Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serotonin (5-hydroxytryptamine, 5-HT) appears to play a role in the pathophysiology of a range of neuropsychiatric disorders, and serotonergic agents are of central importance in neuropharmacology. Genes encoding various components of the 5-HT system are being studied as risk factors in depression, schizophrenia, obsessive-compulsive disorder, aggression, alcoholism, and autism. Recently, pharmacogenetic research has begun to examine possible genetic influences on therapeutic response to drugs affecting the serotonin system. Genes regulating the synthesis (TPH), storage (VMAT2), membrane uptake (HTT), and metabolism (MAOA) of 5-HT, as well as a number of 5-HT receptors (HTR1A, HTR1B, HTR2A, HTR2C, and HTR5A), have been studied and this initial research is reviewed here. After a brief introduction to serotonin neurobiology and a general discussion of appropriate genetic methodology, each of the major 5-HT-related genes and their encoded proteins are reviewed in turn. For each gene, relevant polymorphisms and research on functional variants are discussed; following brief reviews of the disorder or trait association and linkage studies, pharmacogenetic studies performed to date are covered. The critical and manifold roles of the serotonin system, the great abundance of targets within the system, the wide range of serotonergic agents-available and in development-and the promising preliminary results suggest that the serotonin system offers a particularly rich area for pharmacogenetic research.
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PMID:Pharmacogenetics and the serotonin system: initial studies and future directions. 1113 68

ADHD is a polygenic disorder due to the additive effect of genes affecting dopamine, norepinephrine, serotonin, GABA, and other neurotransmitters. Some of the specific loci involved are dopamine genes--DRD2, DRD4, DRD5, and the dopamine transporter; norepinephrine (NE) and epinephrine (EPI) genes--dopamine beta-hydroxylase, ADRA2A, ADRA2C, PNMT, norepinephrine transporter, MAOA, COMT; serotonin genes--TDO2, HTR1A, HTR1DA, serotonin transporter; GABA genes--GABRB3; androgen receptor and other genes. This model is consistent with all of the present knowledge about ADHD including (a) the increased frequency of ADHD in the relatives of ADHD probands, (b) the presence of a wide spectrum of comorbid behaviors (depression, anxiety, learning, conduct, oppositional-defiant, conduct and substance abuse disorders) in ADHD probands and their relatives on both parental sides, (c) the close relationship to Tourette syndrome (TS), (d) the failure to find the genes for TS using linkage analysis, (e) the brain imaging studies showing hypometabolism of the frontal lobes, (f) the relationship between dopamine D2 receptor density and regional blood flow, (g) the correlation between tics and dopamine D2 receptor density in TS, (h) the motor hyperactivity of dopamine transporter and dopamine D3 receptor gene knockout mice, (i) the LeMoal and Shaywitz dopamine deficiency animal models of ADHD, (j) the NE models of ADHD, (k) the failure to explain ADHD on the basis of any single neurotransmitter defect, (l) the response of ADHD to dopamine and alpha 2-adrenergic agonists, (m) the small percentage of the variance of specific behaviors accounted for by each gene, and numerous other aspects of ADHD. The implications of the polygenic model for the understanding, diagnosis and treatment of ADHD and TS, as well as other psychiatric disorders, are reviewed.
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PMID:Clinical and molecular genetics of ADHD and Tourette syndrome. Two related polygenic disorders. 1146 57

The 5-HT1A receptor plays a critical role in the pathophysiology of anxiety and depression as well as in the mode of action of anxiolytic and antidepressant drugs. Human 5-HT1A gene transcription is modulated by a common C-1016G single nucleotide polymorphism (SNP) in its upstream regulatory region. In the present study, we evaluated the role of the HTR1A-1019 polymorphism in the modulation of individual differences in personality traits by an association study of a sample of healthy volunteers. Personality traits were assessed with two different methods, NEO personality inventory (NEO-PI-R) and Tridimensional Personality Questionnaire (TPQ). There was a significant effect of the HTR1A-1019 polymorphism on NEO Neuroticism with carriers of the G allele showing higher scores than individuals homozygous for the C variant. The effect was primarily due to associations with the Neuroticism facets Anxiety and Depression. Carriers of the G allele also exhibited higher TPQ Harm Avoidance scores. Our findings indicate a role of allelic variation in 5-HT1A receptor expression in the development and modulation of anxiety- and depression-related personality traits.
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PMID:Allelic variation in 5-HT1A receptor expression is associated with anxiety- and depression-related personality traits. 1466 15

In the context of a long-term follow-up study, we analysed the possible implication of the 5-HT(1A) receptor gene (HTR1A) -1018C/G polymorphism in the clinical outcome of major depressive patients treated with citalopram. We had previously reported an association between variation on the SERT gene (SLC6A4) and clinical remission after citalopram treatment. In the present 12-week follow-up study, the combined effect of HTR1A and SLC6A4 genes in clinical outcome and response to citalopram was also evaluated. The sample consisted of 130 patients, all of Spanish origin, who were diagnosed as having a current major depressive episode according to DSM-IV criteria. A 21-item Hamilton Depression Rating Scale was used to assess severity of symptoms at the beginning and during the follow-up to determine the outcome and remission status at week 12. Patients were genotyped for HTR1A gene and, in addition, for two polymorphisms at the CYP2C19 gene, which together account for the 87% of the Caucasian poor metabolizer phenotype. Data were analysed adjusting for the effect of poor metabolizers in clinical response. No independent effect was found for the 5-HT(1A) receptor gene in relation to clinical outcome or remission after citalopram treatment. However, a combined genetic effect of HTR1A and SLC6A4 genes was found to influence the clinical outcome of patients [F(4,102) = 2.89, p= 0.02]. When considering the remission status, an increase of patients carrying the risk genotype combination (S/S-G/G) was found among those subjects who did not reach remission (Fisher's exact test = 0.009). Our results suggest that the combined effect of the serotonin transporter and the 5-HT(1A) receptor genes could be related to the clinical outcome of depressive patients treated with citalopram.
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PMID:Evidence for a combined genetic effect of the 5-HT(1A) receptor and serotonin transporter genes in the clinical outcome of major depressive patients treated with citalopram. 1572 38

The serotonin neurotransmitter system in general, and the serotonin 1A receptor in particular, has been broadly implicated in the pathophysiology of mood and anxiety disorders, although the results of genetic association studies have been mixed. In this study, we examined the serotonin 1A receptor gene, HTR1A, for its association with shared genetic risk across a range of anxiety and depression-related phenotypes. Using multivariate structural equation modeling, we selected twin pairs from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders scoring at the extremes of a latent genetic risk factor that underlies susceptibility to neuroticism, major depression, and several anxiety disorders. One member from each selected pair was entered into a 2-stage, case-control association study for the HTR1A gene. In the resulting sample of 589 cases and 539 controls, four SNPs spanning the HTR1A locus, including the C(-1019)G functional promoter polymorphism (rs6295), were screened in stage 1, the positive results of which were tested for replication in stage 2. While one marker met threshold significance criteria in stage 1, this association was not replicated in stage 2. Post-hoc analyses did not reveal association to any of the specific psychiatric phenotypes. Our data suggests that the HTR1A gene may not play a major role in the genetic susceptibility underlying depressive and anxiety-related phenotypes.
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PMID:Association study between the serotonin 1A receptor (HTR1A) gene and neuroticism, major depression, and anxiety disorders. 1816 85

The serotonin-1A (5-HT1A) receptor serves as a hub to regulate the activity and actions of the serotonin system, and is expressed both as a presynaptic autoreceptor on raphe neurons, and as a major postsynaptic receptor in hippocampal, cortical, and hypothalamic regions involved in mood, emotion and stress response. As such, the level of expression of 5-HT1A receptors is implicated in the development of anxiety and depression phenotypes. This review focuses on the C(-1019)G (rs6295) promoter polymorphism of the 5-HT1A receptor gene (HTR1A) and its effect on the activity of transcription factors that recognize the C-allele, including Deaf-1, Hes1 and Hes5; its effects on 5-HT1A receptor expression in pre- and postsynaptic areas; as well as its implication in early postnatal development and adult neurogenesis in the hippocampus and cortex. Although several studies have now replicated the association of the G-allele with depression, panic disorder, neuroticism, and reduced response to antidepressant or antipsychotic treatment, ethnic, disease and genetic heterogeneity among subjects in different studies may obscure such associations. Gene-gene interaction studies suggest that the 5-HT1A receptor G(-1019) allele is a risk allele which could be used as a marker for depression and related mood disorders. Finally, association of the G(-1019) allele with increased raphe 5-HT1A binding potential, increased amygdala reactivity to emotional stimuli, and reduced amygdala volume, particularly in disease states, suggests a functional role for the C(-1019)G site in 5-HT1A receptor dys-regulation and predisposition to mental illness.
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PMID:Transcriptional regulation at a HTR1A polymorphism associated with mental illness. 1863 64

Several reports have been published investigating the relationship between common variants in serotonin-related candidate genes and antidepressant response, and most of the results have been equivocal. We previously reported a significant association between variants in serotonin-related genes and response to the selective serotonin reuptake inhibitor fluoxetine. Here, we attempt to expand upon and replicate these results by (i) resequencing the exonic and putatively regulatory regions of five serotonin-related candidate genes (HTR1A, HTR2A, TPH1, TPH2, and MAOA) in our fluoxetine-treated sample to uncover novel variants; (ii) selecting tagging single nucleotide polymorphisms (SNPs) for these genes from the resequencing data; and (iii) evaluating these tagging SNPs for association with response to the selective serotonin reuptake inhibitor citalopram in an independent sample of participants who are enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical study (N=1953). None of the variants associated previously with fluoxetine response were found to be associated with citalopram response in the STAR*D sample set. Nor were any of the additional tagging SNPs found to be associated with citalopram response. An additional SNP in HTR2A (rs7997012), previously reported to be associated with outcome of citalopram treatment in this sample, but not well tagged by any of the other SNPs we studied, was also genotyped, and was associated with citalopram response (P=0.0002), strongly supporting the previous observation in the same STAR*D sample. Our results suggest that resequencing the serotonin-related genes did not identify any additional common SNPs that have not been identified previously. It appears that genetic variation in these five genes has a marginal effect on response to citalopram, although a previously observed association was supported and awaits replication in an independent sample.
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PMID:Resequencing of serotonin-related genes and association of tagging SNPs to citalopram response. 1907 64

Dysregulations of central noradrenergic and serotonergic neurotransmission have been suggested to contribute to the pathogenesis of neuropsychiatric disorders such as depression. The norepinephrine transporter (NET; SLC6A2) and the serotonin (5-HT)(1A) receptor (5-HT(1A) receptor; HTR1A) play an important role in central nervous monoaminergic homeostasis. As shown previously, variations in the human NET and 5-HT(1A) receptor genes can alter noradrenergic and serotonergic signaling in the brain: a single nucleotide polymorphism (SNP) in the coding region of the NET gene resulting in a F528C substitution increased plasma membrane expression of this NET variant, and a SNP in the human 5-HT(1A) receptor gene leading to the R219L receptor variant almost abolished cellular signal transduction subsequent to receptor activation. The present study aimed at investigating whether these NET and 5-HT(1A) receptor variants are associated with major depression (MD). The sample comprised 426 patients suffering from unipolar MD as well as 643 healthy control subjects for the variants of the 5-HT(1A) receptor and the NET. Both SNPs were shown to be associated with MD. In conclusion, our results favor the hypothesis that monoaminergic neurotransmission in general and the F528C NET and R219L 5-HT(1A) receptor variants in particular are involved in the pathogenesis of depression.
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PMID:Association of major depression with rare functional variants in norepinephrine transporter and serotonin1A receptor genes. 1910

Genes that regulate the serotonin signalling system are potential targets for research in the aetiology of mood disorders and also in the treatment response of serotonin reuptake inhibitors. In this study, we evaluated the association of seven serotonin signal transduction-linked single nucleotide polymorphisms [HTR1A (rs6295), HTR2A (rs6313, rs6311 and rs7997012), HTR6 (rs1805054), TPH1 (rs1800532) and TPH2 (rs1386494)] with major depressive disorder and/or treatment outcome with serotonin reuptake inhibitors. Patients who met the criteria for major depressive disorder were treated for 6 weeks with fluoxetine, paroxetine or citalopram. The treatment response was evaluated with the Montgomery-Asberg Depression Rating Scale, and according to predefined response criteria, the patients were divided into responders, nonresponders, remitters and nonremitters. Altogether, 86 patients completed the entire study according to the study protocol. We had also a control population (N = 395) of healthy blood donors. None of the seven single nucleotide polymorphisms was associated with major depressive disorder or with treatment response in our study population of Finnish individuals.
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PMID:5-HTR1A, 5-HTR2A, 5-HTR6, TPH1 and TPH2 polymorphisms and major depression. 1959 Mar 97

Chronic mild stress (CMS) is suggested to develop dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) stress circuit. Icariin, a major constituent of flavonoids isolated from Epimedium brevicornum, has been previously confirmed to rescue the HPA axis abnormalities in animal models of depression. However, antidepressant treatment of icariin on corticotropin-releasing factor (CRF) system within the LHPA stress circuit and its interaction with serotonergic receptor are still seldom studied in CMS model of animals. The present study further investigated the effects of CMS procedure and subsequent icariin treatment on mRNA and protein levels of CRF, CRF receptor 1 (CRFR1) and CRF binding protein (CRFBP), as well as sucrose intake in rats. Moreover, the levels of cyclic adenosine 3',5'-monophosphate (cAMP) response element binding protein (CREB), glucocorticoid receptor (GR) and 5-hydroxytryptamine 1A receptor (5-HTR1A) in hypothalamus, hippocampus and frontal cortex were simultaneously evaluated for their participations in CRF system in this model. We found that CMS procedure significantly increased CRF expression levels in the brain regions, and decreased GR and 5-HTR1A in hippocampus and frontal cortex, with sucrose intake reduction representing the hedonic deficit in rats. Icariin restored these alterations in CMS rats. These results confirmed the hypothesis that icariin exerted antidepressant-like effect via its regulation of central CRF system. And hippocampus was suggested as an important neural area controlling the LHPA stress circuit in icariin-treated CMS rats. These findings for the first time proved that the potential molecular mechanism of antidepressant action of icariin was targeted on the interaction of the LHPA stress circuit and serotonergic function in CMS rats.
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PMID:Icariin attenuates chronic mild stress-induced dysregulation of the LHPA stress circuit in rats. 1963 74


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