1Eur. J. Pharmacol. 2000 Dec 410: 165-181
TitlePharmacogenetics and the serotonin system: initial studies and future directions.
AbstractSerotonin (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.
SCZ Keywordsschizophrenia
2Genomics 2001 Feb 72: 1-14
TitleGenetic diversity of the human serotonin receptor 1B (HTR1B) gene.
AbstractWe systematically and comprehensively investigated polymorphisms of the HTR1B gene as well as their linkage disequilibrium and ancestral relationships. We have detected the following polymorphisms in our sample via denaturing gradient gel electrophoresis, database comparisons, and/or previously published assays: G-511T, T-261G, -182INS/DEL-181, A-161T, C129T, T371G, T655C, C705T, G861C, A1099G, G1120A, and A1180G. The results of the intermarker analyses showed strong linkage disequilibrium between the C129T and the G861C polymorphisms and revealed four common haplotypes: ancestral (via chimpanzee comparisons), 129T/861C, -161T, and -182DEL-181. The results of association tests with schizophrenia were negative, although A-161T had a nominal P = 0.04 via ASPEX/sib_tdt. The expressed missense substitutions, Phe124Cys, Phe219Leu, Ile367Val, and Glu374Lys, could potentially affect ligand binding or interaction with G proteins and thus modify drug response in carriers of these variants. On average, the human cSNPs and differences among other primates clustered in the more thermodynamically unstable regions of the mRNA, which suggests that the evolutionary survival of nucleotide sequence variation may be influenced by the mRNA structure of this gene.
SCZ Keywordsschizophrenia
3Neuropsychopharmacology 2003 Jan 28: 163-9
TitleSubstance abuse disorder and major depression are associated with the human 5-HT1B receptor gene (HTR1B) G861C polymorphism.
AbstractThe 5-HT(1B) receptor has been implicated in several psychopathologies, including pathological aggression, alcoholism and suicide. To test these and related potential genetic relationships in a single population, the human 5-HT(1B) receptor (h5-HTR(1B)) genotype for the G861C polymorphism was determined in 394 psychiatric patients and 96 healthy volunteers. Structured clinical interviews generated DSM III-R diagnoses. No significant association of the genotype or allele frequencies of the h5-HTR(1B) G861C locus was observed with diagnoses of alcoholism, bipolar disorder, schizophrenia or a history of a suicide attempt. Exploratory analyses indicated an association of the genotype and allele frequencies of the h5-HTR(1B) G861C locus with a history of substance abuse disorder (chi(2) = 9.51, df = 2, p = 0.009; chi(2) = 7.31, df = 1, p = 0.007, respectively) and with a diagnosis of a major depressive episode (chi(2) = 6.83, df = 2, p = 0.033; chi(2) = 5.81, df = 1, p = 0.016, respectively). Significant gene dose effects on the risk for substance abuse disorder and a major depressive episode were observed with the 861C allele (Armitage linearity tendency test: chi(2) = 7.20, df = 1, p = 0.008; chi(2) = 6.80, df = 1, p = 0.009, respectively). Substance abuse disorder and major depression appear to be associated with the h5-HTR(1B) G861C locus in the patient population, but other psychopathologies such as bipolar disorder, schizophrenia, alcoholism, and suicide attempts were not found to be associated with this polymorphism. This preliminary result will need replication, given the limitations of association studies.
SCZ Keywordsschizophrenia
4Neurosci. Lett. 2005 Mar 376: 93-7
TitleNo association between the serotonin 1B receptor gene and schizophrenia in a case-control and family-based association study.
AbstractPrevious studies have demonstrated that polymorphisms in the putative promoter region of the human serotonin receptor 1B (HTR1B) gene affect gene expression [H.F. Sun, Y.T. Chang, C.S. Fann, C.J. Chang, Y.H. Chen, Y.P. Hsu, W.Y. Yu, A.T. Cheng, Association study of novel human serotonin 5-HT(1B) polymorphisms with alcohol dependence in Taiwanese Han, Biol. Psychiatry 51 (2002) 896-901; J. Duan, A.R. Sanders, J.E. Molen, L. Martinolich, B.J. Mowry, D.F. Levinson, R.R. Crowe, J.M. Silverman, P.V. Gejman, Polymorphisms in the 5'-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression, Mol. Psychiatry 8 (2003) 901-910]. And the silent mutation G861C allele has been reported to be associated with several psychiatric disorders. Thus, we performed a case-control association study (456 cases and 557 controls) of the five variants in HTR1B gene (T-261G, -182INS/DEL-181, A-161T, C129T and G861C) with schizophrenia. The results showed that neither the allelic distribution nor the major haplotype distribution (except for a rare haplotype) of five SNPs in patients was significantly different from that in controls. A further family-based association study (229 family trios) of G861C allele suggested that HTR1B was not a susceptible gene with schizophrenia in our sample. In conclusion, these data do not support the idea that HTR1B gene plays a major role in the etiopathogenesis of schizophrenia in Chinese Han population.
SCZ Keywordsschizophrenia
5Pharmacogenomics 2008 Oct 9: 1437-43
TitleVariants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia.
AbstractAbnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics. We conducted a pharmacogenetic study to evaluate whether variants in dopamine-related genes (DRD1-DRD5, AKT1 and GSK3beta) and serotonin receptor genes (HTR1A, HTR1B, HTR1D, HTR2A, HTR2C, HTR6 and HTR7) can be used to predict the efficacy of risperidone treatment for schizophrenia.
A total of 120 first-episode neuroleptic-naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale.
Among the 30 variants that we examined, two SNPs in DRD2 (-241A>G [rs1799978] and TaqIA [rs1800497]) and two SNPs in AKT1 (AKT1-SNP1 [rs3803300] and AKT1-SNP5 [rs2494732]) were significant predictors of treatment response to risperidone.
These data suggest that the SNPs in DRD2 and AKT1 may influence the treatment response to risperidone in schizophrenia patients.
SCZ Keywordsschizophrenia