569-rs6873382-rs7711800-rs10078551-rs2068190 haplotype was overrepresented in the schizophrenia cases. The associations were no longer significant after corrections for multiple comparisons. No association was found in the family sample. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | J Neural Transm (Vienna) 2013 Feb 120: 253-8 |
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| PMID | 22842674 |
| Title | Association and CpG SNP analysis of HTR4 polymorphisms with suicidal behavior in subjects with schizophrenia. |
| Abstract | Suicide is a major contributor to the morbidity and mortality rates in schizophrenia. Genetic and epigenetic factors have been reported to modulate the risk for suicide although the precise mechanism and magnitude of these contributions is unknown. Previous research indicates that suicide attempters present abnormalities in the serotonergic system. The present study aimed to identify genetic and epigenetic risk variants of the serotonin 5-HT? receptor gene (HTR4) for suicidal behavior. We included 234 subjects diagnosed with schizophrenia. For this purpose, we analyzed 11 markers across HTR4 and performed genotype, haplotype and potential methylation analyses, correcting for clinical covariates and ethnic stratification. Three blocks were revealed from the LD analysis. Haplotypes in Block 3 were significantly associated with suicide attempt. The potential methylation analysis was not significant. Our results suggest that HTR4 polymorphisms may not play a major role in the susceptibility for suicidal behavior in subjects with schizophrenia. Moreover, although not significant, the CpG SNP potential methylation analysis would be informative for future methylation analysis on this gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |