Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serotonin receptor 2C (HTR2C) is one of the attractive candidate genes for studying pathophysiology of mental disorders. Here we overviewed the genetic, expression and RNA editing studies suggesting the close relationship between HTR2C and major mental disorders including schizophrenia, bipolar disorder and major depression. We especially focused on the human studies as well as with reference to relevant cellular and animal models. Possible significance of genetic variations affecting expression and RNA editing and appropriate animal models that mimic human mental disorders were discussed.
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PMID:Serotonin receptor 2C and mental disorders: genetic, expression and RNA editing studies. 1941 41

In two previous studies we found an association between HTR2C polymorphisms and the prevalence of the metabolic syndrome in patients using antipsychotics. In this study, we set out to replicate our findings in a third separate sample of patients. Data for this cross-sectional study came from the ongoing Pharmacotherapy Monitoring and Outcome survey study, investigating the association between schizophrenia and metabolic or cardiovascular risk factors. Primary end point was the prevalence of the metabolic syndrome. Primary determinants were two polymorphisms in the HTR2C gene: rs3813929 (-759 C/T) and rs1414334:C>G. Carriership of the variant rs1414334 C-allele was significantly associated with an increase prevalence of the metabolic syndrome (odds ratio (OR) 3.73; 95% confidence interval (CI) 1.29-10.79, P=0.015). No association was found between the HTR2C -759 C/T polymorphism and the metabolic syndrome. This study confirms previous findings that the variant C-allele of the rs1414334 polymorphism is associated with the metabolic syndrome.
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PMID:Association between HTR2C gene polymorphisms and the metabolic syndrome in patients using antipsychotics: a replication study. 2068 28

Second-generation antipsychotics (SGAs), such as risperidone, clozapine and olanzapine, are the most common drug treatments for schizophrenia. SGAs presented an advantage over first-generation antipsychotics (FGAs), particularly regarding avoidance of extrapyramidal symptoms. However, most SGAs, and to a lesser degree FGAs, are linked to substantial weight gain. This substantial weight gain is a leading factor in patient non-compliance and poses significant risk of diabetes, lipid abnormalities (that is, metabolic syndrome) and cardiovascular events including sudden death. The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic-induced weight gain (AIWG). We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases. There has been considerable progress reaffirming previous findings and discovery of novel genetic factors. The HTR2C and leptin genes are among the most promising, and new evidence suggests that the DRD2, TNF, SNAP-25 and MC4R genes are also prominent risk factors. Further promising findings have been reported in novel susceptibility genes, such as CNR1, MDR1, ADRA1A and INSIG2. More research is required before genetically informed, personalized medicine can be applied to antipsychotic treatment; nevertheless, inroads have been made towards assessing genetic liability and plausible clinical application.
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PMID:Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. 2189 53

Prescriptions for second-generation antipsychotics (SGAs) have surpassed those for first-generation agents in the treatment of schizophrenia and bipolar disorder. While SGAs have the benefit of a much reduced risk of causing movement disorders, they have been associated with weight gain and metabolic effects. These adverse reactions are not uncommon, and threaten to have a significant impact on the patient's health over the long-term treatment that the patient requires. Currently, the aetiology of these effects is not known. This article reviews the data exploring the weight gain phenomenon. The literature was reviewed from searches of PubMed and the references of major articles in the field. The SGAs present a heterogeneous risk for weight gain. In addition, different individuals receiving the same drug can exhibit substantially different weight changes. This pattern suggests that a group of factors are associated with the weight gain phenomenon rather than a single mechanism. Coupled with the genetic profile that the patient brings to the treatment, the risk for SGA-induced weight gain will be different for different drugs and different individuals. Targets for exploration of the weight gain phenomenon include receptor interactions involving serotonin, histamine, dopamine, adrenergic, cannabinoid and muscarinic receptors. The association of SGA-induced weight gain and the role of orexigenic and anorexigenic peptides are reviewed. Also, a brief discussion of genetic factors associated with SGA-induced weight gain is presented, including that of the serotonin 5-HT(2C) receptor gene (HTR2C) and the cannabinoid 1 receptor gene (CNR1). The most promising data associated with SGA-induced weight gain include investigations of the histamine H(1), 5-HT(2A), 5-HT(2C), muscarinic M(3) and adrenergic receptors. In addition, work in the genetic area promises to result in a better understanding of the variation in risk associated with different individuals.
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PMID:Atypical antipsychotic-induced weight gain: insights into mechanisms of action. 2213 26

A-to-I RNA editing is a post-transcriptional modification of single nucleotides in RNA by adenosine deamination, which thereby diversifies the gene products encoded in the genome. Thousands of potential RNA editing sites have been identified by recent studies (e.g. see Li et al, Science 2009); however, only a handful of these sites have been independently confirmed. Here, we systematically and quantitatively examined 109 putative coding region A-to-I RNA editing sites in three sets of normal human brain samples by ultra-high-throughput sequencing (uHTS). Forty of 109 putative sites, including 25 previously confirmed sites, were validated as truly edited in our brain samples, suggesting an overestimation of A-to-I RNA editing in these putative sites by Li et al (2009). To evaluate RNA editing in human disease, we analyzed 29 of the confirmed sites in subjects with major depressive disorder and schizophrenia using uHTS. In striking contrast to many prior studies, we did not find significant alterations in the frequency of RNA editing at any of the editing sites in samples from these patients, including within the 5HT(2C) serotonin receptor (HTR2C). Our results indicate that uHTS is a fast, quantitative and high-throughput method to assess RNA editing in human physiology and disease and that many prior studies of RNA editing may overestimate both the extent and disease-related variability of RNA editing at the sites we examined in the human brain.
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PMID:Quantitative analysis of focused a-to-I RNA editing sites by ultra-high-throughput sequencing in psychiatric disorders. 2291 34

The significant impact of microRNAs (miRNAs) on disease pathology is becoming increasingly evident. These small non-coding RNAs have the ability to post-transcriptionally silence the expression of thousands of genes. Therefore, dysregulation of even a single miRNA could confer a large polygenic effect. Schizophrenia is a genetically complex illness thought to involve multiple genes each contributing a small risk. Large genome-wide association studies identified miR-137, a miRNA shown to be involved in neuronal maturation, as one of the top risk genes. To assess the potential mechanism of impact of miR-137 in this disorder and identify its targets, we used a combination of literature searches, ingenuity pathway analysis (IPA), and freely accessible bioinformatics resources. Using TargetScan and the schizophrenia gene resource (SZGR) database, we found that in addition to CSMD1, C10orf26, CACNA1C, TCF4, and ZNF804A, five schizophrenia risk genes whose transcripts are also validated miR-137 targets, there are other schizophrenia-associated genes that may be targets of miR-137, including ERBB4, GABRA1, GRIN2A, GRM5, GSK3B, NRG2, and HTR2C. IPA analyses of all the potential targets identified several nervous system (NS) functions as the top canonical pathways including synaptic long-term potentiation, a process implicated in learning and memory mechanisms and recently shown to be altered in patients with schizophrenia. Among the subset of targets involved in NS development and function, the top scoring pathways were ephrin receptor signaling and axonal guidance, processes that are critical for proper circuitry formation and were shown to be disrupted in schizophrenia. These results suggest that miR-137 may indeed play a substantial role in the genetic etiology of schizophrenia by regulating networks involved in neural development and brain function.
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PMID:Potential Impact of miR-137 and Its Targets in Schizophrenia. 2363 4

Adverse events, response failures and medication non-compliance are common in patients receiving medications for the treatment of mental illnesses. A systematic literature review assessed whether pharmacokinetic (PK) or pharmacodynamic (PD) responses to 26 commonly prescribed antipsychotic and antidepressant medications, including efficacy or side effects, are associated with nucleotide polymorphisms in eight commonly studied genes in psychiatric pharmacotherapy: CYP2D6, CYP2C19, CYP2C9, CYP1A2, CYP3A4, HTR2C, HTR2A, and SLC6A4. Of the 294 publications included in this review, 168 (57%) showed significant associations between gene variants and PK or PD outcomes. Other studies that showed no association often had insufficient control for confounding variables, such as co-medication use, or analysis of medications not substrates of the target gene. The strongest gene-outcome associations were for the PK profiles of CYP2C19 and CYP2D6 (93% and 90%, respectively), for the PD associations between HTR2C and weight gain (57%), and for SLC6A4 and clinical response (54%), with stronger SLC6A4 response associations for specific drug classes (60-83%). The preponderance of evidence supports the validity of analyzing nucleotide polymorphisms in CYP and pharmacodynamic genes to predict the metabolism, safety, or therapeutic efficacy of psychotropic medications commonly used for the treatment of depression, schizophrenia, and bipolar illness.
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PMID:Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric pharmacotherapy. 2415 99

Genetic variants of the methylenetetrahydrofolate reductase (MTHFR) gene involved in homocysteine metabolism may be important predictors of antipsychotic drug-induced weight gain (AIWG). We tested whether two functional MTHFR polymorphisms are related to AIWG. Weight gain was studied in two cohorts of first-episode, initially drug-naive schizophrenia patients; Chinese Han (n = 182) and Spanish Caucasians (n = 72) receiving antipsychotics for 10 wk and 3 months respectively. Blood DNA was genotyped for 677C/T and 1298A/C MTHFR polymorphisms. Patients with the 677 CC genotype had a significantly greater increase in BMI compared to T-allele carriers in both Chinese (p = 0.012) and Spanish (p = 0.017) samples. The 677C/T MTHFR polymorphism showed an additive effect, but no significant interaction, with the -759C/T HTR2C polymorphism previously associated with AIWG. These results suggest that the 677C/T MTHFR polymorphism might, along with the -759C/T HTR2C polymorphism and other genetic factors, provide a useful marker for the important and limiting side effect of AIWG.
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PMID:Methylenetetrahydrofolate reductase (MTHFR) 677C/T polymorphism is associated with antipsychotic-induced weight gain in first-episode schizophrenia. 2422 35

Clozapine treatment is associated with weight gain and cardio-metabolic consequences among patients with schizophrenia. Polymorphisms of leptin, serotonin receptor HTR2C and adiponectin genes have been associated with antipsychotic-induced weight gain and metabolic comorbidity. However, the results of the studies so far are inconclusive. The aim of the present study was first to test for a possible role of serum leptin and adiponectin levels as a marker of weight gain in association with inflammatory cytokines/adipokines (IL-6, IL-1Ra, hs-CRP and adipsin), and second to study associations between SNPs LEP rs7799039 (-2548 A/G), ADIPOQ rs1501299 and HTR2C rs1414334 and weight gain and levels of leptin and adiponectin, in 190 patients with schizophrenia on clozapine treatment, with retrospectively assessed weight change and cross-sectionally measured cytokine levels. A strong association was found between serum levels of leptin and weight gain and cytokines/adipokines related to metabolic comorbidity, especially among female patients (in women leptin vs. weight gain, IL-6 and IL-1Ra, P<0.001; in men leptin vs. weight gain, P=0.026, leptin vs. IL-1Ra, P<0.001). In male patients low adiponectin level was a more specific marker of clozapine-induced weight gain (P=0.037). The results of the present study do not support a major role of SNPs LEP rs7799039, ADIPOQ rs1501299 and HTR2C rs1414334 in the regulation of weight gain or association of serum levels of leptin and adiponectin and corresponding studied SNPs in patients with schizophrenia on clozapine treatment.
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PMID:Association study of the HTR2C, leptin and adiponectin genes and serum marker analyses in clozapine treated long-term patients with schizophrenia. 2528 35

The purpose of this work was to search for associations between the serotonin receptor 2C gene (HTR2C) and the peculiarities of social behavior and social cognition in schizophrenia. To do this, patients with schizophrenia spectrum disorders and healthy control subjects were genotyped for the Cys23Ser HTR2C marker and underwent psychological examination, including assessment of Machiavellianism, recognition of emotions in facial expression, and theory of mind. In addition, we estimated the trait anxiety level as a potential factor affecting the relationship between the gene HTR2C and social behavior. We found a significant association between the Ser allele and a reduction of estimates on the Mach-LV Machiavellianism scale in the total sample of patients (n = 182) and control subjects (n = 189), which did not reach the confidence level in either of the groups. A tendency towards a HTR2C gene influence on the trait anxiety level was also revealed. The association between HTR2C and Machiavellianism was retained if the anxiety level was taken into account. The results suggest a pleiotropic effect of HTR2Con anxiety and Machiavellianism.
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PMID:[Association between serotonin receptor 2C gene Cys23Ser polymorphism and social behavior in schizophrenia patients and healthy individuals]. 2596 90


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