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Abstract Background Both genetic and environmental factors play crucial roles in the development of major depressive disorder (MDD) and suicide attempts (SA). However, the interaction between both items remains unknown. This study aims to explore the interactions between the genetic variants of the serotonin 2 A receptor (HTR2A) and the nitric oxide synthase 1 (NOS1) and environmental factors in patients who experience MDD and SA. Methods A total of 334 patients with MDD and a history of SA (MDD-SA) were recruited alongside 518 patients with MDD with no history of SA (MDD-NSA), and 716 healthy controls (HC). The demographic data and clinical characteristics were collected. Sequenom mass spectrometry was used to detect eight tag-single nucleotide polymorphisms (tagSNPs) in HTR2A (rs1328683, rs17068986, and rs3125) and NOS1 (rs1123425, rs2682826, rs3741476, rs527590, and rs7959232). Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-environment interactions. Results Four tagSNPs (rs17068986, rs3125, rs527590, and rs7959232) exhibited significant differences between the three groups. However, these differences were not significant between the MDD-SA and MDD-NSA groups after Bonferroni correction. A logistic regression analysis revealed that negative life events (OR = 1.495, 95%CI: 1.071–2.087, P = 0.018), self-guilt (OR = 2.263, 95%CI: 1.515–3.379, P

Background: Both genetic and environmental factors play crucial roles in the development of major depressive disorder (MDD) and suicide attempts (SA). However, the interaction between both items remains unknown. This study aims to explore the interactions between the genetic variants of the serotonin 2 A receptor (HTR2A) and the nitric oxide synthase 1 (NOS1) and environmental factors in patients who experience MDD and SA. Methods: A total of 334 patients with MDD and a history of SA (MDD-SA) were recruited alongside 518 patients with MDD with no history of SA (MDD-NSA), and 716 healthy controls (HC). The demographic data and clinical characteristics were collected. Sequenom mass spectrometry was used to detect eight tag-single nucleotide polymorphisms (tagSNPs) in HTR2A (rs1328683, rs17068986, and rs3125) and NOS1 (rs1123425, rs2682826, rs3741476, rs527590, and rs7959232). Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-environment interactions. Results: Four tagSNPs (rs17068986, rs3125, rs527590, and rs7959232) exhibited significant differences between the three groups. However, these differences were not significant between the MDD-SA and MDD-NSA groups after Bonferroni correction. A logistic regression analysis revealed that negative life events (OR = 1.495, 95%CI: 1.071–2.087, P = 0.018), self-guilt (OR = 2.263, 95%CI: 1.515–3.379, P < 0.001), and negative cognition (OR = 2.252, 95%CI: 1.264–4.013, P = 0.006) were all independently associated with SA in patients with MDD. Furthermore, GMDR analysis indicated a significant interaction between HTR2A rs3125 and negative life events. Negative life events in conjunction with the HTR2A rs3125 CG + GG genotype were associated with a higher SA risk in patients with MDD when compared to the absence of negative life events in conjunction with the CC genotype (OR = 2.547, 95% CI: 1.264–5.131, P = 0.009). Conclusion: Several risk factors and a potential interaction between HTR2A rs3125 and negative life events were identified in patients with SA and MDD. The observed interaction likely modulates the risk of MDD and SA, shedding light on the pathogenesis of SA in patients with MDD. [ABSTRACT FROM AUTHOR]

The expanding field of precision gene editing using CRISPR/Cas9 has demonstrated its potential as a transformative technology in the treatment of various diseases. However, whether this genome-editing tool could be used to modify neural circuits in the central nervous system (CNS), which are implicated in complex behavioral traits, remains uncertain. In this study, we demonstrate the feasibility of noninvasive, intranasal delivery of adeno-associated virus serotype 9 (AAV9) vectors containing CRISPR/Cas9 cargo within the CNS resulting in modification of the HTR2A receptor gene. In vitro, exposure to primary mouse cortical neurons to AAV9 vectors targeting the HT2RA gene led to a concentration-dependent decrease in spontaneous electrical activity following multielectrode array (MEA) analysis. In vivo, at 5 weeks postintranasal delivery in mice, analysis of brain samples revealed single base pair deletions and nonsense mutations, leading to an 8.46-fold reduction in mRNA expression and a corresponding 68% decrease in the 5HT-2A receptor staining. Our findings also demonstrate a significant decrease in anxiety-like behavior in treated mice. This study constitutes the first successful demonstration of a noninvasive CRISPR/Cas9 delivery platform, capable of bypassing the blood-brain barrier and enabling modulation of neuronal 5HT-2A receptor pathways. The results of this study targeting the HTR2A gene provide a foundation for the development of innovative therapeutic strategies for a broad range of neurological disorders, including anxiety, depression, attentional deficits, and cognitive dysfunction.

Objective: To characterize the circadian features of the trigeminal ganglion in a mouse model of headache. Background: Several headache disorders, such as migraine and cluster headache, are known to exhibit distinct circadian rhythms of attacks. The circadian basis for these rhythmic pain responses, however, remains poorly understood. Methods: We examined trigeminal ganglion ex vivo and single‐cell cultures from Per2::LucSV reporter mice and performed immunohistochemistry. Circadian behavior and transcriptomics were investigated using a novel combination of trigeminovascular and circadian models: a nitroglycerin mouse headache model with mechanical thresholds measured every 6 h, and trigeminal ganglion RNA sequencing measured every 4 h for 24 h. Finally, we performed pharmacogenomic analysis of gene targets for migraine, cluster headache, and trigeminal neuralgia treatments as well as trigeminal ganglion neuropeptides; this information was cross‐referenced with our cycling genes from RNA sequencing data to identify potential targets for chronotherapy. Results: The trigeminal ganglion demonstrates strong circadian rhythms in both ex vivo and single‐cell cultures, with core circadian proteins found in both neuronal and non‐neuronal cells. Using our novel behavioral model, we showed that nitroglycerin‐treated mice display circadian rhythms of pain sensitivity which were abolished in arrhythmic Per1/2 double knockout mice. Furthermore, RNA‐sequencing analysis of the trigeminal ganglion revealed 466 genes that displayed circadian oscillations in the control group, including core clock genes and clock‐regulated pain neurotransmitters. In the nitroglycerin group, we observed a profound circadian reprogramming of gene expression, as 331 of circadian genes in the control group lost rhythm and another 584 genes gained rhythm. Finally, pharmacogenetics analysis identified 10 genes in our trigeminal ganglion circadian transcriptome that encode target proteins of current medications used to treat migraine, cluster headache, or trigeminal neuralgia. Conclusion: Our study unveiled robust circadian rhythms in the trigeminal ganglion at the behavioral, transcriptomic, and pharmacogenetic levels. These results support a fundamental role of the clock in pain pathophysiology. Plain Language Summary: Several headache diseases, such as migraine and cluster headache, have headaches that occur at the same time each day. We learned that the trigeminal ganglion, an important pain structure in several headache diseases, has a 24‐hour cycle that might be related to this daily cycle of headaches. Our genetic analysis suggests that some medications may be more effective in treating migraine and cluster headache when taken at specific times of the day. Plain Language Summary: Several headache diseases, such as migraine and cluster headache, have headaches that occur at the same time each day. We learned that the trigeminal ganglion, an important pain structure in several headache diseases, has a 24‐hour cycle that might be related to this daily cycle of headaches. Our genetic analysis suggests that some medications may be more effective in treating migraine and cluster headache when taken at specific times of the day. [ABSTRACT FROM AUTHOR]

The prevalence of mental disorders and how they are diagnosed represent some of the major problems in psychiatry. Modern genetic tools offer the potential to reduce the complications concerning diagnosis. However, the vast genetic diversity in the world population requires a closer investigation of any selected populations. In the current research, four polymorphisms, namely rs6265 in BDNF, rs10835210 in BDNF, rs6313 in HTR2A, and rs1800955 in DRD4, were analyzed in a case–control study of 2393 individuals (1639 patients with mental disorders (F20-F29, F30-F48) and 754 controls) from the European part of Russia using the TaqMan SNP genotyping method. Significant associations between rs6265 BDNF and rs1800955 DRD4 and mental impairments were detected when comparing the general group of patients with mental disorders (without separation into diagnoses) to the control group. Associations of rs6265 in BDNF, rs1800955 in DRD4, and rs6313 in HTR2A with schizophrenia in patients from the schizophrenia group separately compared to the control group were also found. The obtained results can extend the concept of a genetic basis for mental disorders in the Russian population and provide a basis for the future improvement in psychiatric diagnostics. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to investigate whether single‐nucleotide polymorphisms (SNPs) in the genes encoding 5‐HTR2A (5‐Hydroxytryptamine (serotonin) receptor 2A) and MTNR1A (melatonin receptor 1A) may contribute to postoperative pain perception after root canal treatment. We hypothesised that SNPs in HTR2A and MTNR1A genes were associated with postoperative pain after root canal treatment. Methodology: This genetic cohort study enrolled patients with single‐rooted teeth diagnosed with pulp necrosis and asymptomatic apical periodontitis before root canal treatment. Root canal treatment was performed in one session using a standardized protocol. Postoperative pain and tenderness were assessed using a visual analogue scale (recorded every day for 7 days and on the 14th and 30th days after root canal treatment). Genomic DNA was extracted from saliva and used to genotype the SNPs in HTR2A (rs4941573 and rs6313) and MTNR1A (rs6553010, rs6847693 and rs13140012) using real‐time polymerase chain reaction. Genotypes were compared using univariate and multivariate Poisson regression with generalized estimating equations (p <.05). Results: In total, 108 patients were enrolled in this study. The SNPs rs6553010 (MTNR1A), rs4941573 and rs6313 (HTR2A) were associated with an increased risk of developing pain after root canal treatment (p <.05). Conclusions: This study suggests that SNPs in HTR2A and MTNR1A influence pain response after root canal treatment. [ABSTRACT FROM AUTHOR]

Background: The shortened life expectancy in schizophrenia (SCZ) patients may be correlated with most cancers, yet there is heterogeneity in the studies examining these correlations. This study explored the expression of SCZrelated genes (HTR2A, COMT, and PRODH) in pan-cancer analysis. It helped to enhance the mechanistic understanding of the SCZ-cancer relationship and their immune mechanisms at the genetic level. Additionally, this study established a survival prediction model for glioblastoma and low-grade glioma (GBMLGG). Methods and results: SCZ-associated genes (HTR2A, COMT, and PRODH) were subjected to pan-cancer analysis. COX regression analysis and survival analysis were carried out for differentially expressed genes in multiple cancers, and finally, GBMLGG was derived as the focus for further detailed analysis. The immune scores and immune cell infiltration analyses were performed. All three genes were considerably linked with immune infiltration in GBMLGG, consistent with survival analysis. Based on the immunocyte analysis, it was observed that CD8+ T cells might be critically involved in the survival of GBMLGG. Genomic heterogeneity studies identified correlations of three genes with GBMLGG in tumor mutational burden (TMB) and mutant-allele tumor heterogeneity (MATH). HTR2A and COMT were significantly negatively correlated in TMB. Furthermore, it was found that HTR2A had a significant positive correlation with MATH, whereas PRODH had a significant negative correlation with MATH. Accordingly, a survival prediction model was constructed for GBMLGG using these three genes and clinical data, with better results obtained when evaluated in two separate datasets. Finally, gene expression validation and further immunocyte analysis were carried out in the single-cell RNA sequencing (scRNA-seq) data of glioma. Conclusion: SCZ-associated genes (HTR2A, COMT, and PRODH) were significantly differentially expressed in the carcinogenesis and survival of multiple cancers. The up or downregulation of gene expression varied across cancer types. In the GBMLGG analysis, upregulation of HTR2A and COMT was significantly positively correlated with carcinogenesis, while the opposite was noted for PRODH. Furthermore, a negative correlation was found between the upregulation of HTR2A and COMT and the survival of GBMLGG, and the opposite was also noted for PRODH. As reflected in the immunocyte analysis, abnormal expression of the three genes might be linked with CD8+ T cell infiltration, which might be critically involved in the survival of GBMLGG patients. The expression of HTR2A and COMT may inversely affect the efficacy of immunotherapy through the TMB pathway and further affect the prognosis of patient survival. The expression of HTR2A might positively indicate the degree of tumor heterogeneity through MATH and further affect the survival and prognosis of patients. The negative correlation of PRODH led to the opposite effect. Finally, the constructed survival prediction model demonstrated good predictive value, which was well validated in scRNA-seq analysis. [ABSTRACT FROM AUTHOR]

Abnormal remodeling of collagen and extracellular matrix caused by the accumulation of senescent fibroblasts in the dermis is the most likely cause of skin aging. Therefore, the application of "senolysis," in which only senescent cells are cleared from the body, has a potential in the development of antiaging treatments for skin. However, markers that label senescent fibroblasts only reflect the state of senescence, and it is important to develop markers as therapeutic targets to aid senolysis application. We investigated the potential of serotonin 2A receptor (HTR2A), which is involved in melanin production in response to ultraviolet light, as a senescent cell marker. The results showed that HTR2A is upregulated in aging dermal fibroblasts but is expressed at low levels in proliferating young cells. Flow cytometry demonstrated the presence of many HTR2A-positive cells in the aging cell population and few in the young cells. Furthermore, antibody-dependent cytotoxicity assays revealed that HTR2A preferentially sensitizes senescent fibroblasts and specifically damages only senescent cells by natural killer cells that recognize it. In conclusion, selective labeling of the novel senescent cell marker, HTR2A, could preferentially eliminate senescent cells and may contribute to the future development of novel skin senolysis approaches. [ABSTRACT FROM AUTHOR]

The prevalence of mental disorders and how they are diagnosed represent some of the major problems in psychiatry. Modern genetic tools offer the potential to reduce the complications concerning diagnosis. However, the vast genetic diversity in the world population requires a closer investigation of any selected populations. In the current research, four polymorphisms, namely rs6265 in BDNF, rs10835210 in BDNF, rs6313 in HTR2A, and rs1800955 in DRD4, were analyzed in a case–control study of 2393 individuals (1639 patients with mental disorders (F20-F29, F30-F48) and 754 controls) from the European part of Russia using the TaqMan SNP genotyping method. Significant associations between rs6265 BDNF and rs1800955 DRD4 and mental impairments were detected when comparing the general group of patients with mental disorders (without separation into diagnoses) to the control group. Associations of rs6265 in BDNF, rs1800955 in DRD4, and rs6313 in HTR2A with schizophrenia in patients from the schizophrenia group separately compared to the control group were also found. The obtained results can extend the concept of a genetic basis for mental disorders in the Russian population and provide a basis for the future improvement in psychiatric diagnostics.

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Green space could influence adult cognition and childhood neurodevelopment , and is hypothesized to be partly driven by epigenetic modifications. However, it remains unknown whether some of these associations are already evident during foetal development. Similar biological signals shape the developmental processes in the foetal brain and placenta.Therefore, we hypothesize that green space can modify epigenetic processes of cognition-related pathways in placental tissue, such as DNA-methylation of the serotonin receptor HTR2A. HTR2A-methylation was determined within 327 placentas from the ENVIRONAGE (ENVIRonmental influence ON early AGEing) birth cohort using bisulphite-PCR-pyrosequencing. Total green space exposure was calculated using high-resolution land cover data derived from the Green Map of Flanders in seven buffers (50 m-3 km) and stratified into low (

Despite more than 2 million American cocaine users monthly, there is no approved drug for treating cocaine use disorder. Cocaine use disorder has a multifactorial aetiology, including both genetic and environmental factors. Both cocaine use and genetic variations demonstrably alter DNA methylation and gene expression in the brain in a complex manner. How these factors interact in the context of cocaine abuse in humans is unknown. We propose that we can identify potential drug targets for treating cocaine use disorders by examining genetic, epigenetic, and expression changes in the brains of individuals that abused cocaine. In this study, we identified the interaction between the epigenetics changes (DNA CpG methylation) and genetic variants (SNPs) in the HTR2A gene in the context of cocaine addiction by using brain tissue collected from individuals that overdosed on cocaine (N = 14) and healthy matched controls (N = 16). We generated DNA CpG methylation profiles in eight regions of HTR2A harbouring frequent SNPs, measuring both allelic and total methylation, and compared these methylation profiles with HTR2A mRNA expression. Furthermore, we examined the influence of common variants rs6311 and rs6313 on cocaine abuse, methylation, and gene expression. We found evidence that rs6311 regulates HTR2A methylation, consistent with earlier studies. Furthermore, the minor alleles for rs6311 and rs6313 are associated with significantly increased expression of a splice isoform in which exon 2 is truncated in both cocaine and control samples. These results reveal specific roles for HTR2A in the context of cocaine abuse, highlighting opportunities to modulate this target for treating cocaine use disorder.

Background. Emotional intelligence is the ability to quickly and correctly recognize the emotional expressions of other people and to express and manage one’s own emotions. It contributes to the success of a person in activities related to communication and interaction with people. Emotional intelligence has been studied largely in the context of organizational and education psychology, but less is known about the influence of genetics on it. Objective. We aim to study emotional intelligence in carriers of different СОМТ, BDNF, DRD2, and HTR2A genotypes. Design. We used three methods to measure emotional intelligence. Mayer-Salovey-Caruso Emotional Intelligence Test is a set of tasks with forced choice and frequency-based correct responses. We also applied two self-report questionnaires by Lyusin and Hall. We recruited 280 participants who took part in all three measures. We also identified their genotypes of the СОМТ, BDNF, DRD2, and HTR2A genes. Results. Carriers of the Val/Met genotype of the COMT gene, A/A genotype of the HTR2A gene and C/C genotype of the DRD2 gene showed the highest level of emotional intelligence, while no differences were found between carriers of the BDNF genotypes. These data were obtained by using the Mayer-Salovey-Caruso Emotional Intelligence Test. Self-report scores of emotional intelligence did not differ between carriers of different genotypes across all four of the genes in question. Conclusion. Mayer-Salovey-Caruso Emotional Intelligence Test scores were differed for carriers of some genotypes, whereas self-reported emotional intelligence scores did not differ between according to genotype.

Many studies have examined the genetic contribution to suicide. However, data on suicide in the Italian population are scarce. We therefore aimed to address this gap by investigating a cohort of 111 Italians for whom a verdict of suicide had been declared in court in Florence, Italy between 2007 and 2017. This cohort included 86 men and 25 women. DNA samples were obtained from tissues or blood, and 22 genes from multiple neurobiological pathways previously shown to be associated with the pathogenesis of suicide were analysed. Next-generation sequencing was used to compare these gene sequences with those from a large, normal population. In this study, we identified 19 gene variants that were present at significantly lower frequencies in our Italian cohort than in the general population. In addition, four missense mutations were identified in four different genes: Monoamine Oxidase A (MAOA), 5-Hydroxytryptamine Receptor 2 A (HTR2A), Sodium Voltage-Gated Channel Alpha Subunit 8 (SCN8A), and Nitric Oxide Synthase 3 (NOS3). Our study identified several potential genetic links with suicide in a cohort of Italians and supports a relationship between specific genetic variants and suicidal behaviour in this population. Key pointsThis study shows a genetic analysis of suicide.This study examines a cohort of 111 Italians for whom a verdict of suicide had been declared in court in Florence, Italy between 2007 and 2017. DNA samples were obtained from tissues or blood, and 22 genes from multiple neurobiological pathways were investigated.The study supports a relationship between specific genetic variants and suicidal behaviour.

Green space could influence adult cognition and childhood neurodevelopment, and is hypothesized to be partly driven by epigenetic modifications. However, it remains unknown whether some of these associations are already evident during foetal development. Similar biological signals shape the developmental processes in the foetal brain and placenta. Therefore, we hypothesize that green space can modify epigenetic processes of cognition-related pathways in placental tissue, such as DNA-methylation of the serotonin receptor HTR2A. HTR2A-methylation was determined within 327 placentas from the ENVIRONAGE (ENVIRonmental influence ON early AGEing) birth cohort using bisulphite-PCR-pyrosequencing. Total green space exposure was calculated using high-resolution land cover data derived from the Green Map of Flanders in seven buffers (50 m-3 km) and stratified into low (<3 m) and high (=3 m) vegetation. Residential nature was calculated using the Land use Map of Flanders. We performed multivariate regression models adjusted for several a priori chosen covariables. For an IQR increment in total green space within a 1,000 m, 2,000 m and 3,000 m buffer the methylation of HTR2A increased with 1.47% (95%CI:0.17;2.78), 1.52% (95%CI:0.21;2.83) and 1.42% (95%CI:0.15;2.69), respectively. Additionally, we found 3.00% (95%CI:1.09;4.91) and 1.98% (95%CI:0.28;3.68) higher HTR2A-methylation when comparing residences with and without the presence of nature in a 50 m and 100 m buffer, respectively. The methylation status of HTR2A in placental tissue is positively associated with maternal green space exposure. Future research is needed to understand better how these epigenetic changes are related to functional modifications in the placenta and the consequent implications for foetal development. [ABSTRACT FROM AUTHOR]

Objectives: HTR2A is previously identified as a susceptibility gene for rheumatoid arthritis (RA). In this study, we performed the association analysis between DNA methylation of HTR2A with RA within peripheral blood samples. Methods: We enrolled peripheral blood samples from 235 patients with RA, 30 osteoarthritis (OA) patients, and 30 healthy controls. The DNA methylation levels of about 218 bp from chr13: 46898190 to chr13: 46897973 (GRCh38/ hg38) around HTR2A cg15692052 from patients were analyzed by targeted methylation sequencing. Results: We measured methylation status for 7 CpGs in the promoter region of HTR2A and obseved overall methylation status are signficantly increased in RA compared with normal inviduals (FDR= 9.05 x 10-5). The average cg15692052 methylation levels (methylation score) showed a positive correlation with CRP (r=0.15, P=0.023). Compared with the OA group or HC group, the proportion of haplotypes CCCCCCC (FDR=0.02 and 2.81 x 10-6) is signficantly increased while TTTTTCC (FDR =0.01) and TTTTTTT(FDR =6.92 x 10-3) are significantly decreased in RA. We find methylation haplotypes combining with RF and CCP could signficantly enhance the performance of the diagnosing RA and its comorbidities (hypertension, interstitial lung disease, and osteoporosis), especially in interstitial lung disease. Conclusions: In our study, we found signficant hypermethylation of promoter region of HTR2A which indicates the potential clinical diagnostic role in rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Many studies have examined the genetic contribution to suicide. However, data on suicide in the Italian population are scarce. We therefore aimed to address this gap by investigating a cohort of 111 Italians for whom a verdict of suicide had been declared in court in Florence, Italy between 2007 and 2017. This cohort included 86 men and 25 women. DNA samples were obtained from tissues or blood, and 22 genes from multiple neurobiological pathways previously shown to be associated with the pathogenesis of suicide were analysed. Next-generation sequencing was used to compare these gene sequences with those from a large, normal population. In this study, we identified 19 gene variants that were present at significantly lower frequencies in our Italian cohort than in the general population. In addition, four missense mutations were identified in four different genes: Monoamine Oxidase A (MAOA), 5-Hydroxytryptamine Receptor 2 A (HTR2A), Sodium Voltage-Gated Channel Alpha Subunit 8 (SCN8A), and Nitric Oxide Synthase 3 (NOS3). Our study identified several potential genetic links with suicide in a cohort of Italians and supports a relationship between specific genetic variants and suicidal behaviour in this population. This study shows a genetic analysis of suicide. This study examines a cohort of 111 Italians for whom a verdict of suicide had been declared in court in Florence, Italy between 2007 and 2017. DNA samples were obtained from tissues or blood, and 22 genes from multiple neurobiological pathways were investigated. The study supports a relationship between specific genetic variants and suicidal behaviour. [ABSTRACT FROM AUTHOR]

Despite more than 2 million American cocaine users monthly, there is no approved drug for treating cocaine use disorder. Cocaine use disorder has a multifactorial aetiology, including both genetic and environmental factors. Both cocaine use and genetic variations demonstrably alter DNA methylation and gene expression in the brain in a complex manner. How these factors interact in the context of cocaine abuse in humans is unknown. We propose that we can identify potential drug targets for treating cocaine use disorders by examining genetic, epigenetic, and expression changes in the brains of individuals that abused cocaine. In this study, we identified the interaction between the epigenetics changes (DNA CpG methylation) and genetic variants (SNPs) in the HTR2A gene in the context of cocaine addiction by using brain tissue collected from individuals that overdosed on cocaine (N = 14) and healthy matched controls (N = 16). We generated DNA CpG methylation profiles in eight regions of HTR2A harbouring frequent SNPs, measuring both allelic and total methylation, and compared these methylation profiles with HTR2A mRNA expression. Furthermore, we examined the influence of common variants rs6311 and rs6313 on cocaine abuse, methylation, and gene expression. We found evidence that rs6311 regulates HTR2A methylation, consistent with earlier studies. Furthermore, the minor alleles for rs6311 and rs6313 are associated with significantly increased expression of a splice isoform in which exon 2 is truncated in both cocaine and control samples. These results reveal specific roles for HTR2A in the context of cocaine abuse, highlighting opportunities to modulate this target for treating cocaine use disorder. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the relationship between the HTR2A 1438A/G (rs6311) SNP and the risk of nicotine addiction in Yakuts. Methods and Results: A total of 292 people of Yakut nationality were tested (77 women and 215 men). Two groups of examined persons were formed: smokers (n=141) and non-smokers (NS, n=151). To determine the association of the studied SNP with the degree of smoking, the smoker group was divided into two subgroups: Heavy smokers (HS) and Light smokers (LS). Subjects who were smokers were classified based on their consumption of cigarettes per day (cpd), as follows: LS (n=10), those who consumed between 1 and 10 cpd, and HS (n=131), those who consumed ≥20 cpd. The study of the HTR2A 1438A/G (rs6311) SNP was performed by PCR and RFLP analysis. The A allele of the HTR2A 1438A/G (rs6311) SNP was associated with more of a risk for the HS group than the LS. Using the A allele as a risk factor, RR analysis showed a significant association with a risk factor when comparing HS with LS (RR=1.086; 95% CI=1.032-1.142; P=0.049). The analysis of the OR and RR between the HS and LS showed that the AA and AG genotypes were associated with an increased risk for heavy smoking (OR=9.714; 95% CI=1.196-78.874; RR =1.126; 95% CI=1.027-1.235; P=0.026). We cannot dismiss the possibility that our results may reflect the small sample size. Despite this potential limitation, the significant associations should not be disregarded and merit further investigation for clarification of these results.

Social anxiety disorder (SAD) is a highly prevalent and comorbid anxiety disorder with rather unclear underlying mechanisms. Here, we aimed to characterize neurobiological changes occurring in mice expressing symptoms of social fear and to identify possible therapeutic targets for SAD. Social fear was induced via social fear conditioning (SFC), a validated animal model of SAD. We assessed the expression levels of the immediate early genes (IEGs) cFos, Fosl2 and Arc as markers of neuronal activity and the expression levels of several genes of the GABAergic, serotoninergic, oxytocinergic, vasopressinergic and neuropeptide Y (NPY)-ergic systems in brain regions involved in social behavior or fear-related behavior in SFC+ and SFC− mice 2 h after exposure to a conspecific. SFC+ mice showed a decreased number and density of cFos-positive cells and decreased expression levels of IEGs in the dorsal hippocampus. SFC+ mice also showed alterations in the expression of NPY and serotonin system-related genes in the paraventricular nucleus of the hypothalamus, basolateral amygdala, septum and dorsal raphe nucleus, but not in the dorsal hippocampus. Our results describe neuronal alterations occurring during the expression of social fear and identify the NPY and serotonergic systems as possible targets in the treatment of SAD. [ABSTRACT FROM AUTHOR]

Aim of study was set to investigate the association of women urinary incontinence (UI) with serotonin receptor HTR2A T102C and beta 3-adrenergic receptor ADRB3 Trp64Arg genes polymorphisms. The study included 110 women with Urge, Stress, and Mixed UI types and the control group – 105 continent women. Both groups have filled in the ICIQ-FLUTS questionnaire and their blood genotyping was performed. Urge UI subgroup was older and had higher body mass index (BMI) in comparison to other UI types and control group. More than half of all women had family history of UI in Stress UI and Mixed UI subgroups. The frequency of HTR2A T102C gene polymorphism’s minor allele C and genotype CC was significantly more expressed in Urge UI subgroup, as compared with control group (C-77.3 vs 58.7%, p = 0.007 and CC-57.6 vs 31.1%, p = 0.015). The ADRB3 Trp64Arg gene polymorphism did not differ between groups. The regression analysis revealed CC genotype (OR = 3.06, 95% CI: 1.11–8.43; p = 0.030) and allele C (OR = 2.53, 95% CI: 1.16–5.53; p = 0.020) were risk factors for development of Urge UI. We conclude that HTR2A T102C gene polymorphism affected the development of Urge UI.

The 5-HT2A serotonin receptor (HTR2A) has been reported to be involved in the serotonin- or serotonin receptor 2A agonist-induced melanogenesis in human melanoma cells. However, the molecular mechanisms underlying HTR2A in regulating melanogenesis remain poorly understood. In this research, cultured mouse melanoma cell line B16F10, human skin, and zebrafish embryos were used to elucidate the downstream signaling of HTR2A in regulating melanogenesis and to verify the potential application of HTR2A in the treatment of pigment-associated cutaneous diseases. We demonstrated that HTR2A antagonists (AT1015 and ketanserin) attenuated the melanogenesis induction of serotonin in both mouse melanoma cells and zebrafish embryos. The agonists of HTR2A (DOI and TCB-2) increased melanin synthesis and transfer in B16F10 cells, human skin tissue, and zebrafish embryos. Furthermore, the HTR2A agonists increased the expression of proteins related to melanosome organization and melanocyte dendrites to facilitate the melanocyte migration and melanosome transport. HTR2A antagonists and genetic knockout of zebrafish htr2aa (the homologue of mammalian HTR2A gene) were also used to clarify that HTR2A mediates serotonin and DOI in regulating melanogenesis. Finally, through small scale screening of the candidate downstream pathway, we demonstrated that HTR2A mediates the melanogenesis induction of its ligands by activating the PKA/CREB signaling pathway. In this research, we further confirmed that HTR2A is a crucial protein to mediate melanocyte function. Meanwhile, this research supports that HTR2A could be designed as a drug target for the development of chemicals to treat cutaneous diseases with melanocytes or melanogenesis abnormality. [ABSTRACT FROM AUTHOR]

Searching for genetic causes of depressive and anxiety disorders has been going on for about three decades. However, the accumulated experimental data do not allow us to come to a final conclusion about the influence of certain genes on the risk of the disease and the severity of its course. Most studies of candidate genes were carried out using samples of patients with different nosological forms of depression. The aim of our work was to check whether the previously found associations are common for all depressive spectrum disorders or there are loci that specifically affect the risk of developing a certain disease. The study involved patients with disorders characterized by severe depressive symptoms (n = 357). Patients were divided into three samples according to the diagnosis: depressive episode (DE), recurrent depression (RD), and mixed anxiety and depressive disorder (MADD). The polymorphic locus 40 bp VNTR of gene SLC6A3 was associated with all studied disorders; the LL genotype was less common in patients and was associated with a low risk of disease. The polymorphism 120 bp VNTR in gene DRD4 was associated with RD and MADD. The rs6311 locus of gene HTR2A was associated with DE and MADD. A specific genetic risk factor for RD in the studied samples was the rs53576 polymorphism of gene OXTR. The genotype homozygous for the minor allele (AA) was associated with a low risk of RD. None of the studied polymorphic loci influenced the severity of depression symptoms. The loci rs6311 of gene HTR2A and 120 bp VNTR of gene DRD4 were associated with symptoms of situational and personality anxiety. The severity of situational anxiety symptoms was also influenced by the loci rs53576 of gene OXTR and 16–17 bp VNTR of gene SLC6A4. [ABSTRACT FROM AUTHOR]

Previously, we showed that transcription factor 21 (TCF21) promotes chicken preadipocyte differentiation. However, the genome-wide TCF21 binding sites and its downstream target genes in chicken adipogenesis were unknown. ChIP-Seq and RNA-Seq were used to screen candidate targets of TCF21. qPCR and luciferase reporter assay were applied to verify the sequencing results. Western blotting, oil red-O staining and pharmacological treatments were performed to investigate the function of 5-hydroxytryptamine receptor 2A (HTR2A), one of the bonafide direct downstream binding targets of TCF21. A total of 94 candidate target genes of TCF21 were identified. ChIP-qPCR, RT-qPCR, and luciferase reporter assay demonstrated that HTR2A is one of the bonafide direct downstream binding targets of TCF21. HTR2A expression in adipose tissue was upregulated in fat line broilers. Also, the abundance of HTR2A gradually increased during the adipogenesis process. Interestingly, pharmacological enhancement or inhibition of HTR2A promoted or attenuated the differentiation of preadipocytes, respectively. Furthermore, HTR2A inhibition impaired the TCF21 promoted adipogenesis. We profiled the genome-wide TCF21 binding sites in chicken differentiated preadipocytes revealing HTR2A as the direct downstream target of TCF21 in adipogenesis. • Novel targets of TCF21 are identified in chicken preadipocytes. • HTR2A promotes chicken adipogenesis. • TCF21 promotes chicken adipogenesis via regulating the transcription of HTR2A. [ABSTRACT FROM AUTHOR]

We investigated the associations of DRD3 rs6280, HTR1A rs6295, BDNF rs6265, SCL6A4 rs16965628, and 5HT2A rs7322347 with schizophrenia in a case–control study, and associations of these genetic variants with several clinical features. We also investigated markers of inflammatory response (C-reactive protein, IL-2, IL-6, IL-10), the activity of leukocytic elastase (LE) and α1-proteinase inhibitor (a1-PI), antibodies to S100B and myelin basic protein (MBP) in schizophrenia. Clinical symptoms were assessed on three scales: Positive and Negative Syndrome Scale, The Bush – Francis Catatonia Rating Scale and Frontal Assessment Battery. All SNPs were typed using predesigned TaqMan SNP genotyping assays. The biomarkers related to the immune system were routinely tested using ELISA kits. The association with schizophrenia was found for DRD3 rs6280 (p = 0.05) and HTR2A rs7322347 (p = 0.0013). We found differences between groups by parameters of LE and a1-PI and LE/a1-PI (p < 0.001). And IL-6 was evaluated in the schizophrenia group (p < 0.001). We showed that patients with the TT allele (BDNF rs6265) had more severe impairments in frontal lobe function. a1-PI can serve as a marker for assessing the severity of frontal lobe damage in patients with frontal dementia. We found some biological parameters reflecting the severity of frontal dysfunction in schizophrenia.

We investigated the associations of DRD3 rs6280, HTR1A rs6295, BDNF rs6265, SCL6A4 rs16965628, and 5HT2A rs7322347 with schizophrenia in a case–control study, and associations of these genetic variants with several clinical features. We also investigated markers of inflammatory response (C-reactive protein, IL-2, IL-6, IL-10), the activity of leukocytic elastase (LE) and α1-proteinase inhibitor (a1-PI), antibodies to S100B and myelin basic protein (MBP) in schizophrenia. Clinical symptoms were assessed on three scales: Positive and Negative Syndrome Scale, The Bush – Francis Catatonia Rating Scale and Frontal Assessment Battery. All SNPs were typed using predesigned TaqMan SNP genotyping assays. The biomarkers related to the immune system were routinely tested using ELISA kits. The association with schizophrenia was found for DRD3 rs6280 (p = 0.05) and HTR2A rs7322347 (p = 0.0013). We found differences between groups by parameters of LE and a1-PI and LE/a1-PI (p < 0.001). And IL-6 was evaluated in the schizophrenia group (p < 0.001). We showed that patients with the TT allele (BDNF rs6265) had more severe impairments in frontal lobe function. a1-PI can serve as a marker for assessing the severity of frontal lobe damage in patients with frontal dementia. We found some biological parameters reflecting the severity of frontal dysfunction in schizophrenia. [ABSTRACT FROM AUTHOR]

The 5-HT2A serotonin receptor (HTR2A) has been reported to be involved in the serotonin- or serotonin receptor 2A agonist-induced melanogenesis in human melanoma cells. However, the molecular mechanisms underlying HTR2A in regulating melanogenesis remain poorly understood. In this research, cultured mouse melanoma cell line B16F10, human skin, and zebrafish embryos were used to elucidate the downstream signaling of HTR2A in regulating melanogenesis and to verify the potential application of HTR2A in the treatment of pigment-associated cutaneous diseases. We demonstrated that HTR2A antagonists (AT1015 and ketanserin) attenuated the melanogenesis induction of serotonin in both mouse melanoma cells and zebrafish embryos. The agonists of HTR2A (DOI and TCB-2) increased melanin synthesis and transfer in B16F10 cells, human skin tissue, and zebrafish embryos. Furthermore, the HTR2A agonists increased the expression of proteins related to melanosome organization and melanocyte dendrites to facilitate the melanocyte migration and melanosome transport. HTR2A antagonists and genetic knockout of zebrafish htr2aa (the homologue of mammalian HTR2A gene) were also used to clarify that HTR2A mediates serotonin and DOI in regulating melanogenesis. Finally, through small scale screening of the candidate downstream pathway, we demonstrated that HTR2A mediates the melanogenesis induction of its ligands by activating the PKA/CREB signaling pathway. In this research, we further confirmed that HTR2A is a crucial protein to mediate melanocyte function. Meanwhile, this research supports that HTR2A could be designed as a drug target for the development of chemicals to treat cutaneous diseases with melanocytes or melanogenesis abnormality.

Previous research reported that serotonin receptor 2A gene (HTR2A) polymorphisms were associated with memory. However, it is unknown whether these genetic variants were associated with both true and false memories. The current study of 336 Han Chinese subjects tested 30 single nucleotide polymorphisms (SNPs) within the HTR2A gene for potential associations with true and false memories. False memories were assessed using the Deese-Roediger-McDermott (DRM) paradigm, in which people falsely remember semantically related (but unpresented) words. We found that 11 SNPs within the HTR2A gene were associated with true memory (p=0.000076-0.043). The associations between true memory and seven adjacent SNPs (i.e., rs1923888, rs1745837, rs9567739, rs3742279, rs655888, rs655854, and rs2296972) were still significant after multiple testing corrections. Haplotype-based association analysis revealed that, true memory was positively associated with haplotype A-C-C-G-C-T-A for these seven adjacent SNPs (p=0.000075), which was still significant after multiple testing correction. Only one SNP rs655854 was associated with false memory (p=0.023), and it was not significant after multiple testing correction. This study replicates, in an Asian population, that genetic variation in HTR2A is associated with episodic memory, and also suggests that this association is restricted to true memory.

Background: This study aimed to discover the association between parameters of event-related potentials (ERPs) and categorization of images of visual scenes, both emotionally-charged and neutral, in carriers of different genotypes of the COMT, HTR2A, BDNF genes. Methods: Electroencephalogram (EEG) and ERPs were recorded at 128 leads, with two ear referents. Images of different visual scenes were presented to the study participants sequentially on a monitor screen. The participants’ task was to examine these images and indicate what emotions (negative, neutral or positive) they elicit. Comparison of event-related potentials was carried out using unpaired Student t-test in EEGLAB toolbox. Results: COMT. A stronger reaction, as reflected in the amplitude of the ERPs, in participants with the recessive homozygous Met/Met genotype was observed on latency around 200 ms to the stimuli, assessed as positive. Carriers of dominant homozygous Val/Val genotype had higher amplitude of 200 ms peak when assessed scene images as either neutral or negative in comparison to other genotypes. Participant with the Val/Met heterozygous genotype had higher amplitude of ERP that Met/Met group on same latency when assessed stimuli as negative. HTR2A . Significant increase in negativity in the parietal-occipital regions revealed in the range of 350-420 ms in participants with the recessive homozygous A/A genotype when choosing any type of assessment, compared to carriers of the heterozygous genotype A/G and the dominant homozygous G/G genotype. BDNF. Participants with Val/Val genotype categorized the visual images more thoroughly, as reflected in greater activation of the parietal-occipital zones and higher amplitude on ERP peak on 190 ms (negative assessment) and 160 ms (neutral assessment) then Val/Met carriers. Conclusions: The COMT, HTR2A, BDNF gene different genotypes are associated with the process of categorizing emotionally charged and neutral visual scenes, and this relationship is reflected in the ERP parameters.

Background: This study aimed to discover the association between parameters of event-related potentials (ERPs) and categorization of images of visual scenes, both emotionally-charged and neutral, in carriers of polymorphisms of the COMT, HTR2A, BDNF genes. Methods: Electroencephalogram (EEG) and ERPs were recorded at 128 leads, with two ear referents. Images of different visual scenes were presented to the study participants sequentially on a monitor screen. The participants’ task was to examine these images and indicate what emotions (negative, neutral or positive) they elicit. Comparison of event-related potentials was carried out using unpaired Student t-test in EEGLAB toolbox. Results: COMT. A stronger reaction, as reflected in the amplitude of the ERPs, in participants with the recessive homozygous Met/Met genotype was observed on latency around 200 ms to the stimuli, assessed as positive. Carriers of dominant homozygous Val/Val genotype had higher amplitude of 200 ms peak when assessed scene images as either neutral or negative in comparison to other genotypes. Participant with the Val/Met heterozygous genotype had higher amplitude of ERP that Met/Met group on same latency when assessed stimuli as negative. HTR2A . Significant increase in negativity in the parietal-occipital regions revealed in the range of 350-420 ms in participants with the recessive homozygous A/A genotype when choosing any type of assessment, compared to carriers of the heterozygous genotype A/G and the dominant homozygous G/G genotype. BDNF. Participants with Val/Val genotype categorized the visual images more thoroughly, as reflected in greater activation of the parietal-occipital zones and higher amplitude on ERP peak on 190 ms (negative assessment) and 160 ms (neutral assessment) then Val/Met carriers. Conclusions: The COMT, HTR2A, BDNF gene polymorphisms are associated with the process of categorizing emotionally charged and neutral visual scenes, and this relationship is reflected in the ERP parameters.

Plasma fibroblast growth factor 21 (FGF21) levels and hepatic FGF21, serotonin 2a receptor (htr2a), and stromal cell-derived factor 2 like 1 (Sdf2l1) expression are increased in insulin-resistant C57BL6J mice fed a high-fat diet. Here we show that plasma FGF21 levels and hepatic FGF21, Sdf2l1, and htr2a expression were decreased in 6-week-old db/db mice compared with C57BL6J mice, whereas they were increased in 6-week-old KKAy mice compared with KK mice. Expression of hepatic htr2b was increased in db/db mice and KKAy mice compared with controls. Treatment with the selective htr2b antagonist SB204741 suppressed the hyperglycemia in either db/db mice or KKAy mice. Treatment with SB20471 reversed the decreases in plasma FGF21 levels and hepatic FGF21, Sdf2l1, and htr2a expression in db/db mice, whereas it suppressed the increases in plasma FGF21 levels and hepatic FGF21, Sdf2l1, and htr2a expression in KKAy mice. Moreover, treatment with SB204741 increased plasma FGF21 levels and expression of hepatic FGF21, htr2a, and Sdf2l1 in C57BL6J mice, whereas it decreased plasma FGF21 levels and hepatic FGF21 expression in KK mice. These findings suggest that pharmacologic inhibition of htr2b ameliorates the hyperglycemia and altered expression of hepatic FGF21, Sdf2l1 and htr2a in obese and diabetic db/db and KKAy mice.

The aim of the study was to characterize the pattern of transcript isoforms of HTR2A exon II in lymphocytes of the blood as peripheral biomarkers of schizophrenia development and the effectiveness of antipsychotic therapy. We primarily observed an increase in mRNA levels and elevation of alternative variants in a sample of drug-naïve schizophrenic patients compared to the control group. There was no association of the expression level of HTR2A transcript isoforms with the effectiveness of the antipsychotic therapy. Antipsychotic-induced akathisia was associated with a significant reduction in the mRNA levels of the studied isoforms. In summary, our results suggest that levels of HTR2A exon II transcript isoforms are upregulated in patients with schizophrenia, but at the same time, elevated expression level of the studied HTR2A transcripts is associated with fewer side effects of the therapy.

ObjectiveTo assess the influence of genetic and environmental risk factors upon postpartum depression.DesignCase-control, prospective study.SettingThe University of California at San Francisco Obstetric and Gynecology Clinic.ParticipantsMothers screened for postpartum depression six weeks after delivery with the Edinburgh Postnatal Depression Scale and recruited as cases and controls.MeasurementsEligible subjects completed a series of assessments and a structured clinical interview to confirm diagnosis of depression. Deoxyribonucleic acid was obtained for genotyping of 81 single nucleotide polymorphisms in 12 genes hypothesized to be postpartum depression-related.ResultsTwenty-four cases and 24 controls were eligible for analysis. Three single necleotide polymorphisms in the serotonin 2A receptor (HTR2A) gene were associated with postpartum depression. The strongest association at a functional promoter polymorphism (rs6311), a functional promoter single nucleotide polymorphisms (p=0.002, odds ratio 0.25, 95% confidence interval:0.10-0.63), was a finding robust to population stratification. Gene-wide association was significant for HTR2A (permuted p=0.008), but not when corrected for all 12 genes. Analysis of demographic and psychosocial risk factors identified distressed relationship, unplanned pregnancy, and a previous history of depression as significant predictive variables (p≤0.05).ConclusionsThis pilot data suggests deoxyribonucleic acid variations in HTR2A may be associated with postpartum depression. Psychosocial variables were also identified as risk factors. The relative influence of these variables on the manifestation of postpartum depression is yet to be determined.

Obsessive–compulsive disorder (OCD) is an important neuropsychiatric disorder worldwide. Common treatments of OCD include serotonergic antidepressants, which can cause potentially serious side effects. We assessed the effects of Lactobacillus casei (L. casei) Shirota consumption in an animal model of OCD. OCD-like symptoms were induced in rats by the chronic injection of the D2/D3 dopamine agonist quinpirole hydrochloride. Rats were classified into five groups of 6 rats. Four groups were injected chronically with quinpirole (0.5 mg/kg, twice weekly for 5 weeks). They were fed with L. casei Shirota (109 CF/g, daily for 4 weeks) (group 1), fluoxetine (10 mg/kg, daily for 4 weeks) (group 2), combination of L. casei Shirota and fluoxetine (group 3), and normal saline (positive control group). The last group did not receive dopamine agonist and was only injected with saline (negative control group). Expression levels of brain-derived neurotrophic factor (Bdnf), solute carrier family 6 member 4 (Slc6a4), and 5-hydroxytryptamine receptor type 2A (Htr2a) were assessed in orbitofrontal cortex tissues of all rats. Behavioral tests showed improvement of OCD signs in rats treated with L. casei Shirota, fluoxetine, and a combination of drugs. Quantitative PCR analysis showed a remarkable decrease in the expression of Bdnf and an increase in the expression of Htr2a in quinpirole-treated rats. After treatment with L. casei Shirota and fluoxetine, the expression level of Bdnf was increased remarkably, whereas Htr2a expression was decreased. The current study showed the effectiveness of L. casei Shirota in the treatment of OCD in a rat model. The beneficial effects of this probiotic are possibly exerted through the modulation of serotonin-related genes expression. [ABSTRACT FROM AUTHOR]

5-Hydroxytryptamine receptor 2A (HTR2A) is a central regulator of fetal brain development and cognitive function in adults. However, the roles of HTR2A in the cardiovascular system are not fully understood. Here in this study, we explored the function of HTR2A in cardiac hypertrophy. Significantly, the expression levels of HTR2A mRNA and protein levels were upregulated in hypertrophic hearts of human patients. Besides, the expression of HTR2A was also upregulated in isoproterenol (ISO)-induced cardiac hypertrophy in the mouse. Next, the expression of HTR2A was knocked down with shRNA or overexpressed with adenovirus in neonatal rat cardiomyocytes, and ISO was used to induce cardiomyocyte hypertrophy. We showed that HTR2A knockdown repressed ISO-induced cardiomyocyte hypertrophy, which was demonstrated by decreased cardiomyocyte size and repressed expression of hypertrophic fetal genes (e.g., myosin heavy chain beta (β-Mhc), atrial natriuretic peptide (Anp), and brain natriuretic peptide (Bnp)). By contrast, HTR2A overexpression promoted cardiomyocyte hypertrophy. Of note, we observed that HTR2A promoted the activation (phosphorylation) of AKT-mTOR (mammalian target of rapamycin) signaling in cardiomyocytes, and repression of AKT-mTOR with perifosine or rapamycin blocked the effects of HTR2A on cardiomyocyte hypertrophy. Finally, we showed that HTR2A regulated AKT-mTOR signaling through activating the PI3K-PDK1 pathway, and inhibition of either PI3K or PDK1 blocked the roles of HTR2A in regulating AKT-mTOR signaling and cardiomyocyte hypertrophy. Altogether, these findings demonstrated that HTR2A activated PI3K-PDK1-AKT-mTOR signaling and promoted cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: 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.Results: 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.Limitations: 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.Conclusions: 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. [ABSTRACT FROM AUTHOR]

Relapse during abstinence in cocaine use disorder (CUD) is often hastened by high impulsivity (predisposition toward rapid unplanned reactions to stimuli without regard to negative consequences) and high cue reactivity (e.g., attentional bias towards drug reward stimuli). A deeper understanding of the degree to which individual biological differences predict or promote problematic behaviors may afford opportunities for clinical refinement and optimization of CUD diagnostics and/or therapies. Preclinical evidence implicates serotonin (5-HT) neurotransmission through the 5-HT2A receptor (5-HT2AR) as a driver of individual differences in these relapse-related behaviors. Regulation of 5-HT2AR function occurs through many mechanisms, including DNA methylation of the HTR2A gene, an epigenetic modification linked with the memory of gene-environment interactions. In the present study, we tested the hypothesis that methylation of the HTR2A may associate with relapse-related behavioral vulnerability in cocaine-dependent participants versus healthy controls. Impulsivity was assessed by self-report (Barratt Impulsiveness Scale; BIS-11) and the delay discounting task, while levels of cue reactivity were determined by performance in the cocaine-word Stroop task. Genomic DNA was extracted from lymphocytes and the bisulfite-treated DNA was subjected to pyrosequencing to determine degree of methylation at four cytosine residues of the HTR2A promoter (-1439, -1420, -1224, -253). We found that the percent methylation at site -1224 after correction for age trended towards a positive correlation with total BIS-11 scores in cocaine users, but not healthy controls. Percent methylation at site -1420 negatively correlated with rates of delay discounting in healthy controls, but not cocaine users. Lastly, the percent methylation at site -253 positively correlated with attentional bias toward cocaine-associated cues. DNA methylation at these cytosine residues of the HTR2A promoter may be differentially associated with impulsivity or cocaine-associated environmental cues. Taken together, these data suggest that methylation of the HTR2A may contribute to individual differences in relapse-related behaviors in CUD.

The precipitous increase in occurrence of non-alcoholic steatohepatitis (NASH) is a serious threat to public health worldwide. The pathogenesis of NASH has not yet been thoroughly studied. We aimed to elucidate the interplay between serotonin (5-hydroxytryptamine, 5-HT) and NASH. The serum 5-HT levels in patients with non-alcoholic fatty liver disease (NAFLD) and a rat fed with high fat-sucrose diet (HFSD) were evaluated using liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF MS)/MS. The peripheral Tph1 inhibitor, LP533401, and a tryptophan (TRP)-free diet were administered to rats with NASH, induced by HFSD. BRL-3A cells were treated with 1 mM free fatty acids (FFAs) and/or 50 μM 5-HT, and then small interfering RNA (siRNA) targeting the 5-HT2A receptor (HTR2A) and the PPARγ pharmaceutical agonist, pioglitazone, were applied. We found a marked correlation between 5-HT and NASH. The absence of 5-HT, through the pharmaceutical blockade of Tph1 (LP533401) and dietary control (TRP-free diet), suppressed hepatic lipid load and the expression of inflammatory factors (Tnfα, Il6, and Mcp-1). In BRL-3A cells, 50 μM 5-HT induced lipid accumulation and upregulated the expression of lipogenesis-ralated genes (Fas, Cd36, and Plin2) and the inflammatory response. Specifically, HTR2A knockdown and evaluation of PPARγ agonist activity revealed that HTR2A promoted hepatic steatosis and inflammation by activating PPARγ2. These results suggested that duodenal 5-HT was a risk factor in the pathological progression of NASH. Correspondingly, it may represent an attractive therapeutic target for preventing the development of NASH via the regulation of the HTR2A/PPARγ2 signaling pathway.

Genetic polymorphism in many candidates associated with psychiatric disorder and Schizophrenia (SCZ). The current research is directed to see if the polymorphisms of Dopamine Receptor D3 (DRD3) or of the 5-Hydroxytryptamine Type 2A (HTR2A) genes is related to SCZ patients. From those admitted to AlRasheed Hospital, fifty patients with SCZ (half of them are males and the other half are females), in addition to control group (25 healthy individuals) were included in this study. Blood samples from each individual in both, healthy and control groups were collected, DNA was extracted. Specific primers for exon1 and another for exon 2 have been used to amplify the genes of DRD3 receptor and HTR2A. The data generated in this study indicated significant positive association between T102C polymorphism of HTR2A A1804G transition and DRD3 gene sequence, that resulted in the substitution of Ser9Gly amino acid Iraqi SCZ patients. [ABSTRACT FROM AUTHOR]

Relapse during abstinence in cocaine use disorder (CUD) is often hastened by high impulsivity (predisposition toward rapid unplanned reactions to stimuli without regard to negative consequences) and high cue reactivity (e.g., attentional bias towards drug reward stimuli). A deeper understanding of the degree to which individual biological differences predict or promote problematic behaviors may afford opportunities for clinical refinement and optimization of CUD diagnostics and/or therapies. Preclinical evidence implicates serotonin (5-HT) neurotransmission through the 5-HT2A receptor (5-HT2AR) as a driver of individual differences in these relapse-related behaviors. Regulation of 5-HT2AR function occurs through many mechanisms, including DNA methylation of the HTR2A gene, an epigenetic modification linked with the memory of gene-environment interactions. In the present study, we tested the hypothesis that methylation of the HTR2A may associate with relapse-related behavioral vulnerability in cocaine-dependent participants versus healthy controls. Impulsivity was assessed by self-report (Barratt Impulsiveness Scale; BIS-11) and the delay discounting task, while levels of cue reactivity were determined by performance in the cocaine-word Stroop task. Genomic DNA was extracted from lymphocytes and the bisulfite-treated DNA was subjected to pyrosequencing to determine degree of methylation at four cytosine residues of the HTR2A promoter (-1439, -1420, -1224, -253). We found that the percent methylation at site -1224 after correction for age trended towards a positive correlation with total BIS-11 scores in cocaine users, but not healthy controls. Percent methylation at site -1420 negatively correlated with rates of delay discounting in healthy controls, but not cocaine users. Lastly, the percent methylation at site -253 positively correlated with attentional bias toward cocaine-associated cues. DNA methylation at these cytosine residues of the HTR2A promoter may be differentially associated with impulsivity or cocaine-associated environmental cues. Taken together, these data suggest that methylation of the HTR2A may contribute to individual differences in relapse-related behaviors in CUD. [ABSTRACT FROM AUTHOR]

The precipitous increase in occurrence of non-alcoholic steatohepatitis (NASH) is a serious threat to public health worldwide. The pathogenesis of NASH has not yet been thoroughly studied. We aimed to elucidate the interplay between serotonin (5-hydroxytryptamine, 5-HT) and NASH. The serum 5-HT levels in patients with non-alcoholic fatty liver disease (NAFLD) and a rat fed with high fat-sucrose diet (HFSD) were evaluated using liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF MS)/MS. The peripheral Tph1 inhibitor, LP533401, and a tryptophan (TRP)-free diet were administered to rats with NASH, induced by HFSD. BRL-3A cells were treated with 1 mM free fatty acids (FFAs) and/or 50 μM 5-HT, and then small interfering RNA (siRNA) targeting the 5-HT2A receptor (HTR2A) and the PPARγ pharmaceutical agonist, pioglitazone, were applied. We found a marked correlation between 5-HT and NASH. The absence of 5-HT, through the pharmaceutical blockade of Tph1 (LP533401) and dietary control (TRP-free diet), suppressed hepatic lipid load and the expression of inflammatory factors (Tnfα , Il6 , and Mcp-1). In BRL-3A cells, 50 μM 5-HT induced lipid accumulation and upregulated the expression of lipogenesis-ralated genes (Fas , Cd36 , and Plin2) and the inflammatory response. Specifically, HTR2A knockdown and evaluation of PPARγ agonist activity revealed that HTR2A promoted hepatic steatosis and inflammation by activating PPARγ2. These results suggested that duodenal 5-HT was a risk factor in the pathological progression of NASH. Correspondingly, it may represent an attractive therapeutic target for preventing the development of NASH via the regulation of the HTR2A/PPARγ2 signaling pathway. [ABSTRACT FROM AUTHOR]

Feminist scholars have called for gender researchers to consider gene-environment interactions for gender-imbalanced disorders (Salk and Hyde Psychology of Women Quarterly, 36, 395–411, 2012). Responding to these calls, the present study integrates objectification theory (Fredrickson and Roberts Psychology of Women Quarterly, 21, 173–206, 1997) and genetic research. In the tested model, objectification experiences are associated with disordered eating through body surveillance and body shame, and serotonin transporter (SLC6A4) genotypes (5-HTTLPR and rs25531), serotonin 2A receptor SNP genotypes (HTR2A rs6311), and the epistatic interaction between those genotypes function as moderators. U.S. undergraduate women (n = 526) completed self-reports of objectification, body surveillance, body shame, and disordered eating and donated buccal cells for genetic analyses. The association between objectification and disordered eating was mediated by body shame, but not body surveillance. The paths from objectification to both body surveillance and body shame were moderated by genotypes. The indirect effect of objectification on disordered eating through body shame was only present for SLC6A4 L′ and rs6311 G homozygotes. Our results are consistent with previous evidence that serotonin system genetic variation is associated with disordered eating risk. They provide evidence of a non-deterministic genetic effect that is context-dependent and subtle. These findings also reinforce efforts to develop personalized prevention and treatment approaches for eating disorders. [ABSTRACT FROM AUTHOR]

Background: Serotonin system genes are commonly studied in obsessive‐compulsive disorder (OCD), but genetic studies to date have produced inconsistent results, possibly because phenotypic heterogeneity has not been adequately accounted for. In this paper, we studied candidate serotonergic genes and homogenous phenotypic subgroups as presented through obsessive‐compulsive (OC) trait dimensions in a general population of children and adolescents. We hypothesized that different serotonergic gene variants are associated with different OC trait dimensions and, furthermore, that they vary by sex. Methods: Obsessive‐compulsive trait dimensions (Cleaning/Contamination, Counting/Checking, Symmetry/Ordering, Superstition, Rumination, and Hoarding) were examined in a total of 5,213 pediatric participants in the community using the Toronto Obsessive‐Compulsive Scale (TOCS). We genotyped candidate serotonin genes (directly genotyping the 5‐HTTLPR polymorphism in SLC6A4 for 2018 individuals and using single nucleotide polymorphism (SNP) array data for genes SLC6A4,HTR2A, and HTR1B for 4711 individuals). We assessed the association between variants across these genes and each of the OC trait dimensions, within males and females separately. We analyzed OC traits as both (a) dichotomized based on a threshold value and (b) quantitative scores. Results: The [LG + S] variant in 5‐HTTLPR was significantly associated with hoarding in males (p‐value of 0.003 and 0.004 for categorical and continuous analyses, respectively). There were no significant findings for 5‐HTTLPR in females. Using SNP array data, there were significant findings for rumination in males for HTR2A SNPs (p‐value of 1.04e‐6 to 5.20e‐6). Conclusions: This represents the first genetic association study of OC trait dimensions in a community‐based pediatric sample. Our strongest results indicate that hoarding and rumination may be distinct in their association with serotonin gene variants and that serotonin gene variation may be specific to sex. Future genetic association studies in OCD should properly account for heterogeneity, using homogenous subgroups stratified by symptom dimension, sex, and age group. [ABSTRACT FROM AUTHOR]

Objective: To determine whether genetic variants in a pharmacokinetic gene (the number of CYP2C19 reduced function alleles [RFAs]), and in pharmacodynamic genes (HTR2A, SLC6A4, and GRIK4) influence sertraline tolerability and response in a cohort of pediatric patients with anxiety and depressive disorders. Methods: A retrospective analysis was performed using the electronic medical record data of 352 patients <19 years of age being treated for anxiety and/or depressive disorders with sertraline and who underwent routine clinical CYP2C19 genotyping. Additional genotyping and analysis of variants in HTR2A, SLC6A4, and GRIK4 were conducted for 249 patients. Multivariate regression models testing for associations with CYP2C19 were adjusted for concomitant use of interacting medications. Combinatorial classification and regression tree (CART) analyses containing all pharmacokinetic and pharmacodynamic genes and clinical factors were performed. Results: The maximum sertraline dose during the initial titration period of sertraline was inversely associated with the number of CYP2C19 RFAs and sertraline dose at 60 (p = 0.025) and 90 days (p = 0.025). HTR2A rs6313 was associated with sertraline dose (p = 0.011) and time to the average maximum sertraline dose (p = 0.039). Regarding efficacy, the number of CYP2C19 RFAs was not associated with the sertraline dose at the time of response (p = 0.22), whereas for the pharmacodynamic genes, only HTR2A rs6313 was associated with response dose (p = 0.022). An association was observed between predicted expression levels of SLC6A4 and the duration on sertraline (p = 0.025). Combinatorial CART and multivariate regression analyses implicated that pharmacodynamic genes and clinical factors influence the maximum sertraline dose and response dose. The total number of side effects was not associated with any of the variants tested. Conclusion: Both pharmacokinetic and pharmacodynamic factors, in addition to clinical and demographic components, influence sertraline dose, response, and tolerability, thereby necessitating further research to assess for the validity of these pharmacogenetic associations in children and adolescents. [ABSTRACT FROM AUTHOR]

The level of cerebellar activity in stroke patients has been shown to correlate with the extent of functional recovery. We reasoned that the cerebellum may be an important player in post-stroke rehabilitation. Because the neurons in the deep cerebellar nuclei (DCN) represent virtually all of the output from the cerebellum, in this study, using environmental enrichment (EE) to promote rehabilitation, we investigated the influence of the optogenetic neuronal modulation of DCN on EE-induced rehabilitation. We found that neuronal inhibition of the DCN almost completely blocked motor recovery in EE treated mice, but the stroke mice with neuronal activation of the DCN achieved a similar recovery level as those in the EE treated group. No difference was observed in anxiety-like behavior. Moreover, Htr2a in the DCN, the gene encoding 5-HT2A receptor, was shown to be a hub gene in the protein-protein interaction network identified using RNA-seq. This indicated that 5-HT2A receptor-mediated signaling may be responsible for DCN-dependent functional improvement in EE. We further verified this using the 5-HT2A receptor antagonist, MDL100907, to inhibit the function of 5-HT2A receptor in the DCN. This treatment resulted in impaired recovery in EE treated mice, who performed at a level as poor as the stroke-only group. Thus, this work contributes to an understanding of the importance of the DCN activation in EE-induced post-stroke rehabilitation. Attempts to clarify the mechanism of 5-HT2A receptor-mediated signaling in the DCN may also lead to the creation of a pharmacological mimetic of the benefits of EE-induced rehabilitation. [ABSTRACT FROM AUTHOR]

Objective: We aimed to test the association of polymorphisms in HTR2A , TPH1 , and TPH2 genes with attempted suicide in rural China. Participants and methods: On the basis of a case–control study, we recruited 1200 pairs of participants from Shandong Province, China. The blood samples of 712 suicide attempters and 739 nonsuicide attempters were collected finally. We tested seven single nucleotide polymorphisms: rs6313 and rs6311 in HTR2A , rs4537731, rs1800532, and rs1799913 in TPH1 , and rs4448731 and rs4641527 in TPH2. Results: In univariate analysis, allele C of rs4537731 was associated negatively with attempted suicide among total and male samples; however, the association was not statistically significant in multivariate analysis after adjusting for other potential confounding factors. No association between other six single nucleotide polymorphisms and attempted suicide was found in the total, male, or female samples. Conclusion: This study did not support the effect of these seven serotonergic gene polymorphisms on attempted suicide in rural China. [ABSTRACT FROM AUTHOR]

Abstract Objectives Tobacco smoking is a complex and multifactorial disease involving both environmental and genetic factors. In the Mexican mestizo population, single-nucleotide polymorphisms (SNPs) associated with cigarette smoking and a greater degree of nicotine addiction have been identified; however, no possible roles have been explored in regard to the age of onset of smoking or in the success of quitting. Methods In this study, 151 Mexican mestizo, who smoke cigarettes, were included. They were grouped according to the age at which they started smoking: those who started smoking before 18 years of age (early smokers, ES) and those who started smoking ≥18 years of age (late smokers, LS). In addition, relapse in smoking was evaluated at the first month after the end of treatment. Genetic association was evaluated characterizing 10 SNPs in 4 genes (CHRNA5, CHRNA3, NRXN1, and HTR2A). Results According to the dominant model of genetic inheritance, rs6313 (CT+TT) of the HTR2A gene was associated (p = 0.0201) with cigarette consumption at early ages (OR = 2.68, CI = 1.18–6.07). When the risk of relapse was analyzed one month after the end of treatment, regardless of the age of onset, the T allele (rs6313) of HTR2A appeared to be a risk factor for relapse (OR = 2.92, 95% CI = 1.06–8.11); the T allele was found more frequently in those who relapsed (50.0%) compared with people who maintained abstinence (25.4%) (p = 0.0332). Conclusions Our findings suggest that in Mexican mestizos who smoke cigarettes, the presence of the T allele in rs6313 of the HTR2A gene increases the risk for the early onset of cigarette smoking as well as the risk for relapsing one month after completing smoking cessation treatment. Highlights • Individuals who started smoking in adolescence have high nicotine dependence. • The rs6313 in the HTR2A was associated with cigarette smoking at early ages. • The T allele (rs6313/ HTR2A) was found more often in smokers who relapsed. [ABSTRACT FROM AUTHOR]

Objective: Fluoxetine is an effective and well-tolerated pharmacological treatment for children and adolescents with major depressive disorder (MDD). However, a high percentage of patients do not respond. There is a substantial genetic contribution to this variable clinical outcome. Based on previous genetic results of our group and given the lack of pharmacogenetics studies of antidepressant response with a long follow-up period, we evaluated the influence of single nucleotide polymorphisms (SNPs) in genes related to the serotonergic pathway on remission and recovery in children and adolescents diagnosed with MDD after 12 months of initiating fluoxetine treatment. Methods: The assessment was performed in 46 patients. All of them were visited at least once a month during the 12-month follow-up. Psychiatrists interviewed patients and their parents to explore clinical improvement. A total of 75 genotyped SNPs in 10 candidate genes were included in the genetic association analysis with remission and recovery. Bonferroni correction for multiple testing was applied to avoid false positive results. Results: The HTR2A rs7997012 SNP was significantly associated after Bonferroni correction with clinical improvement. Particularly, the homozygotes for the major allele (GG) showed the highest percentage of remitters and the highest score reductions on the Clinical Global Impressions-Severity (CGI-S) scale. Moreover, although the results were on the border of statistical significance, the GG homozygotes also tended to experience fewer readmissions during the follow-up period Conclusions: These results provide more evidence of the involvement of genetic variants related to the serotonergic pathway in the antidepressant response. Studies with larger cohorts are needed to integrate all relevant variants into clinical predictors of antidepressant response. [ABSTRACT FROM AUTHOR]