Polymorphisms in the Regulatory Region of the Human Serotonin 5-HT2A Receptor Gene (HTR2A) Influence Gene Expression

doi:10.1016/j.biopsych.2005.12.018

Biological Psychiatry

Volume 61, Issue 2, 15 January 2007, Pages 167-173

https://doi.org/10.1016/j.biopsych.2005.12.018 Get rights and content

Background

Genomic variation in the regulatory region of the serotonin (5-HT) 2A receptor gene (HTR2A) may contribute to altered levels of 5-HT_2A receptor and to psychiatric disease.

Methods

Frequency and linkage disequilibrium (LD) were determined for promoter single nucleotide polymorphisms (SNPs) -1438A/G, -1420C/T, and -783A/G in 156 subjects. Functional relevance of -1438A/G and -783A/G was assayed in vitro using a luciferase reporter assay and ex vivo using quantitative real time polymerase chain reaction in a set of human fibroblast cell lines.

Results

Significant LD was observed between SNPs -1438A/G and -783A/G. In vitro assays showed no significant differences in promoter activity between the A- and G-allele of -1438 locus when expressed with the major alleles at -1420C/T and -783A/G; however, when the minor allele G at -783 was expressed with G-allele at -1438, promoter activity was significantly decreased. 5-HT_2A receptor mRNA expression in human fibroblast cell lines confirmed that -783A/G polymorphism significantly modified the effects of -1438A/G SNP.

Conclusions

Our results demonstrate that SNP -783A/G modifies the effects of the major SNP -1438A/G. Future studies examining the association of -1438A/G polymorphism with diseases and 5-HT_2A receptor expression analyses should account for this epistasis.

Section snippets

Genotyping

The sample for this study consisted of 156 individuals recruited by Vanderbilt University Department of Psychiatry. All procedures involving human subjects were approved by the Vanderbilt University Institutional Review Board and were performed after written consent was obtained from participants. The characteristics of the individuals were as follows: mean age 42 ± 11 years, 58 men and 98 women; race—Caucasian (86.3%), African American (7.8%), Asian (3.3%), Hispanic (1.3%), other (1.3%). DNA

Genotyping

We evaluated the most common polymorphisms, -1438A/G, -1420C/T, and -783A/G occurring in the 1.5-kb putative promoter region of the HTR2A receptor gene in a population of 156 human subjects (Table 1). All allele frequencies for each locus were found to be in Hardy–Weinberg equilibrium. Linkage disequilibrium was evaluated using the likelihood ratio test; -1438A/G and -783A/G were found to be in significant LD (D′ = .98, p = .0008), and -1438A/G and -1420C/T were not in significant LD, although

Discussion

In this report, we describe genotype data on three SNPs, -1438A/G, -1420C/T, and -783A/G, from 156 unrelated subjects. This study, which to our knowledge provides the first published data on -783A/G SNP, found that the minor allele occurred at 7% frequency. We also found that -1438A/G and -783A/G polymorphisms are in linkage disequilibrium (LD). The location of the SNPs and putative transcription factor binding sites is consistent with the possibility that these polymorphisms may alter promoter

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Differential expression of HTR2A and MAOA genes in the prefrontal cortex and hypothalamus of suicide victims from Mexican population
2022, Neuroscience Letters
The main aim of the current study was to investigate whether the expression levels of the HTR2A and MAOA genes are altered in the postmortem brain of suicide victims from Mexican population.
On the basis of a case– control study, we examined the expression levels of HTR2A and MAOA genes in the postmortem prefrontal cortex (Brodmann area 8/9) and hypothalamus (ventromedial nucleus) tissues from 20 suicide victims and 20 control subjects from a Mexican population. Gene-expression profile quantification was carried out by qPCR and determined by the $2^{- Δ Δ C t}$ method.
In suicide victims, the expression levels of the HTR2A gene were significantly higher in the prefrontal cortex. In contrast, the expression of the MAOA gene in the hypothalamus of the suicide victims was significantly higher than in the control subjects. These results were consistent regardless of age, sex, postmortem interval, or pH of brain tissue.
The evidence suggests that the pattern of differential expression of HTR2A and MAOA genes in the brain may be involved in suicide, providing a possible molecular basis for the brain abnormalities in suicide victims.
The association of A-1438G and T102C polymorphisms in HTR2A and 120 bp duplication in DRD4 with alcoholic dependence in a northeastern Brazilian male population
2020, Gene Reports
Around the world, 3.3 million deaths are related to alcohol abuse. In Brazil, there are more than 4 million people with this behavior. Alcohol Dependence (AD) is a complex psychiatric disorder characterized by excessive alcohol consumption influenced by genetic and environmental factors. HTR2A and DRD4 are genes related to the serotonergic and dopaminergic systems and alterations in their sequences are associated with the etiology of AD. Our work analyzed the association between A-1438G (rs6311) and T102C (rs6313) polymorphisms in HTR2A and 120 bp duplication in DRD4 with the susceptibility to AD in that group of people.
Blood samples were collected from 300 men from Northeastern Brazil (150 alcohol-dependents and 150 controls). After DNA extraction, the determination of HTR2A and DRD4 genotypes was performed through PCR-RFLP method. The allele and genotype frequencies and association of polymorphisms with AD were determined using chi-square and Fisher's exact test, as well as, odds ratio (OR) with confidence interval of 95%. Value of p < 0.05 was considered significant.
Significantly, the low education, intake of doses per day, smoking and a positive family background of alcoholics were predominant in alcoholics patients than controls (p < 0.05). The results showed no differences were found between polymorphisms in the HTR2A and DRD4 genes herein investigated with AD. However, we observed a significant association between the GG (GG: OR = 6.68; 95% CI: 2.85 to 15.68; p < 0.0001), CC (CC: OR = 4.34; 95% CI: 1.68 to 11.1; p = 0.003), AG + GG (AG + GG: OR = 5.96; 95% CI: 2.68 to 13.2; p = 0.0001) and, TC + CC (TC + CC: OR = 4.38; 95% CI: 1.79 to 10.6; p = 0.001) genotypes in the HRT2A gene and family background with susceptibility to AD in our population.
Therefore, we suggest that the homozygous and heterozygous genotypes of the A-1438G and T102C polymorphism in the HTR2A gene, together with the positive family AD history, may be associated with the development of AD in the northeastern Brazilian male population displaying a dominant inheritance model. Further work is strongly encouraged to confirm the role of these polymorphisms in AD.
The association of HTR2A polymorphisms with obsessive-compulsive disorder and its subtypes: A meta-analysis
2020, Journal of Affective Disorders
Genetic risk factors that contribute to obsessive-compulsive disorder (OCD) have yet to be elucidated. Historically, serotonergic dysfunction has been implicated. Evidence from the literature points towards the serotonin receptor 2A gene (HTR2A) as a primary candidate. Our meta-analysis investigated whether polymorphisms in HTR2A are associated with OCD or its subtypes, based on sex and age of onset.
Studies employing case-control or family-based designs were systematically searched, and those meeting eligibility underwent quality assessment, resulting in 18 studies. A random-effects meta-analysis using standard inverse-variance weighting to compute odds ratio (OR) was conducted. To examine sensitivity, results were also obtained using a more conservative statistical method.
Three HTR2A variants were identified: T102C, G-1438A, and C516T. T102C and G-1438A were analyzed together due to strong linkage disequilibrium, where the 102T allele co-occurs with -1438A allele. Results reported as OR [95%CI] showed that the T/A allele were significantly associated with OCD, 1.14 [1.01, 1.29]. After stratification, results remained significant for females, 1.20 [1.00, 1.45], and early-onset OCD, 1.27 [1.02, 1.58], but not males, 1.06 [0.91, 1.23]. No associations were found for late-onset OCD, 0.98 [0.70, 1.37], or C516T, 1.22 [0.14, 10.37], but conclusions cannot be drawn from two studies.
Associations no longer reached significance with the conservative statistical approach. HTR2A alone cannot explain OCD complexity and limited samples reporting genetic data according to subtypes.
These results suggest a possible association of HTR2A polymorphisms with OCD, but further investigations considering sex and age of onset with larger samples is needed.
Effects of the 5-HT2A and DRD3 genotypes on cortical morphology and functional connectivity density in drug-naïve first episode schizophrenia
2020, Schizophrenia Research
The 5-hydroxytryptamine 2A receptor (5-HT2A) and dopamine D3 receptor (DRD3) have been extensively studied as promising candidate genes for schizophrenia. Magnetic resonance imaging studies have demonstrated that schizophrenia is associated with widespread structural and functional abnormalities in the brain. Serotonin and dopamine receptors play crucial roles in the development of the human cerebral cortex and brain activity. However, how the 5-HT2A and DRD3 genes impact brain structure and function in schizophrenia remains unknown. In the present study, we investigated the main effect of disease state and the interaction effect between disease state and genotype of these two genes on cortical volume, thickness, surface area and functional connectivity density (FCD) in fifty-five drug-naïve first episode schizophrenia patients and fifty-three healthy controls. We found that the differences in local FCD (lFCD) and global FCD (gFCD) between patients and healthy controls were predominantly located in brain hub regions. The significant interaction effects of disease state and 5-HT2A and DRD3 genes on brain structure and function were mainly located in the temporal cortex. Our findings may help to improve the understanding of the relationship between 5-HT2A and DRD3 genotypes and schizophrenia pathogenesis.
Functional pharmacogenetics of serotonin receptors in psychiatric drug action
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There is substantial evidence for the importance of serotonin system dysfunction in the biology of mood, anxiety disorders, and psychotic illness, as well as in the behavioral disturbances associated with neurodegenerative disorders. Interactions with serotonin receptors are likely to contribute to the mechanisms of action of many psychiatric drugs. There is substantial individual difference in response to drug treatment—not all patients show benefit, the treatment is often inadequate, and adverse effects of drugs may reduce their tolerability. Genetic factors are likely to contribute substantially to this individual variability; variability in serotonin receptor genes can influence both response to drug treatment and the emergence of adverse effects. This chapter concentrates on the functional pharmacogenetics of the main serotonin receptors involved in psychiatric drug action. The 5-HT_1A, 5-HT_2A, and 5-HT_2C receptors are the main focus; however, 5-HT_1B, 5-HT₄, 5-HT₆, and 5-HT₇ receptors are also discussed. The genes for these receptors exhibit polymorphisms that in some cases have functional effects on the expression or structure of the gene product. Epigenetic factors too can influence gene expression and several examples of one epigenetic mechanism, DNA methylation, of these genes are mentioned. The potential involvement of these functional changes in DNA sequence or methylation of serotonin receptor genes in the pharmacological mechanism of psychiatric drug action, notably treatment response and development of side effects, is discussed.

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Original articlePolymorphisms in the Regulatory Region of the Human Serotonin 5-HT2A Receptor Gene (HTR2A) Influence Gene Expression

Background

Methods

Results

Conclusions

Section snippets

Genotyping

Genotyping

Discussion

Schizophr Res

Life Sci

Brain Res

Brain Res Mol Brain Res

Biol Psychiatry

Neuroscience

Eur Neuropsychopharmacol

Brain Res

Psychiatry Res

Brain Res

Lancet

J Affect Disord

J Affect Disord

Neuroscience

Biol Psychiatry

Biol Psychiatry

Psychiatry Res

J Affect Disord

Psychiatry Res

Biol Psychiatry

Genomics

Lancet

Lancet

Biol Psychiatry

Decreased serotonin 5-HT(2A) receptor-stimulated phosphoinositide signaling in fibroblasts from melancholic depressed patients

Neuropsychopharmacology

Autoradiographic demonstration of increased serotonin 5-HT2 and beta-adrenergic receptor binding sites in the brain of suicide victims

Arch Gen Psychiatry

Original article
Polymorphisms in the Regulatory Region of the Human Serotonin 5-HT_2A Receptor Gene (HTR2A) Influence Gene Expression