5-HT2A Receptor Gene Research Articles

Association of the C(-1019)G 5-HT1A functional promoter polymorphism with antidepressant response.

Antidepressants, such as serotonin or noradrenaline reuptake inhibitors (e.g. fluoxetine, nefadozone) or 5-HT1A agonists (flibanserin), desensitize the 5-HT1A autoreceptor, which may contribute to their clinical efficacy. The 5-HT1A receptor gene is repressed by NUDR/DEAF-1 in raphe cells at the C-, but not at the G-allele of the C(-1019)G polymorphism that is associated with major depression and suicide. Depressed patients (n=118) were treated with antidepressants including fluoxetine or nefadozone combined with pindolol or flibanserin alone. The severity of depression was assesssed using the Hamilton Rating Scale for Depression. Although patients had similar severity initially, those with the homozygous G(-1019) genotype responded significantly less to flibanserin (p=0.039) and in pooled antidepressant treatment groups (p=0.0497) and were approximately twice as likely to be non-responders as those with the C(-1019)C genotype. These results implicate the C(-1019)G 5-HT1A gene polymorphism as a potential marker for antidepressant response, suggesting a role for repression of the 5-HT1A gene.

The –1438A/G polymorphism in the 5-hydroxytryptamine type 2A receptor gene affects promoter activity

The -1438A/G single nucleotide polymorphism (SNP) lies just upstream of two alternative promoters for the 5-hydroxytryptamine type 2A (5-HT2A) receptor gene (HTR2A) and is in strong linkage disequilibrium with the 102T/C SNP. Both SNPs are associated with numerous psychiatric disorders and related phenotypes. A possible functional affect of the -1438A/G SNP might underlie associations of both linked SNPs with these neuropsychiatric disorders. A prior investigation into affects of this SNP on promoter function, lacking the more downstream promoter, found no significant difference with a reporter gene assay. To investigate possible functional effects of -1438A/G on either promoter, two different reporter gene assays were used in three cell lines. Promoter activity was consistently detected that, in the presence of the SV40 enhancer, was significantly greater in the presence of the A allele relative to the G allele but only in cell lines that express endogenous HTR2A, suggesting that transcriptional factor(s) and the presence of both promoters might be necessary to elicit this effect. These findings show that the -1438A/G SNP has the potential to modulate HTR2A promoter activity and might be the functional variant responsible for the associations of both SNPs with many neuropsychiatric phenotypes.

Association of the -1438 G/A and 102 T/C polymorphism of the 5-Ht2A receptor gene with irritable bowel syndrome 5-Ht2A gene polymorphism in irritable bowel syndrome.

The aim of this study is to investigate whether there were any association between the 102 T/C and -1438 G/A polymorphisms of the 5-HT2A receptor gene and IBS, and abdominal pain, anxiety and depression. Genes involved in serotonin (5-HT) metabolism are good candidates for the pathogenesis of irritable bowel syndrome (IBS). Recently, a silent polymorphism in the 5-HT2A receptor gene was identified that is defined by a T to C transition at position 102. Also, a novel G to A base change at position -1438 of the promoter region has been detected in 5-HT2A receptor gene. Fifty-four patients with IBS diagnosed according to the Rome 1 criteria and 107 healthy individuals were included in the study. PCR was used to amplify a 468-bp (G-->A) and 342-bp (T-->C) fragment of genomic DNA containing the polymorphism. Hospital anxiety and depression scale was used to assess the risk of depression and anxiety. Severity of chronic abdominal pain was determined by visual analogue scale (VAS). It was shown that there was a high incidence of homozygote C allele of the 102T/C polymorphism (%22.2; OR: 7.89, P = 0.04) and homozygote A allele of the -1438 G/A promoter region (%%37; OR: 11.14, P = 0.01) in patients with IBS. The risk of having an anxiety disorder was 83.3% in patients with C/C genotype, which was higher than other allele carrying patients, and overall mean (%52.7). (chi = 8.56, P = 0.014). The patients with T/T genotype had a VAS score of 54.93 +/- 2.59 mm, which was significantly higher than that of the patients with other genotypes (p1 = 0.02, p2 = 0.001). This study suggests that the patients with homozygote C allele of the 102 T/C polymorphisms or homozygote A allele of the -1438 G/A polymorphism of the 5-HT2A receptor gene, have a high risk of IBS. On the other hand, T/T genotype of 102 T/C polymorphism may be associated with more severe pain in patient with IBS.

Association of the serotonin transporter and receptor gene polymorphisms in neuropsychiatric symptoms in Alzheimer disease.

Serotonin has been linked to neuropsychiatric symptoms in Alzheimer disease, mainly agitation/aggression, depression, and psychosis. Neuropsychiatric symptoms have been associated with polymorphisms of the promoter region (5-HTTPR ) and intron 2 of the serotonin transporter gene (5-HTTVNTR) or the 5-HT2A and 5-HT2C receptor genes in some but not all studies. To examine the association of the serotonin promoter, transporter, and receptor genes with neuropsychiatric symptoms in patients with Alzheimer disease. The sample included 96 patients with Alzheimer disease from the outpatient clinic of the University of California Los Angeles Alzheimer's Disease Research Center, Los Angeles. The Neuropsychiatric Inventory was used to measure neuropsychiatric symptoms, and blood samples were available for genetic analysis. Based on the literature, we hypothesized that the 5-HT2A and 5-HT2C receptor polymorphisms would be associated with agitation/aggression and psychosis and the 5-HTTPR or 5-HTTVNTR polymorphisms, with agitation/aggression or depression and anxiety. One-way analyses of variance were performed with age, ethnicity, sex, or education as covariates. The 102T genotype of the 5-HT2A receptor was significantly associated with delusions (P =.045) and agitation/aggression (P =.002). We did not replicate previous associations of the 5-HT2C receptor polymorphism with psychosis or of the 5-HTTPR polymorphism with agitation/aggression, psychosis, or depression. We did not find any associations with the 5-HTTVNTR polymorphism and agitation/aggression, depression, or anxiety. The 5-HT2A receptor polymorphism may contribute to the expression of psychosis and agitation/aggression in patients with Alzheimer disease. Absence of other positive associations may be due to the relatively small sample size and/or potentially small effect size of the polymorphisms and requires further study.

Association study of serotonin-2A receptor gene polymorphism and panic disorder in patients from Canada and Germany

The T102C serotonin-2A (5-HT2A) receptor gene polymorphism has been studied extensively in a number of complex psychiatric conditions with mixed results. Recently a genetic association has been described between this polymorphism and panic disorder in a Japanese sample. To evaluate the impact of the T102C polymorphism in panic disorder we genotyped triad families (panic disorder patient and parents), and cases with controls in Canadian and German samples. No significant transmission disequilibrium was observed between the alleles of the T102C 5-HT2A receptor gene polymorphism and panic disorder, nor was a significant excess of either allele found in the case control analysis. Our data suggest thus that this polymorphism is unlikely to play a major role in the pathogenesis of panic disorder.

The effects of 5-HT1A receptor gene polymorphism on clinical response to fluvoxamine

Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Japan Nominated presentations for Dr Paul Janssen award

Association of a functional 1019C>G 5-HT1A receptor gene polymorphism with panic disorder with agoraphobia.

Panic disorder is a common anxiety disorder which frequently co-occurs with agoraphobia. A functional promoter polymorphism in the serotonin receptor 1A (5-HT1A) gene has been found to be associated with major depression as well as anxiety- and depression-related personality traits. We investigated a possible association between this 5-HT1A gene promoter polymorphism and panic disorder by genotyping the 1019C>G single nucleotide polymorphism in 134 panic-disorder patients with and without agoraphobia and matched 134 controls. In our sample no significant evidence of allelic association in the combined panic-disorder group was found. However, our results show a significant association with the G allele in patients with panic disorder with agoraphobia (p=0.03, n=101). In conclusion, our findings do not support a major contribution of this polymorphism to the pathogenesis of panic disorder, but provide evidence for a possible role in the subgroup with agoraphobia.

Polymorphisms of the tryptophan hydroxylase gene and serotonin 1A receptor gene in suicide victims among Japanese.

Akita Prefecture, Japan, has consistently recorded the highest level of suicide rates in all of Japan. In this study, we attempted to determine whether genetic differences between suicide victims and the normal population in Akita exist. We also researched the geographical differences in polymorphisms of the genes between people living in Akita Prefecture and those living in other prefectures with lower suicide rates as recorded in previously-published studies. Specifically, we investigated two serotonin-related genes including three substitutions connected to human emotional states such as despondency and depression: the tryptophan hydroxylase (TPH) gene (A779C and A218C in the intron) and the serotonin1A (5-HT1A) receptor gene (Pro 16Leu in the cording region). 134 suicide victims and 325 healthy volunteers were examined. For this process, we used two analytical procedures: (1) polymerase chain reaction (PCR) followed by single-strand conformational polymorphisms analysis for the A779C of TPH and the 5-HT1A receptor genes and (2) PCR followed by restriction fragment length polymorphism analysis for the A218C of TPH gene. No significant differences of the genotypes and the allele frequencies between the suicide samples and those of the healthy controls were discerned. Moreover, the genotype distributions of the TPH and 5-HT1A receptor genes were compared between Akita Prefecture and other prefectures, but no significant differences were found. In conclusion, no significant relation could be established statistically concerning the serotonin related genes between the suicide samples and control samples in Akita.

Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia

A meta-analysis of whole-genome linkage scans confirmed linkage between schizophrenia and markers on the long arm of chromosome 13. The gene HTR2A, which codes for the 5HT2a receptor, is located in this area. The T102C single nucleotide polymorphism of HTR2A has been the subject of much research. The production of the C-allele form of HTR2A is significantly less than that of the T-allele form in normal controls and schizophrenic patients. Although the association of schizophrenia with the C allele of HTR2A was confirmed by a meta-analysis 5 years ago, there was a continuous debate because negative findings were also considerable, which may have been due to ethnic differences in association. We performed another meta-analysis, since the number of available studies of this association has recently doubled. In the meta-analysis of 31 case-control association studies, we found a significant association between the C allele of the T102C polymorphism and schizophrenia, which was more pronounced in European samples than in the entire sample. We found significant heterogeneity in the allele-wise analysis (C vs. T) and homozygous genotype-wise analysis (CC vs. TT), both of which were at least partially explained by differences between samples from Asian and European countries. In East Asian countries, there was not a significant association with the C allele or CC homozygosity, indicating strong genetic differences and noncombinability of data between European and East Asian populations. Interestingly, the frequency of the T allele was much higher in East Asian patients and controls (59.5% and 57.5%, respectively) than in European patients and controls (40% and 43.5%, respectively). In five family-based association studies, we did not find significant evidence for association of the C allele with schizophrenia; yet, the pooled OR was 1.3 (95% CI=0.9–1.8, z=1.47, p=0.14), which is consistent with the results of the case-control studies. The effects of other genes, environmental effects on DNA methylation, or different methods of classification may be the causes for such heterogeneity, but more study in this area is needed.

The 1438G/A polymorphism of the 5-HT2Areceptor gene is associated with aura in migraine

Objective: To find out the role of the 1438G/A polymorphism of the 5-HT2A promoter region in migraine. Study design: A polymerase chain reaction (PCR) analysis of the 1438G/A polymorphism was performed in 61 migraineurs and 57 healthy controls. Methods: The results of 1438G/A polymorphism were compared between the migraineurs and controls as well as between migraineurs with aura (MA) and those without aura (MOA). Results: The 1438 G/A polymorphism of 5-HT2A receptor gene was similar in both migraineurs and controls (p = 0.6). There was a significant relationship between the presence of G/G genotype and MA (p = 0.02) while A/A and A/G genotypes were similar in both MA and MOA (p > 0.05). Conclusion: The 1438G/A polymorphism of the 5-HT2A receptor gene is not associated with increased risk of migraine. The polymorphism of the gene is involved in determining the type of migraine. MA and MOA seem to be genetically distinct disorders.

Freud-1: A Neuronal Calcium-Regulated Repressor of the 5-HT1A Receptor Gene

Altered regulation of 5-HT1A receptors is implicated in mood disorders such as anxiety and major depression. To provide insight into its transcriptional regulation, we previously identified a novel DNA element [14 bp 5'-repressor element (FRE)] of the 5-HT1A receptor gene that mediates repression in neuronal and non-neuronal cells (Ou et al., 2000). We have now cloned a novel DNA binding protein [five' repressor element under dual repression binding protein-1 (Freud-1)] that binds to FRE to mediate repression of the 5-HT1A receptor or heterologous promoters. Freud-1 is evolutionarily conserved and contains two DM-14 basic repeats, a predicted helix-loop-helix DNA binding domain, and a protein kinase C conserved region 2 (C2)/calcium-dependent lipid binding (CalB) calcium/phospholipid binding domain. An intact CalB domain was required for Freud-1-mediated repression. In serotonergic raphe cells, overexpression of Freud-1 repressed the 5-HT1A promoter and decreased 5-HT1A receptor protein levels, whereas transfection of antisense to Freud-1 derepressed the 5-HT1A gene and increased 5-HT1A receptor protein expression. Calcium-dependent signaling blocked Freud-1-FRE binding and derepressed the 5-HT1A promoter. Treatment with inhibitors of calmodulin or CAM-dependent protein kinase reversed calcium-mediated inhibition of Freud-1. Freud-1 RNA and protein were present in raphe nuclei, hippocampus, cortex, and hypothalamus, and Freud-1 protein was colocalized with 5-HT1A receptors, suggesting its importance in regulating 5-HT1A receptors in vivo. Thus, Freud-1 represents a novel calcium-regulated repressor that negatively regulates basal 5-HT1A receptor expression in neurons and may play a role in the altered regulation of 5-HT1A receptors associated with anxiety or major depression.

T102C and –1438 G/A polymorphisms of the 5-HT2A receptor gene in Turkish patients with obsessive–compulsive disorder

Objective. – This study aimed to investigate the possible association between T102C and –1438 G/A polymorphism in the 5-HT2A receptor gene and susceptibility to and clinical features of obsessive–compulsive disorder (OCD). Method. – Fifty-eight patients with OCD and 83 healthy controls were included in the study. All patients were interviewed and rated by Yale-Brown Obsessive–Compulsive Scale. T102C and –1438 G/A polymorphisms of 5-HT2A receptor gene were determined by PCR technique in DNAs of peripheral leucocytes. Results. – OCD patients and healthy controls did not show significant differences in genotype distribution for both polymorphisms investigated. We found that frequencies of the TT genotype for T102C polymorphism and the AA genotype for –1438 G/A polymorphism were significantly higher in patients with severe OCD compared to those with moderate or moderate–severe OCD. Conclusion. – The –1438 G/A and T102C polymorphisms of the 5-HT2A receptor gene are not associated with an increased risk of OCD. Our data suggest that the TT genotype of T102C and the AA genotype of –1438 G/A polymorphism might be a factor in clinical severity of OCD.

Monoamine Oxidase A Gene Polymorphism, 5-HT2A Receptor Gene Polymorphism and Incidence of Nausea Induced by Fluvoxamine

Selective serotonin reuptake inhibitors cause a side effect of nausea with high frequency, but there have been no accurate methods to predict its incidence. The authors first investigated whether a functional polymorphism in the monoamine oxidase A (MAOA-VNTR) and a –1438G/A polymorphism in the promoter region of the 5-HT_2A gene were associated with the incidence of nausea induced by fluvoxamine. Fluvoxamine was administered for 6 weeks with a specific dosage plan (50–200 mg/day) in 66 Japanese major depressive patients. The frequency of MAOA-VNTR allele 1 was significantly higher in the patients without nausea than in ones with nausea in the statistical analysis including the patients whose plasma levels were below the average and who were considered to be pharmacodynamically more sensitive to nausea. This study showed that the genetic polymorphism of MAOA-VNTR might affect the incidence of nausea induced by SSRIs. If this finding is replicated in other studies with more subjects, MAOA-VNTR polymorphism would be of great clinical use to predict the incidence of nausea induced by SSRIs.

T102C Polymorphisms at the 5-HT2A Receptor Gene in Turkish Schizophrenia Patients: A Possible Association with Prognosis

Background: Serotonergic system abnormalities have been implicated in the pathogenesis of schizophrenia. The 5-HT2A receptor gene polymorphism has long been implicated to play a role in the pathogenesis of schizophrenia. Aim: In this study, we assessed the relationship of schizophrenia and its subgroups with 5-HT2A receptor gene polymorphism, and attempted to evaluate a possible correlation between the severity and prognosis of the illness and 5-HT2A receptor gene polymorphism. Method: Our study comprised 141 unrelated subjects who strictly met DSM-IV criteria for schizophrenia, and 79 healthy unrelated controls, all of Turkish origin. A clinical evaluation of all patients was accomplished applying the Brief Psychiatric Rating Scale (BPRS) test. The analysis of 5-HT2A receptor gene polymorphism was performed using the polymerase chain reaction technique. Results: Regarding 5-HT2A receptor gene polymorphisms, no statistically significant difference was found between schizophrenic patients and control subjects (p > 0.05). There was no significant difference between the average of BPRS points of the patients and 5-HT2A receptor gene polymorphisms (p > 0.05). Although there was no correlation between the duration of illness and polymorphism (p > 0.05), the frequency of hospitalization was found to be higher in the patients with T/C and T/T genotypes compared with the patients with C/C genotype (p < 0.05). Conclusion: Our findings indicate that the T102C polymorphisms of the 5-HT2A receptor gene does not play a substantial role in schizophrenia nor help evaluate susceptibility to schizophrenia. Since the 5-HT2A receptor gene polymorphism is associated with the frequency of hospitalization of the patients, it may be an indicator of prognosis in schizophrenia or help differentiate the patients who are somewhat refractory to antipsychotic treatment.

Tardive dyskinesia is not associated with the polymorphisms of 5-HT2A receptor gene, serotonin transporter gene and catechol- o-methyltransferase gene

Background. – The pathophysiology of tardive dyskinesia (TD) is not completely understood. Aim. – To assess the relationship of TD with 5-HT2A receptor gene, serotonin transporter gene (5 HTT), and catechol- o-methyltransferase (COMT) gene polymorphisms. Method. – Our study comprised 111 unrelated subjects who strictly met DSM-IV criteria for schizophrenia and 32 TD, and 79 healthy unrelated controls; all the subjects were of Turkish origin. The analyses of 5-HT2A receptor gene, 5 HTT gene, and COMT gene polymorphisms were performed using polymerase chain reaction (PCR) technique. Results. – The polymorphisms of these genes were not significantly different between the schizophrenic patients, TD and control subjects. Conclusion. – Our findings indicated that 5-HT2A receptor gene, 5 HTT gene, and COMT gene polymorphisms were similar in schizophrenia with non-TD, schizophrenia with TD, and healthy controls. These polymorphisms, though, do not help to evaluate the susceptibility to TD.

5-Hydroxytryptamine 5-HT2A receptor and 5-hydroxytryptamine transporter polymorphisms in acute myocardial infarction

This study was designed to analyse possible associations between DNA polymorphisms in the 5-hydroxytryptamine (5-HT; serotonin) 5-HT2A receptor and the 5-HT transporter (5-HTT) genes, and myocardial infarction (MI). 5-HT has been shown to be involved in cardiovascular pathophysiology. In addition to platelet aggregation and vascular contraction, 5-HT induces hyperplasia of artery smooth muscle cells. Recently, a 5-HT transporter gene polymorphism has been associated with MI. To determine the influence of genetic variation at the 5-HT2A receptor (T102C polymorphism) and the 5-HTT (insertion/deletion polymorphism) on the risk of developing early MI, we genotyped 210 MI patients of &lt;55 years old and 238 healthy control subjects for DNA polymorphisms in these genes. In addition, we genotyped 95 patients with late-onset MI (&gt;60 years old) to analyse the effects of these polymorphisms on the age at which the first MI episode occurred. The 5-HT2A receptor polymorphism was not associated with MI in our population. In addition, since the 5-HT2A receptor gene and genotype frequencies did not differ between patients with early and late onset of MI, this polymorphism does not appear to have an effect on age at the first MI episode. Gene and genotype frequencies for the 5-HTT promoter did not differ between patients &lt;55 years old and healthy controls (independent of smoking status). However, homozygotes for the deletion (the ss genotype, where s denotes the short allele) were present at a significantly higher frequency in patients &gt;60 years old compared with patients &lt;55 years old (P = 0.009; P = 0.004 when only smokers were compared). According to our data, the ss genotype would seem to have a protective role against MI, delaying the age of onset of the first episode, especially among smokers. This could be a consequence of the lower 5-HTT levels linked to the s allele, so that individuals homozygous for the ss genotype may have lower 5-HT re-uptake by platelets.

Candidate genes in eating disorders.

Environmental influences, as well as biological and genetic factors influence risk for eating disorders. Family and twin studies have shown that eating disorders are familial and suggest the influence of genetic factors on their etiology. Positive associations have been observed for some candidate genes that have been studied (such as 5HT2A receptor gene); however, the field has been plagued by nonreplications. In this paper we review the extant association studies of eating disorders.

Erratum: Analysis of structural polymorphisms and C-1018G promoter variant of the 5-HT1A receptor gene as putative risk factors in major depression

Erratum: Analysis of structural polymorphisms and C-1018G promoter variant of the 5-HT1A receptor gene as putative risk factors in major depression

Role of 5-HT2A Receptor Gene T102C Polymorphism in Coronary Artery Disease and Serum Lipid Level

Background and Objectives:The 5-HT2A receptor is one of the main mediators of a serotonin-evoked coronary artery contraction. This is because vasoconstriction is selectively blocked by the 5-HT2 receptor antagonist, with the 5-HT2A receptor gene mRNA being detected in spastic coronary arteries. The relationship between the T102C polymorphism of the 5-HT2A receptor gene and the response to the 5-HT2A antagonist (clozapine) has recently been established, suggestive of a functional implication. Previous studies have observed an association between low cholesterol levels and mental disorders, but the underlying cause has not been determined. It has been established that the T102C polymorphism of the 5-HT2A serotonin receptor gene and a variety of psychological problems are related, but the relationship between the serum lipid level and this genetic polymorphism has not been reported. We investigated the influence of this polymorphism on coronary artery disease, including vasospastic angina and the clinical parameters, such as the lipid profile. Subjects and Methods:After a diagnostic angiography was performed, the genotype was identified from the genomic DNA extracted from the peripheral blood of 646 patients without specific psychiatric diseases. Results:There were no differences in the genotype frequencies between coronary artery disease, coronary artery disease with vasospasm, and the normal control groups, even from a subgroup analysis of the clinical parameters. Contrary to previous reports, the genotype distribution was not related to a myocardial infarction or hypertension. The lipid profile analysis showed significantly lower total cholesterol (193.5 vs. 202.1 mg/dL, p=0.016) and HDL-cholesterol (42.7 vs. 46.2 mg/dL, p=0.003) levels in the CC genotype than the other genotypes, and the frequencies of CC genotype showed a significantly decreasing trend between the HDLcholesterol (p=0.003) and total cholesterol (p=0.003) quartiles. From a multivariate analysis, only the HDL-cholesterol level was significantly associated with a lower frequency of the CC genotype (p=0.006). Conclusion:The T102C polymorphism is not related to coronary artery disease, including vasospasm of the coronary artery, but the CC genotype of this polymorphism is related to low HDL-cholesterol. We identified a novel genetic polymorphism of the serotonin receptor, which affects the HDL-cholesterol level. Because previous observational studies have shown an association between low cholesterol levels and mental disorders, our data should be considered when analyzing the serum lipid levels and serotonin receptor function in humans. (Korean Circulation J 2003;33 (4):269-276)

Association Analysis of Serotonin 2A Receptor Gene T102c Polymorphism and Schizophrenia

The serotonin neurotransmitter has been associated with the pathogenesis of mood disorders and schizophrenia. Serotonin receptors genes may therefore be candidate genes for the study of the genetics of these disorders. In this study, patients with schizophrenia (n=235) and controls (nn=344) were analysed to determine the correlation between the 5HT2A receptor gene T102C polymorphism and schizophrenia. No association was found between the studied polymorphism and schizophrenia (pn=0.854 for alleles and pn=0.945 for genotypes). Results were also not significant when analysed by gender (for male p-0.861—allele frequency and pn=0.467—genotype frequency, for female pn=0.857—allele frequency and pn=0.833—genotype frequency). Subgroups with regard to schizophrenia subtypes, age of onset and clinical course of schizophrenia were analysed with negative results.