| 1 | Psychiatr. Genet. 2000 Sep 10: 109-15 |
|---|---|
| PMID | 11204346 |
| Title | An association between a polymorphism of the tryptophan hydroxylase gene and aggression in schizophrenia and schizoaffective disorder. |
| Abstract | Serotonergic pathways have been implicated in impulsive and aggressive behavior. Polymorphisms in the regulatory region of the serotonin transporter (5-HTT), in intron 7 of the tryptophan hydroxylase (TPH) gene and in the MAOA gene were previously reported to be associated with mood and anxiety disorders, impulsivity and aggression. In this study, we analyzed these polymorphisms in men and women with schizophrenia or schizoaffective disorder (n = 84) who met our criteria for violence (history of two or more assaults on others) or nonviolence (no history of either assaultive or threatening behavior). In males, a modest association between TPH genotype and history of violence (chi-square test = 6.703, degrees of freedom = 2, P = 0.035) was not statistically significant after correction for multiple comparisons (corrected P = 0.21). The TPH L allele was more frequent in violent males (chi-square = 5.323, degrees of freedom = 1, P = 0.021) but this difference also failed to withstand correction (corrected P = 0.126). No significant associations were found for either the 5-HTT or MAOA polymorphisms in males or females. These results tend to support previous reports by New et al. (1996; 1998) of an association between the TPH L allele and impulsive aggression in males with personality disorder, but larger studies are needed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 2 | Eur. J. Pharmacol. 2000 Dec 410: 165-181 |
| PMID | 11134668 |
| Title | Pharmacogenetics and the serotonin system: initial studies and future directions. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 3 | Am. J. Med. Genet. 2001 Mar 105: 168-71 |
| PMID | 11304831 |
| Title | Association analysis of the functional monoamine oxidase A gene promoter polymorphism in psychiatric disorders. |
| Abstract | Functional characterization studies revealed that transcriptional activity of the human monoamine oxidase A (MAOA) gene is modulated by a polymorphic repetitive sequence located approximately 1.2 kb upstream of the ATG codon. To investigate the possible influence of the allelic variants of the MAOA gene-linked polymorphic region (MAOA-LPR) on the genetic predisposition to psychiatric disorders, we have performed a case-control association study. 174 patients with affective disorders and 258 patients with schizophrenia according to DSM-IV, as well as 229 population controls were tested. Statistical analysis showed no significant differences in allele or genotype frequencies between control and patient groups. Our results suggest that there is no association between MAOA-LPR genotype and susceptibility to recurrent major depression, bipolar disorder, and schizophrenia in our population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 4 | Am. J. Med. Genet. 2002 Jul 114: 491-6 |
| PMID | 12116182 |
| Title | Schizophrenia and functional polymorphisms in the MAOA and COMT genes: no evidence for association or epistasis. |
| Abstract | Several lines of evidence suggest that psychosis is associated with altered dopaminergic neurotransmission. Dopamine is catabolized by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). We hypothesized that the genes encoding MAOA and COMT might contain genetic variation conferring increased risk to schizophrenia. In order to test this hypothesis, we genotyped the 941T > G and the promoter VNTR polymorphisms in the MAOA gene and the V158M COMT polymorphism in 346 DSMIV schizophrenics and 334 controls. We also genotyped the-287A > G COMT promoter polymorphism in 177 schizophrenics and 173 controls. No significant differences were found in allele or genotype frequencies between affecteds and controls for any of the polymorphisms. As both genes are involved in degrading catecholamines, we also sought evidence for additive and epistatic effects but none was observed. Our data, therefore, do not support the hypothesis that genetic variation in MAOA and COMT is involved individually or in combination in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 5 | Am. J. Med. Genet. 2002 Jul 114: 491-6 |
| PMID | 12116182 |
| Title | Schizophrenia and functional polymorphisms in the MAOA and COMT genes: no evidence for association or epistasis. |
| Abstract | Several lines of evidence suggest that psychosis is associated with altered dopaminergic neurotransmission. Dopamine is catabolized by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). We hypothesized that the genes encoding MAOA and COMT might contain genetic variation conferring increased risk to schizophrenia. In order to test this hypothesis, we genotyped the 941T > G and the promoter VNTR polymorphisms in the MAOA gene and the V158M COMT polymorphism in 346 DSMIV schizophrenics and 334 controls. We also genotyped the-287A > G COMT promoter polymorphism in 177 schizophrenics and 173 controls. No significant differences were found in allele or genotype frequencies between affecteds and controls for any of the polymorphisms. As both genes are involved in degrading catecholamines, we also sought evidence for additive and epistatic effects but none was observed. Our data, therefore, do not support the hypothesis that genetic variation in MAOA and COMT is involved individually or in combination in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 6 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Jul 120B: 29-34 |
| PMID | 12815735 |
| Title | Aggressive behavior in schizophrenia is associated with the low enzyme activity COMT polymorphism: a replication study. |
| Abstract | We have previously reported that increased aggressive behavior in schizophrenic patients may be associated with a polymorphism at codon 158 of the catechol O-methyltransferase (COMT) gene that encodes a low enzyme activity variant. The finding has been replicated by one group, but not others. The discordant findings could be due to statistical errors or methodological issues in the assessment of aggressive/violent behavior. Consequently, additional studies are needed. Patients with schizophrenia (SZ) were assessed for violent behavior using the Lifetime History of Aggression (LHA) scale, an 11-item questionnaire that includes Aggression, Self-Directed Aggression, and Consequences/Antisocial Behavior subscales. DNA was genotyped for the COMT 158 polymorphism, as well as a functional polymorphism in the monoamine oxidase A (MAOA) gene promoter. Similar to our previously reported findings, a statistically significant association was found between aggressive behavior in SZ and the COMT 158 polymorphism; mean LHA scores were higher in subjects homozygous for 158Met, the low enzyme activity COMT variant (F(2,105) = 5.616, P = 0.005). Analysis of the major LHA subscales revealed that the association with 158Met was due to high scores on the Aggression, and Self-Directed Aggression subscales, but not the Consequences/Antisocial Behavior subscale. No significant association was detected for the MAOA gene alone. Our findings provide further support that COMT is a modifying gene that plays a role in determining interindividual variability in the proclivity for outward and self-directed aggressive behavior found in some schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 7 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Jul 120B: 29-34 |
| PMID | 12815735 |
| Title | Aggressive behavior in schizophrenia is associated with the low enzyme activity COMT polymorphism: a replication study. |
| Abstract | We have previously reported that increased aggressive behavior in schizophrenic patients may be associated with a polymorphism at codon 158 of the catechol O-methyltransferase (COMT) gene that encodes a low enzyme activity variant. The finding has been replicated by one group, but not others. The discordant findings could be due to statistical errors or methodological issues in the assessment of aggressive/violent behavior. Consequently, additional studies are needed. Patients with schizophrenia (SZ) were assessed for violent behavior using the Lifetime History of Aggression (LHA) scale, an 11-item questionnaire that includes Aggression, Self-Directed Aggression, and Consequences/Antisocial Behavior subscales. DNA was genotyped for the COMT 158 polymorphism, as well as a functional polymorphism in the monoamine oxidase A (MAOA) gene promoter. Similar to our previously reported findings, a statistically significant association was found between aggressive behavior in SZ and the COMT 158 polymorphism; mean LHA scores were higher in subjects homozygous for 158Met, the low enzyme activity COMT variant (F(2,105) = 5.616, P = 0.005). Analysis of the major LHA subscales revealed that the association with 158Met was due to high scores on the Aggression, and Self-Directed Aggression subscales, but not the Consequences/Antisocial Behavior subscale. No significant association was detected for the MAOA gene alone. Our findings provide further support that COMT is a modifying gene that plays a role in determining interindividual variability in the proclivity for outward and self-directed aggressive behavior found in some schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 8 | Schizophr. Res. 2003 May 61: 31-7 |
| PMID | 12648733 |
| Title | Association between a promoter variant in the monoamine oxidase A gene and schizophrenia. |
| Abstract | Monoaminergic transmission has been implicated in the pathophysiology of schizophrenia. We investigated a putative functional promoter polymorphism in the monoamine oxidase A (MAOA) gene in schizophrenic patients (n=133) and control subjects (n=377). In men, there was an association between the less efficiently transcribed alleles and schizophrenia (chi(2)=4.01, df=1, p<0.05). In women, no significant differences were found. The present results support the involvement of the MAOA gene in men with schizophrenia in the investigated Swedish population but should be interpreted with caution until replicated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 9 | Schizophr. Res. 2003 May 61: 31-7 |
| PMID | 12648733 |
| Title | Association between a promoter variant in the monoamine oxidase A gene and schizophrenia. |
| Abstract | Monoaminergic transmission has been implicated in the pathophysiology of schizophrenia. We investigated a putative functional promoter polymorphism in the monoamine oxidase A (MAOA) gene in schizophrenic patients (n=133) and control subjects (n=377). In men, there was an association between the less efficiently transcribed alleles and schizophrenia (chi(2)=4.01, df=1, p<0.05). In women, no significant differences were found. The present results support the involvement of the MAOA gene in men with schizophrenia in the investigated Swedish population but should be interpreted with caution until replicated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 10 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Jul 128B: 19-20 |
| PMID | 15211623 |
| Title | Polymorphisms in the MAOA, MAOB, and COMT genes and aggressive behavior in schizophrenia. |
| Abstract | Some studies have reported associations between COMT and MAO genotypes and aggression, though results have been inconsistent. We examined the relationship between Overt aggression scale (OAS) scores, and both MAOA and MAOB polymorphisms in a well-powered sample of 346 subjects with schizophrenia. We also examined COMT in a Stage II replication sample of 150 individuals, and combined these results with our previously reported (Stage I) findings for COMT. We found no evidence of any associations between OAS ratings and any of the polymorphisms investigated under different genetic models. There was no evidence of epistatic interaction between MAOA and COMT on OAS scores. These results fail to support the theory that functional polymorphisms within the MAOA, MAOB, or COMT genes, as determinants of catecholamine enzymatic activity, are risk factors for aggressive behavior. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 11 | Psychiatry Res 2004 Jun 127: 1-7 |
| PMID | 15261699 |
| Title | Polymorphisms of dopamine degradation enzyme (COMT and MAO) genes and tardive dyskinesia in patients with schizophrenia. |
| Abstract | Several lines of evidence suggest that tardive dyskinesia (TD) may be associated with altered dopaminergic neurotransmission. We hypothesized that deranged dopamine degradation enzyme activities might be related to the susceptibility to TD through altered dopaminergic neurotransmission in the central nervous system. In the present study, we investigated the relationship between the gene polymorphisms of three dopamine degradation enzymes and TD. We genotyped the valine/methionine polymorphism of codon 108/158 in the catechol-O-methyltransferase (COMT) gene, the 30-bp repeat polymorphism in the promoter of the monoamine oxidase A (MAOA) gene, and the A/G polymorphism in intron 13 of the monoamine oxidase B (MAOB) gene in 206 Japanese patients with schizophrenia. No significant difference was found in total scores on the Abnormal Involuntary Movement Scale (AIMS) among the subject groups, sorted according to the COMT, MAOA and MAOB genotypes. Moreover, no significant difference was found in allele frequencies between patients with TD and patients without TD for any of the polymorphisms. As both COMT and MAO genes are involved in degrading catecholamines, we also sought evidence for additive and epistatic effects, but none was observed. Our data, therefore, do not support the hypothesis that polymorphisms in COMT, MAOA, and MAOB genes are involved individually or in combination in the predisposition to TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 12 | Brain Res. 2006 Jun 1097: 26-30 |
| PMID | 16725119 |
| Title | Gene-gene interaction between MAOA and COMT in suicidal behavior: analysis in schizophrenia. |
| Abstract | A large body of evidence suggests that suicidal behavior is associated with altered noradrenergic neurotransmission. Norepinephrine is degraded by monoamine oxidase A (MAOA) and catechol-O-methyl transferase (COMT). Our hypothesis is that the genes encoding MAOA and COMT might contain genetic variants conferring increased risk for suicidal behavior in schizophrenia and that both genes may interact each other. In order to test this hypothesis, we genotyped the promoter VNTR polymorphism in the MAOA gene and three COMT polymorphisms: -287A>G, Val/Met and 3'UTR C Ins/Del in a cohort of 270 schizophrenics in which 92 attempted suicide. No association between suicide attempt and the MAOA VNTR (P = 0.382), Val108/158Met (P = 0.788) or -287A>G (P = 0.420) polymorphisms was found, however, a slight significant finding was found for 3'UTR polymorphism (P = 0.050). Haplotype analysis for COMT gene revealed no association between suicide attempts and haplotype distribution (P = 0.451). As we tested for epistasis between MAOA VNTR and COMT Val/Met, we found no significant interaction in conferring risk for suicide attempts (P = 0.545). These results suggest that epistasis between MAOA and COMT genes may not influence suicidal behavior in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 13 | Brain Res. 2006 Jun 1097: 26-30 |
| PMID | 16725119 |
| Title | Gene-gene interaction between MAOA and COMT in suicidal behavior: analysis in schizophrenia. |
| Abstract | A large body of evidence suggests that suicidal behavior is associated with altered noradrenergic neurotransmission. Norepinephrine is degraded by monoamine oxidase A (MAOA) and catechol-O-methyl transferase (COMT). Our hypothesis is that the genes encoding MAOA and COMT might contain genetic variants conferring increased risk for suicidal behavior in schizophrenia and that both genes may interact each other. In order to test this hypothesis, we genotyped the promoter VNTR polymorphism in the MAOA gene and three COMT polymorphisms: -287A>G, Val/Met and 3'UTR C Ins/Del in a cohort of 270 schizophrenics in which 92 attempted suicide. No association between suicide attempt and the MAOA VNTR (P = 0.382), Val108/158Met (P = 0.788) or -287A>G (P = 0.420) polymorphisms was found, however, a slight significant finding was found for 3'UTR polymorphism (P = 0.050). Haplotype analysis for COMT gene revealed no association between suicide attempts and haplotype distribution (P = 0.451). As we tested for epistasis between MAOA VNTR and COMT Val/Met, we found no significant interaction in conferring risk for suicide attempts (P = 0.545). These results suggest that epistasis between MAOA and COMT genes may not influence suicidal behavior in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 14 | J Psychiatry Neurosci 2007 May 32: 185-92 |
| PMID | 17476365 |
| Title | Monoamine oxidase-A polymorphisms might modify the association between the dopamine D2 receptor gene and alcohol dependence. |
| Abstract | Low monoamine oxidase (MAO) activity and the neurotransmitter dopamine are 2 important factors in the development of alcohol dependence. MAO is an important enzyme associated with the metabolism of biogenic amines. Therefore, the present study investigates whether the association between the dopamine D2 receptor (DRD2) gene and alcoholism is affected by different polymorphisms of the MAO type A (MAOA) gene. A total of 427 Han Chinese men in Taiwan (201 control subjects and 226 with alcoholism) were recruited for the study. Of the subjects with alcoholism, 108 had pure alcohol dependence (ALC) and 118 had both alcohol dependence and anxiety, depression or both (ANX/DEP ALC). All subjects were assessed with the Chinese Version of the Modified Schedule of Affective Disorders and schizophrenia-Lifetime. Alcohol dependence, anxiety and major depressive disorders were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria. The genetic variant of the DRD2 gene was only associated with the ANX/DEP ALC phenotype, and the genetic variant of the MAOA gene was associated with pure ALC. Subjects carrying the MAOA 3-repeat allele and genotype A1/A1 of the DRD2 were 3.48 times (95% confidence interval = 1.47-8.25) more likely to be ANX/DEP ALC than the subjects carrying the MAOA 3-repeat allele and DRD2 A2/A2 genotype. The MAOA gene may modify the association between the DRD2 gene and ANX/DEP ALC phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 15 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2007 Aug 24: 457-9 |
| PMID | 17680543 |
| Title | [Association study of the polymorphisms of monoamine oxidase A genes with schizophrenia]. |
| Abstract | To investigate the relationship between monoamine oxidase A (MAOA) gene polymorphisms and schizophrenia in a Chinese Han population. Two hundred and twelve schizophrenic patients and 168 healthy controls were recruited according to CCMD-3. The polymorphisms of MAOA gene were determined with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The case-control association analysis was adopted to analyze the frequencies of genotype and allele in schizophrenic patients and controls. (1) The genotypes of MAOA gene were consistent with Hardy-Weinberg equilibrium in patient group and control group (chi2 = 0.618, df= 2, P> 0.05; chi2 = 3.173, df= 2, P> 0.05). (2) The distributions of genotypes or alleles of MAOA genes had no significant difference between patient group and control group (P> 0.05). (3)Divided by sex, the frequency of CT genotype in male patients was higher than that in male controls (chi2 = 7.654, P= 0.022). (4) There were no significant differences of genotypic and allelic distribution in MAOA genes between schizophrenic patients with positive family history and schizophrenic patients with negative family history and among different clinical subtypes in schizophrenic patients (P> 0.05). No association between MAOA gene and schizophrenia is found in Chinese Han population, but CT genotype is likely to be a susceptible factor of male schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 16 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2007 Aug 24: 457-9 |
| PMID | 17680543 |
| Title | [Association study of the polymorphisms of monoamine oxidase A genes with schizophrenia]. |
| Abstract | To investigate the relationship between monoamine oxidase A (MAOA) gene polymorphisms and schizophrenia in a Chinese Han population. Two hundred and twelve schizophrenic patients and 168 healthy controls were recruited according to CCMD-3. The polymorphisms of MAOA gene were determined with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The case-control association analysis was adopted to analyze the frequencies of genotype and allele in schizophrenic patients and controls. (1) The genotypes of MAOA gene were consistent with Hardy-Weinberg equilibrium in patient group and control group (chi2 = 0.618, df= 2, P> 0.05; chi2 = 3.173, df= 2, P> 0.05). (2) The distributions of genotypes or alleles of MAOA genes had no significant difference between patient group and control group (P> 0.05). (3)Divided by sex, the frequency of CT genotype in male patients was higher than that in male controls (chi2 = 7.654, P= 0.022). (4) There were no significant differences of genotypic and allelic distribution in MAOA genes between schizophrenic patients with positive family history and schizophrenic patients with negative family history and among different clinical subtypes in schizophrenic patients (P> 0.05). No association between MAOA gene and schizophrenia is found in Chinese Han population, but CT genotype is likely to be a susceptible factor of male schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 17 | Methods Mol. Biol. 2008 -1 448: 187-212 |
| PMID | 18370235 |
| Title | Epigenetic alterations of the dopaminergic system in major psychiatric disorders. |
| Abstract | Although there is evidence to link schizophrenia (SCZ) and bipolar disorder (BD) to genetic and environmental factors, specific individual or groups of genes/factors causative of the disease have been elusive to the research community. An understanding of the molecular aberrations that cause these mental illnesses requires comprehensive approaches that examine both genetic and epigenetic factors. Because of the overwhelming evidence for the role of environmental factors in the disease presentation, our initial approach involved deciphering how epigenetic changes resulting from promoter DNA methylation affect gene expression in SCZ and BD. Apparently, the central reversible but covalent epigenetic modification to DNA is derived from methylation of the cytosine residues that is potentially heritable and can affect gene expression and downstream activities. Environmental factors can influence DNA methylation patterns and hence alter gene expression. Such changes can be especially problematic in individuals with genetic susceptibilities to specific diseases. Recent reports from our laboratory provided compelling evidence that both hyper- and hypo-DNA methylation changes of the regulatory regions play critical roles in defining the altered functionality of genes in major psychiatric disorders such as SCZ and BD. In this chapter, we outline the technical details of the methods that could help to expand this line of research to assist with compiling the differential methylation-mediated epigenetic alterations that are responsible for the pathogenesis of SCZ, BD, and other mental diseases. We use the genes of the extended dopaminergic (DAergic) system such as membrane-bound catechol-O-methyltransferase (MB-COMT), monoamine oxidase A (MAOA), dopamine transporter 1 (DAT1), tyrosine hydroxylase (TH), dopamine (DA) receptors1 and 2 (DRD1/2), and related genes (e.g., reelin [RELN] and brain-derived neurotrophic factor [BDNF]) to illustrate the associations between differential promoter DNA methylations and disease phenotype. It is our hope that comprehensive analyses of the DAergic system as the prototype could provide the impetus and molecular basis to uncover early markers for diagnosis, help in the understanding of differences in disease severity in individuals with similar or identical genetic makeup, and assist with the identification of novel targets for therapeutic applications. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 18 | Hum. Mutat. 2008 Jul 29: 891-902 |
| PMID | 18444257 |
| Title | Mutations in human monoamine-related neurotransmitter pathway genes. |
| Abstract | Biosynthesis and metabolism of serotonin and catecholamines involve at least eight individual enzymes that are mainly expressed in tissues derived from the neuroectoderm, e.g., the central nervous system (CNS), pineal gland, adrenal medulla, enterochromaffin tissue, sympathetic nerves, and ganglia. Some of the enzymes appear to have additional biological functions and are also expressed in the heart and various other internal organs. The biosynthetic enzymes are tyrosine hydroxylase (TH), tryptophan hydroxylases type 1 and 2 (TPH1, TPH2), aromatic amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DbetaH), and phenylethanolamine N-methyltransferase (PNMT), and the specific catabolic enzymes are monoamine oxidase A (MAO-A) and catechol O-methyltransferase (COMT). For the TH, DDC, DBH, and MAOA genes, many single nucleotide polymorphisms (SNPs) with unknown function, and small but increasing numbers of cases with autosomal recessive mutations have been recognized. For the remaining genes (TPH1, TPH2, PNMT, and COMT) several different genetic markers have been suggested to be associated with regulation of mood, pain perception, and aggression, as well as psychiatric disturbances such as schizophrenia, depression, suicidality, and attention deficit/hyperactivity disorder. The genetic markers may either have a functional role of their own, or be closely linked to other unknown functional variants. In the future, molecular testing may become important for the diagnosis of such conditions. Here we present an overview on mutations and polymorphisms in the group of genes encoding monoamine neurotransmitter metabolizing enzymes. At the same time we propose a unified nomenclature for the nucleic acid aberrations in these genes. New variations or details on mutations will be updated in the Pediatric Neurotransmitter Disorder Data Base (PNDDB) database (www.bioPKU.org). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 19 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Mar 147B: 174-8 |
| PMID | 17894408 |
| Title | Meta-study on association between the monoamine oxidase A gene (MAOA) and schizophrenia. |
| Abstract | The human monoamine oxidase A gene (MAOA) has attracted considerable attention as a candidate gene for schizophrenia based both on its chromosomal position and its enzyme function as a key factor in neurotransmitter catabolism pathways. However studies to date have reported inconsistent findings regarding the association between the variable number tandem repeat (VNTR) and T941G polymorphisms and schizophrenia. In an attempt to clarify this inconsistency we conducted a meta-analysis based on both alleles and genotypes (up to February 2006). In this study, however, we found no significant evidence of association with the two schizophrenia susceptibility polymorphisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 20 | Eur Arch Psychiatry Clin Neurosci 2008 Sep 258: 350-6 |
| PMID | 18437281 |
| Title | Neither single-marker nor haplotype analyses support an association between monoamine oxidase A gene and bipolar disorder. |
| Abstract | Monoamine oxidase A (MAOA) abnormality has been suggested as a crucial factor in the pathogenesis of mood disorder, because MAOA is associated with the metabolism of monoamines such as serotonin and norepinephrine. Various MAOA gene polymorphisms have been investigated for possible associations with bipolar disorder (BD), but the results are controversial. Our goal was to investigate whether MAOA gene polymorphisms, especially the promoter uVNTR polymorphism and the EcoRV polymorphism, are associated either with BD or with different clinical subtypes of BD. A total of 714 Han Chinese subjects in Taiwan (305 controls and 409 BD patients) were recruited for study. All subjects were interviewed with the Chinese Version of the Modified Schedule of Affective Disorders and schizophrenia-Lifetime; BD was diagnosed according to DSM-IV criteria. Genotyping for MAOA polymorphisms was performed using PCR and restriction fragment length polymorphism. The MAOA promoter polymorphisms uVNTR and EcoRV were not associated with BD or any of its subtypes, in either the frequencies of alleles or genotypes. In multiple logistic regression and haplotype frequency analysis, we confirmed these negative results in both females and males. Our results suggest that MAOA polymorphisms do not play a major role in pathogenesis of BD or its clinical subtypes in Han Chinese. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 21 | Prim Care Companion J Clin Psychiatry 2009 -1 11: 16-20 |
| PMID | 19333405 |
| Title | Prolactin levels in olanzapine treatment correlate with positive symptoms of schizophrenia: results from an open-label, flexible-dose study. |
| Abstract | This study was designed to investigate the relationship between the treatment effect of olanzapine and the serum prolactin level in schizophrenia and to investigate the factors that may act as predictors of response for olanzapine treatment. Sixty patients who met the DSM-IV criteria for schizophrenia were included in the study. None of the patients were drug-naive, and they were given olanzapine in a flexible dose of 10-30 mg/day for 3 months after a 7-day drug washout period. Serum prolactin levels were measured at baseline (after drug washout) and at months 1, 2, and 3 during olanzapine treatment. A psychiatrist performed monthly ratings of symptoms using the Positive and Negative Syndrome Scale Manual (PANSS Manual). The Generalized Estimating Equations-I was used for data correlation analysis. Data were gathered from July 2005 to July 2006. In general, the serum prolactin level was decreased in schizophrenia patients with olanzapine treatment, although the difference is not statistically significant (p = .974, p = .246, and p = .363 for the first, second, and third months, respectively). There was a close relationship between the improvement in positive symptoms and the change in serum prolactin levels before and after olanzapine treatment (p = .002). Moreover, the serum prolactin level also had a positive association with female gender (p = .008). The present study demonstrated no significant correlation between serum prolactin level, MAOA polymorphism, and DRD4 genotype. This finding suggests that the serum prolactin level may be a useful biological marker to predict the effectiveness of antipsychotics in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 22 | Brain Res. 2009 Sep 1287: 67-73 |
| PMID | 19573521 |
| Title | Association between monoamine oxidase (MAO)-A gene variants and schizophrenia in a Chinese population. |
| Abstract | Monoamine oxidase (MAO) A is a critical enzyme in the catabolism of dopamine. Dysfunction of dopaminergic systems has been implicated in the pathophysiology of schizophrenia, suggesting that MAOA gene variation might be associated with the disorder. MAOA gene variation was compared between 234 Chinese schizophrenic patients and 121 healthy controls. Three polymorphic markers of the MAOA gene were analyzed using PCR techniques: two MAOA restriction fragment length polymorphisms (RFLP), -941G/T and -1460C/T, and the variable number tandem repeats (VNTR) in the promoter region. Linkage disequilibrium and haplotype analyses were performed with Bonferroni correction for multiple testing. In single marker analyses the 941T allele was significantly associated with schizophrenia in men (p=0.01). Haplotype analyses revealed a significant overall difference (p=0.03) between schizophrenia and control men, with higher frequencies of haplotypes containing the major allele (T) of -941T/G and the short allele (3 repeats) of the VNTR polymorphisms. No significant associations were detected for females using single markers or haplotypes. These findings suggest that genetic variants in MAOA may play a role in susceptibility to schizophrenia in Chinese men. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 23 | Brain Res. 2009 Sep 1287: 67-73 |
| PMID | 19573521 |
| Title | Association between monoamine oxidase (MAO)-A gene variants and schizophrenia in a Chinese population. |
| Abstract | Monoamine oxidase (MAO) A is a critical enzyme in the catabolism of dopamine. Dysfunction of dopaminergic systems has been implicated in the pathophysiology of schizophrenia, suggesting that MAOA gene variation might be associated with the disorder. MAOA gene variation was compared between 234 Chinese schizophrenic patients and 121 healthy controls. Three polymorphic markers of the MAOA gene were analyzed using PCR techniques: two MAOA restriction fragment length polymorphisms (RFLP), -941G/T and -1460C/T, and the variable number tandem repeats (VNTR) in the promoter region. Linkage disequilibrium and haplotype analyses were performed with Bonferroni correction for multiple testing. In single marker analyses the 941T allele was significantly associated with schizophrenia in men (p=0.01). Haplotype analyses revealed a significant overall difference (p=0.03) between schizophrenia and control men, with higher frequencies of haplotypes containing the major allele (T) of -941T/G and the short allele (3 repeats) of the VNTR polymorphisms. No significant associations were detected for females using single markers or haplotypes. These findings suggest that genetic variants in MAOA may play a role in susceptibility to schizophrenia in Chinese men. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 24 | Behav. Genet. 2010 May 40: 415-23 |
| PMID | 20033274 |
| Title | Catechol-o-methyltransferase genotype and childhood trauma may interact to impact schizotypal personality traits. |
| Abstract | We attempt to identify gene by childhood abuse interactions which predispose to the development of schizotypal traits in a familial bipolar disorder (BD) sample. Self-report measures of schizotypal personality traits (schizotypal Personality Scale) and childhood maltreatment (Childhood Trauma Questionnaire) were administered to 222 participants from 44 families with BD. Variants of catechol-o-methyltransferase (COMT) and four other dopamine pathway-related genes: DRD4, DRD2,MAOA, and SLC6A3, were typed. BD type I (BD I) subjects scored significantly higher than their unaffected relatives on the schizotypal Personality Scale. The val allele of the Val158 Met polymorphism of the COMT gene was associated with increased schizotypal personality trait scores in individuals exposed to higher levels of self-reported childhood trauma (p < 0.05). There was no direct effect of the val158met polymorphism on schizotypal personality traits. Further, no passive correlation between COMT genotype and childhood trauma was found. We raise the possibility that genetically-driven variation in COMT may interact with childhood trauma to contribute to the risk of developing schizotypal personality traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 25 | Hum Psychopharmacol 2010 Jul 25: 397-403 |
| PMID | 20589923 |
| Title | Association study between antipsychotic-induced restless legs syndrome and polymorphisms of monoamine oxidase genes in schizophrenia. |
| Abstract | This study aimed to investigate whether the monoamine oxidase (MAO) A and B genes are associated with antipsychotic-induced restless legs syndrome (RLS) in schizophrenia. We assessed antipsychotic-induced RLS symptoms in 190 Korean schizophrenic patients and divided the subjects into two groups: those with RLS symptoms (n = 96) and those without RLS symptoms (n = 94). Genotyping was performed for the variable number of tandem repeat (VNTR) polymorphism of the MAOA gene and A644G polymorphism of the MAOB gene. There was no significant difference in the genotype and allele frequencies of all polymorphisms investigated between these two groups. However, the result of global haplotype analysis showed a significant difference in haplotype frequencies between male subjects with and without RLS symptoms (p = 0.013). The interaction between two polymorphisms had a significant effect on the RLS scores of both male (p = 0.047) and female (p = 0.028) patients. These data do not suggest that the MAOA gene VNTR and MAOB gene A644G polymorphisms are associated with antipsychotic-induced RLS symptoms in schizophrenia. However, we found that the haplotype frequencies differed between the male schizophrenic patients with and without RLS symptom and the interaction between the two polymorphisms had a significant influence on the RLS scores of patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 26 | Hum Psychopharmacol 2010 Jul 25: 397-403 |
| PMID | 20589923 |
| Title | Association study between antipsychotic-induced restless legs syndrome and polymorphisms of monoamine oxidase genes in schizophrenia. |
| Abstract | This study aimed to investigate whether the monoamine oxidase (MAO) A and B genes are associated with antipsychotic-induced restless legs syndrome (RLS) in schizophrenia. We assessed antipsychotic-induced RLS symptoms in 190 Korean schizophrenic patients and divided the subjects into two groups: those with RLS symptoms (n = 96) and those without RLS symptoms (n = 94). Genotyping was performed for the variable number of tandem repeat (VNTR) polymorphism of the MAOA gene and A644G polymorphism of the MAOB gene. There was no significant difference in the genotype and allele frequencies of all polymorphisms investigated between these two groups. However, the result of global haplotype analysis showed a significant difference in haplotype frequencies between male subjects with and without RLS symptoms (p = 0.013). The interaction between two polymorphisms had a significant effect on the RLS scores of both male (p = 0.047) and female (p = 0.028) patients. These data do not suggest that the MAOA gene VNTR and MAOB gene A644G polymorphisms are associated with antipsychotic-induced RLS symptoms in schizophrenia. However, we found that the haplotype frequencies differed between the male schizophrenic patients with and without RLS symptom and the interaction between the two polymorphisms had a significant influence on the RLS scores of patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 27 | Eur Child Adolesc Psychiatry 2010 Mar 19: 199-210 |
| PMID | 20024596 |
| Title | From nature versus nurture, via nature and nurture, to gene x environment interaction in mental disorders. |
| Abstract | It is now generally accepted that complex mental disorders are the results of interplay between genetic and environmental factors. This holds out the prospect that by studying G x E interplay we can explain individual variation in vulnerability and resilience to environmental hazards in the development of mental disorders. Furthermore studying G x E findings may give insights in neurobiological mechanisms of psychiatric disorder and so improve individualized treatment and potentially prevention. In this paper, we provide an overview of the state of field with regard to G x E in mental disorders. Strategies for G x E research are introduced. G x E findings from selected mental disorders with onset in childhood or adolescence are reviewed [such as depressive disorders, attention-deficit/hyperactivity disorder (ADHD), obesity, schizophrenia and substance use disorders]. Early seminal studies provided evidence for G x E in the pathogenesis of depression implicating 5-HTTLPR, and conduct problems implicating MAOA. Since then G x E effects have been seen across a wide range of mental disorders (e.g., ADHD, anxiety, schizophrenia, substance abuse disorder) implicating a wide range of measured genes and measured environments (e.g., pre-, peri- and postnatal influences of both a physical and a social nature). To date few of these G x E effects have been sufficiently replicated. Indeed meta-analyses have raised doubts about the robustness of even the most well studied findings. In future we need larger, sufficiently powered studies that include a detailed and sophisticated characterization of both phenotype and the environmental risk. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 28 | Hum Psychopharmacol 2011 Aug 26: 386-91 |
| PMID | 21823169 |
| Title | Genetic interactions in the adrenergic system genes: analysis of antipsychotic-induced weight gain. |
| Abstract | Atypical antipsychotics (AP) have high affinity for many neurotransmitter receptors. Among these receptors, APs are antagonist at ?-adrenergic and ?-adrenergic receptors, and this pharmacological property has been postulated to be involved in the mechanism of action of these drugs with respect to both clinical response and adverse effects. We tested the hypotheses that AP-induced weight gain is associated with genetic variation in adrenergic receptors and pathway enzymes. We analyzed nine genetic polymorphisms across seven adrenergic genes (ADRA1A, ADRA2A, ADRA2C, ADRB3, DBH, MAOA and COMT). One hundred thirty-nine patients with schizophrenia were prospectively assessed for AP-induced weight gain. The HelixTree software (Golden Helix, Bozeman, MT, USA) was employed to detect differences in genotypic distribution between weight gainer and non-weight gainer groups. Furthermore, for the dopamine ?-hydroxylase haplotype, we were able to obtain both the molecular and the statistical phases, analyzing the phenotype considering both phases. Weight gain was not associated with any adrenergic gene. Our results suggest that genetic polymorphisms in the adrenergic system may not play a major role in AP-induced weight gain; however, adrenergic 2A receptor gene that produced previously the most consistent associations with this phenotype showed a significant interaction with the monoamine oxidase A in weight gainers. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 29 | Behav Brain Funct 2011 -1 7: 42 |
| PMID | 21978760 |
| Title | Association study of monoamine oxidase A/B genes and schizophrenia in Han Chinese. |
| Abstract | Monoamine oxidases (MAOs) catalyze the metabolism of dopaminergic neurotransmitters. Polymorphisms of isoforms MAOA and MAOB have been implicated in the etiology of mental disorders such as schizophrenia. Association studies detected these polymorphisms in several populations, however the data have not been conclusive to date. Here, we investigated the association of MAOA and MAOB polymorphisms with schizophrenia in a Han Chinese population. Two functional single nucleotide polymorphisms (SNPs), rs6323 of MAOA and rs1799836 of MAOB, were selected for association analysis in 537 unrelated schizophrenia patients and 536 healthy controls. Single-locus and Haplotype associations were calculated. No differences were found in the allelic distribution of rs6323. The G allele of rs1799836 was identified as a risk factor in the development of schizophrenia (P = 0.00001). The risk haplotype rs6323T-rs1799836G was associated with schizophrenia in female patients (P = 0.0002), but the frequency difference was not significant among male groups. Our results suggest that MAOB is a susceptibility gene for schizophrenia. In contrast, no significant associations were observed for the MAOA functional polymorphism with schizophrenia in Han Chinese. These data support further investigation of the role of MAO genes in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 30 | Front Psychiatry 2012 -1 3: 32 |
| PMID | 22529823 |
| Title | Connectomic intermediate phenotypes for psychiatric disorders. |
| Abstract | Psychiatric disorders are phenotypically heterogeneous entities with a complex genetic basis. To mitigate this complexity, many investigators study so-called intermediate phenotypes (IPs) that putatively provide a more direct index of the physiological effects of candidate genetic risk variants than overt psychiatric syndromes. Magnetic resonance imaging (MRI) is a particularly popular technique for measuring such phenotypes because it allows interrogation of diverse aspects of brain structure and function in vivo. Much of this work however, has focused on relatively simple measures that quantify variations in the physiology or tissue integrity of specific brain regions in isolation, contradicting an emerging consensus that most major psychiatric disorders do not arise from isolated dysfunction in one or a few brain regions, but rather from disturbed interactions within and between distributed neural circuits; i.e., they are disorders of brain connectivity. The recent proliferation of new MRI techniques for comprehensively mapping the entire connectivity architecture of the brain, termed the human connectome, has provided a rich repertoire of tools for understanding how genetic variants implicated in mental disorder impact distinct neural circuits. In this article, we review research using these connectomic techniques to understand how genetic variation influences the connectivity and topology of human brain networks. We highlight recent evidence from twin and imaging genetics studies suggesting that the penetrance of candidate risk variants for mental illness, such as those in SLC6A4, MAOA, ZNF804A, and APOE, may be higher for IPs characterized at the level of distributed neural systems than at the level of spatially localized brain regions. The findings indicate that imaging connectomics provides a powerful framework for understanding how genetic risk for psychiatric disease is expressed through altered structure and function of the human connectome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 31 | BMC Neurosci 2012 -1 13: 95 |
| PMID | 22867132 |
| Title | Testosterone regulation of sex steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra. |
| Abstract | Increased risk of schizophrenia in adolescent males indicates that a link between the development of dopamine-related psychopathology and testosterone-driven brain changes may exist. However, contradictions as to whether testosterone increases or decreases dopamine neurotransmission are found and most studies address this in adult animals. Testosterone-dependent actions in neurons are direct via activation of androgen receptors (AR) or indirect by conversion to 17?-estradiol and activation of estrogen receptors (ER). How midbrain dopamine neurons respond to sex steroids depends on the presence of sex steroid receptor(s) and the level of steroid conversion enzymes (aromatase and 5?-reductase). We investigated whether gonadectomy and sex steroid replacement could influence dopamine levels by changing tyrosine hydroxylase (TH) protein and mRNA and/or dopamine breakdown enzyme mRNA levels [catechol-O-methyl transferase (COMT) and monoamine oxygenase (MAO) A and B] in the adolescent male rat substantia nigra. We hypothesized that adolescent testosterone would regulate sex steroid signaling through regulation of ER and AR mRNAs and through modulation of aromatase and 5?-reductase mRNA levels. We find ER? and AR in midbrain dopamine neurons in adolescent male rats, indicating that dopamine neurons are poised to respond to circulating sex steroids. We report that androgens (T and DHT) increase TH protein and increase COMT, MAOA and MAOB mRNAs in the adolescent male rat substantia nigra. We report that all three sex steroids increase AR mRNA. Differential action on ER pathways, with ER? mRNA down-regulation and ER? mRNA up-regulation by testosterone was found. 5? reductase-1 mRNA was increased by AR activation, and aromatase mRNA was decreased by gonadectomy. We conclude that increased testosterone at adolescence can shift the balance of sex steroid signaling to favor androgenic responses through promoting conversion of T to DHT and increasing AR mRNA. Further, testosterone may increase local dopamine synthesis and metabolism, thereby changing dopamine regulation within the substantia nigra. We show that testosterone action through both AR and ERs modulates synthesis of sex steroid receptor by altering AR and ER mRNA levels in normal adolescent male substantia nigra. Increased sex steroids in the brain at adolescence may alter substantia nigra dopamine pathways, increasing vulnerability for the development of psychopathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 32 | Pharmacol Rep 2012 -1 64: 528-35 |
| PMID | 22814006 |
| Title | Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients. |
| Abstract | Therapeutic effects of all clinically used antipsychotics are related to the reduction of dopaminergic transmission in the limbic system. The aim of present study was two-fold. First, efficacy of atypical drugs (ziprasidone and olanzapine) against schizophrenia symptoms was compared to that offered by a typical antipsychotic medication, perazine. Second, associations between some dopaminergic genes polymorphisms and therapeutic response to antipsychotics were assessed in the same group of schizophrenia patients. One hundred ninety one Caucasian patients admitted with exacerbation of paranoid schizophrenia were genotyped for polymorphisms of the DRD2 [the ins/del -141C (rs1799732) and exon 8 (rs 71653615)], DRD2/ANKK1 Taq IA(rs 1800497), DAT1 (the 40 bp VNTR), COMT (rs 4680), and MAOA gene (the 30 bp VNTR in promoter). The patients were randomly assigned to the treatment with perazine, olanzapine or ziprasidone given as monotherapy for 3 months. Treatment efficacy was measured from baseline (T0) to T1 (14 days) and T2 (3 months). A retention rate was also assessed at T1 and T2. The three antipsychotics did not differ in terms of reduction of the PANSS score or retention rate at the follow-up. There was no interaction between the investigated polymorphisms and response to the antipsychotic treatment. The present results suggest that: i) there are no major differences in short-term efficacy or effectiveness of atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs; ii) the studied polymorphisms are not primarily involved in treatment response to antipsychotics in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 33 | Pharmacol Rep 2012 -1 64: 528-35 |
| PMID | 22814006 |
| Title | Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients. |
| Abstract | Therapeutic effects of all clinically used antipsychotics are related to the reduction of dopaminergic transmission in the limbic system. The aim of present study was two-fold. First, efficacy of atypical drugs (ziprasidone and olanzapine) against schizophrenia symptoms was compared to that offered by a typical antipsychotic medication, perazine. Second, associations between some dopaminergic genes polymorphisms and therapeutic response to antipsychotics were assessed in the same group of schizophrenia patients. One hundred ninety one Caucasian patients admitted with exacerbation of paranoid schizophrenia were genotyped for polymorphisms of the DRD2 [the ins/del -141C (rs1799732) and exon 8 (rs 71653615)], DRD2/ANKK1 Taq IA(rs 1800497), DAT1 (the 40 bp VNTR), COMT (rs 4680), and MAOA gene (the 30 bp VNTR in promoter). The patients were randomly assigned to the treatment with perazine, olanzapine or ziprasidone given as monotherapy for 3 months. Treatment efficacy was measured from baseline (T0) to T1 (14 days) and T2 (3 months). A retention rate was also assessed at T1 and T2. The three antipsychotics did not differ in terms of reduction of the PANSS score or retention rate at the follow-up. There was no interaction between the investigated polymorphisms and response to the antipsychotic treatment. The present results suggest that: i) there are no major differences in short-term efficacy or effectiveness of atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs; ii) the studied polymorphisms are not primarily involved in treatment response to antipsychotics in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 34 | J Clin Psychopharmacol 2012 Jun 32: 394-7 |
| PMID | 22544010 |
| Title | Different impacts of aquaporin 4 and MAOA allele variation among olanzapine, risperidone, and paliperidone in schizophrenia. |
| Abstract | Apoptosis has been considered to be involved in schizophrenia. Water channels are modulated just before apoptosis. In the aquaporin family, aquaporin 4 (AQP-4) is most highly expressed in the brain and is supposed to play an important role in a neuronal environment. In this clinical study, we investigated the relationship between the AQP-4 polymorphism and drug response in schizophrenia under the control of the MAOA (monoamine oxidase A) promoter gene. We recruited 91 patients with schizophrenia, and they were randomized to receive olanzapine (n = 44), risperidone (n = 23), or paliperidone (n = 24). Genotyping of AQP-4 and MAOA polymorphisms was done in all patients. Patients with the AQP-4 non-C polymorphism needed a higher dosage of olanzapine for treatment (z = 4.163, P = 0.041), and patients with a short form of the MAOA polymorphism needed a higher dosage of risperidone for treatment (z = 5.124, P = 0.024). Patients who smoked cigarettes needed a higher dosage of olanzapine for treatment (z = 4.905, P = 0.027), but cigarette smoking did not affect the dosage of paliperidone. The AQP-4 polymorphism may have an effect in influencing the dosage of olanzapine. However, the roles of AQP-4 polymorphisms in the blood-brain barrier and different neuroprotective effects need further exploration in future studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 35 | ISRN Psychiatry 2012 -1 2012: 852949 |
| PMID | 23738213 |
| Title | Monoamine oxidase a and B gene polymorphisms and negative and positive symptoms in schizophrenia. |
| Abstract | Given that schizophrenia is a heterogeneous disorder, the analysis of clinical characteristics could help to identify homogeneous phenotypes that may be of relevance in genetic studies. Linkage and association studies have suggested that a locus predisposing to schizophrenia may reside within Xp11. We analyzed uVNTR and rs1137070, polymorphisms from MAOA and rs1799836 of MAOB genes to perform single SNP case-control association study in a sample of 344 schizophrenia patients and 124 control subjects. Single polymorphism analysis of uVNTR, rs1137070 and rs1799836 SNPs did not show statistical differences between cases and controls. Multivariate ANOVA analysis of clinical characteristics showed statistical differences between MAOB/rs1799836 and affective flattening scores (F = 4.852, P = 0.009), and significant association between MAOA/uVNTR and affective flattening in female schizophrenia patients (F = 4.236, P = 0.016) after Bonferroni's correction. Our preliminary findings could suggest that severity of affective flattening may be associated by modifier variants of MAOA and MAOB genes in female Mexican patients with schizophrenia. However, further large-scale studies using quantitative symptom-based phenotypes and several candidate variants should be analyzed to obtain a final conclusion. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 36 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jan 159B: 104-11 |
| PMID | 22162429 |
| Title | Study of a possible role of the monoamine oxidase A (MAOA) gene in paranoid schizophrenia among a Chinese population. |
| Abstract | Monoamine oxidase A (MAOA) is the enzyme responsible for degradation of several monoamines, such as dopamine and serotonin that are considered as being two of the most important neurotransmitters involved in the pathophysiology of schizophrenia. To study a possible role of the MAOA gene in conferring susceptibility to schizophrenia, the present study genotyped the variable number of tandem repeat (VNTR) polymorphism and 41 SNPs across this gene among 555 unrelated patients with paranoid schizophrenia and 567 unrelated healthy controls. Quantitative real-time PCR analysis was employed to quantify expression of MAOA mRNA in 73 drug-free patients. While none of these genotyped DNA markers showed allelic association with paranoid schizophrenia, haplotypic association was found for the VNTR-rs6323, VNTR-rs1137070, and VNTR-rs6323-rs1137070 haplotypes in female subjects. Nevertheless, no significant change of the expression of MAOA mRNA was detected in either female or male patients with paranoid schizophrenia. Our study suggests that the interaction between genetic variants within the MAOA gene may contribute to an increased risk of paranoid schizophrenia, but the precise mechanism needs further investigation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 37 | Psychiatr. Genet. 2012 Feb 22: 42-5 |
| PMID | 21610556 |
| Title | Associations of MAOA-VNTR or 5HTT-LPR alleles with attention-deficit hyperactivity disorder symptoms are moderated by platelet monoamine oxidase B activity. |
| Abstract | The monoamine systems have been suggested to play a role in the biological basis of attention-deficit hyperactivity disorder (ADHD) symptoms. Thus, polymorphisms, for example, in the monoamine oxidase A (MAOA) and the serotonin transporter (5HTT) genes have been associated with ADHD-like phenotypes. Furthermore, platelet monoamine oxidase B (MAOB) activity has frequently been linked to impulsiveness-related traits. In this study, we have studied ADHD symptoms with regard to the combination of platelet MAOB activity and MAOA-variable number of tandem repeats (VNTR) or 5HTT-LPR genotype. The study group consisted of 156 adolescent twin pairs, that is, 312 individuals, who participated in a previous study. ADHD symptoms were scored with a structured clinical interview of both the twins and a parent using Kiddie Schedule for Affective Disorders and schizophrenia for School-Age Children-Present and Lifetime Version. The presence of a short 5HTT-LPR or short MAOA-VNTR allele, in combination with high levels of platelet MAOB enzyme activity was associated with higher scores of ADHD-like problems (P<0.001 and 0.01, respectively). This re-examination of ADHD scores in a nonclinical sample suggests that effects of MAOA-VNTR and 5HTT-LPR are moderated by platelet MAOB activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 38 | Hum. Genet. 2012 Jul 131: 1081-7 |
| PMID | 22198720 |
| Title | Effects of MAOA promoter methylation on susceptibility to paranoid schizophrenia. |
| Abstract | This study was undertaken to analyze DNA methylation profiling at the monoamine oxidase A (MAOA) locus, in order to determine whether abnormal DNA methylation is involved in the development of schizophrenia. We recruited a total of 371 patients with paranoid schizophrenia (199 males and 172 females) and 288 unrelated control subjects (123 males and 165 females) for analysis of DNA methylation. Diagnosis was made based on the Structured Clinical Interview for DSM-VI. Genomic DNA extracted from peripheral blood was chemically modified using bisulfite, and DNA methylation profiles of the MAOA promoter were determined by BSP-sequencing. DNA methylation ratios of individual CpG residues and overall methylation ratios were measured on each subject. The results showed that there was no significant difference in overall DNA methylation ratios between patients and controls either in the female group (P = 0.42) or in the male group (P = 0.24). Of 15 CpG residues that showed significant differences in DNA methylation status between the patient group and the control group in females, eight of which had an increased level and seven, a decreased level, with a combined P value of 1 (df = 160). In male subjects, however, six individual CpG residues showed an increased methylation level with a combined P value of 5.80E-35 (df = 158). In conclusion, abnormalities of DNA methylation at the MAOA promoter may be associated with schizophrenia in males. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 39 | Front Hum Neurosci 2013 -1 7: 1 |
| PMID | 23355817 |
| Title | Dopaminergic foundations of schizotypy as measured by the German version of the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE)-a suitable endophenotype of schizophrenia. |
| Abstract | The concept of schizotypy or "psychosis proneness" captures individual differences in perceptual, cognitive, and affective experiences that may relate to a range of psychotic disorders. The concept is an important way to assess the contribution of pre-existing psychological and genetically based biological features to the development of illnesses such as schizophrenia (so called endophenotypes). The Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE) is a widely used multi-dimensional measure of the construct and consists of four scales which mirror several groups of psychotic symptoms: Unusual Experiences (UnEx; positive symptoms), Cognitive Disorganization (CogDis; cognitive symptoms), Introvertive Anhedonia (IntAn; negative symptoms), and Impulsive Nonconformity (ImpNon; impulsive and antisocial symptoms). For the purpose of evaluating the suitability of schizotypy as an endophenotype of schizophrenia the current version of the O-LIFE was translated into German: its psychometric properties (including re-test reliability and construct validity) were examined in a large sample (n > 1200) and compared to those of the English original. The German version was both highly reliable and consistent with the original. The study aimed to show that schizotypy as measured by the O-LIFE can indeed be regarded as an endophenotype of schizophrenia in terms of genetic associations regarding relevant dopamine-related candidate polymorphisms of schizotypy [i.e., Val(158)Met-polymorphism of the COMT gene, uVNTR of the MAOA gene, Taq1A-polymorphism of the DRD2 gene, VNTR of the SLC6A3 (DAT) gene]. We also wanted to compare the genetic associations of the O-LIFE to those published using other operationalizations of schizotypy. Our results show a large number of significant associations and borderline-significant trends between the O-LIFE sub-scales and a range of genes, thereby supporting using the O-LIFE in the search for endophenotypic markers. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 40 | Front Hum Neurosci 2013 -1 7: 1 |
| PMID | 23355817 |
| Title | Dopaminergic foundations of schizotypy as measured by the German version of the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE)-a suitable endophenotype of schizophrenia. |
| Abstract | The concept of schizotypy or "psychosis proneness" captures individual differences in perceptual, cognitive, and affective experiences that may relate to a range of psychotic disorders. The concept is an important way to assess the contribution of pre-existing psychological and genetically based biological features to the development of illnesses such as schizophrenia (so called endophenotypes). The Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE) is a widely used multi-dimensional measure of the construct and consists of four scales which mirror several groups of psychotic symptoms: Unusual Experiences (UnEx; positive symptoms), Cognitive Disorganization (CogDis; cognitive symptoms), Introvertive Anhedonia (IntAn; negative symptoms), and Impulsive Nonconformity (ImpNon; impulsive and antisocial symptoms). For the purpose of evaluating the suitability of schizotypy as an endophenotype of schizophrenia the current version of the O-LIFE was translated into German: its psychometric properties (including re-test reliability and construct validity) were examined in a large sample (n > 1200) and compared to those of the English original. The German version was both highly reliable and consistent with the original. The study aimed to show that schizotypy as measured by the O-LIFE can indeed be regarded as an endophenotype of schizophrenia in terms of genetic associations regarding relevant dopamine-related candidate polymorphisms of schizotypy [i.e., Val(158)Met-polymorphism of the COMT gene, uVNTR of the MAOA gene, Taq1A-polymorphism of the DRD2 gene, VNTR of the SLC6A3 (DAT) gene]. We also wanted to compare the genetic associations of the O-LIFE to those published using other operationalizations of schizotypy. Our results show a large number of significant associations and borderline-significant trends between the O-LIFE sub-scales and a range of genes, thereby supporting using the O-LIFE in the search for endophenotypic markers. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 41 | Behav Brain Funct 2014 -1 10: 26 |
| PMID | 25073638 |
| Title | Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis. |
| Abstract | Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major monoamine metabolites in the central nervous system (CNS). Their cerebrospinal fluid (CSF) concentrations, reflecting the monoamine turnover rates in CNS, are partially under genetic influence and have been associated with schizophrenia. We have hypothesized that CSF monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms (SNPs) in genes implicated in monoaminergic pathways and psychosis. We have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [tryptophan hydroxylase 1 (TPH1), TPH2, tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), dopamine beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), monoamine oxidase A (MAOA) and MAOB] and monoamine metabolite concentrations in CSF in 74 patients with psychotic disorder. There were 42 nominally significant associations between SNPs and CSF monoamine metabolite concentrations, which exceeded the expected number (20) of nominal associations given the total number of tests performed. The strongest association (p = 0.0004) was found between MAOB rs5905512, a SNP previously reported to be associated with schizophrenia in men, and MHPG concentrations in men with psychotic disorder. Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls. The present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 42 | Psychiatry Res 2014 Oct 219: 261-7 |
| PMID | 24930580 |
| Title | Pharmacogenetics of adverse events in schizophrenia treatment: comparison study of ziprasidone, olanzapine and perazine. |
| Abstract | The primary aim of the present study was to assess the possible associations between dopaminergic, serotonergic, and glutamatergic system-related genes and adverse events after antipsychotic treatment in paranoid schizophrenia patients. The second aim of the study was to compare the intensity of these symptoms between atypical (ziprasidone and olanzapine) and typical (perazine) antipsychotic drugs. One-hundred and ninety-one Polish patients suffering from paranoid schizophrenia were genotyped for polymorphisms of DRD2, DAT1, COMT, MAOA, SERT, 5HT2A, and GRIK3. The patients were randomized to treatment with perazine, olanzapine or ziprasidone monotherapy for 3 months. The intensity of side effects (changes in body weights and extrapyramidal symptoms (EPS)) was measured at baseline and after 12 weeks of antipsychotic treatment. After 3 months of therapy, the weight increase was the greatest in the group treated with olanzapine and the least in the group treated with ziprasidone. None of the examined gene polymorphisms was associated with the body weight changes. Perazine treatment was associated with the significantly highest intensity of EPS. None of the examined polymorphisms was associated with the changes in extrapyramidal adverse events after antipsychotic treatment. The selected polymorphisms are not primarily involved in changes in body weights and EPS related to antipsychotic treatment in paranoid schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 43 | J. Child Neurol. 2014 Dec 29: NP207-11 |
| PMID | 24356376 |
| Title | Interaction between MAOA and FOXP2 in association with autism and verbal communication in a Korean population. |
| Abstract | Expression levels of monoamine oxidase A (MAOA), the enzyme that related to monoamine neurotransmitters metabolism such as serotonin, are related to schizophrenia and autism spectrum disorder. Forkhead box protein P2 (FOXP2), a transcription factor, is associated with abnormal language development and is expressed in several areas of the central nervous system in response to serotonin. For this reason, we undertook interaction analysis between MAOA and FOXP2 in autism spectrum disorder, including testing the verbal communication score of the childhood autism rating scale. In interaction analysis, the FOXP2-TCGC (rs12531289-rs1350135-rs10230087-rs2061183) diplotype and MAOA-TCG (rs6323-rs1801291-rs3027407) haplotype were significantly associated with autism spectrum disorder in males. However, when the interaction term was omitted, neither MAOA nor FOXP2 was associated with autism spectrum disorder or verbal communication. These results indicate that language and speech ability is affected by an interaction between FOXP2 and MAOA, but not by either gene separately. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 44 | Mol. Biol. Rep. 2014 May 41: 3457-64 |
| PMID | 24510409 |
| Title | Association study between monoamine oxidase A (MAOA) gene polymorphisms and schizophrenia: lack of association with schizophrenia and possible association with affective disturbances of schizophrenia. |
| Abstract | Monoamine oxidase A (MAOA) catalyzes monoamine neurotransmitters including dopamine, 5-hydroxytryptamine (5-HT, serotonin), and norepinephrine. MAOA also plays a key role in emotional regulation. The aim of this study was to investigate the associations between the exonic single nucleotide polymorphisms (SNPs) of the MAOA gene located on the X chromosome and schizophrenia. We also analyzed the relationships between these SNPs and the common clinical symptoms of schizophrenia such as persecutory delusion, auditory hallucinations, affective disturbances, and poor concentration. Two hundred seventy five Korean schizophrenia patients and 289 control subjects were recruited. Three SNPs [rs6323 (Arg294Arg), rs1137070 (Asp470Asp), and rs3027407 (3'-untranslated region)] of the MAOA gene were selected and genotyped by direct sequencing. The common clinical symptoms of schizophrenia according to the Operation Criteria Checklist were analyzed. Three examined SNPs showed no associations with male and female schizophrenia, respectively (p>0.05). In the analysis of the common clinical symptoms of schizophrenia patients, three examined SNPs were associated with affective disturbances, especially restricted affect and blunted affect in male schizophrenia, respectively (restricted affect, p=0.002, OR=2.71, 95% CI 1.45-5.00; blunted affect, p=0.009, OR 2.25, 95% CI 1.22-4.12). The SNPs were not associated with other clinical symptoms of schizophrenia (persecutory delusion, auditory hallucinations, and poor concentration). These results suggest that exonic SNPs (rs6323, rs1137070, and rs3027407) of the MAOA gene may be contributed to affective disturbances of Korean males schizophrenia, especially restricted affect and blunted affect. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 45 | Mol. Neurobiol. 2015 Jul -1: -1 |
| PMID | 26227907 |
| Title | MAOA Variants and Genetic Susceptibility to Major Psychiatric Disorders. |
| Abstract | Monoamine oxidase A (MAOA) is a mitochondrial enzyme involved in the metabolism of several biological amines such as dopamine, norepinephrine, and serotonin, which are important neurochemicals in the pathogenesis of major psychiatric illnesses. MAOA is regarded as a functional plausible susceptibility gene for psychiatric disorders, whereas previous hypothesis-driven association studies obtained controversial results, a reflection of small sample size, genetic heterogeneity, or true negative associations. In addition, MAOA is not analyzed in most of genome-wide association studies (GWAS) on psychiatric disorders, since it is located on Chromosome Xp11.3. Therefore, the effects of MAOA variants on genetic predisposition to psychiatric disorders remain obscure. To fill this gap, we collected psychiatric phenotypic (schizophrenia, bipolar disorder, and major depressive disorder) and genetic data in up to 18,824 individuals from diverse ethnic groups. We employed classical fixed (or random) effects inverse variance weighted methods to calculate summary odds ratios (OR) and 95 % confidence intervals (CI). We identified a synonymous SNP rs1137070 showing significant associations with major depressive disorder (p?=?0.00067, OR?=?1.263 for T allele) and schizophrenia (p?=?0.0039, OR?=?1.225 for T allele) as well as a broad spectrum of psychiatric phenotype (p?=?0.000066, OR?=?1.218 for T allele) in both males and females. The effect size was similar between different ethnic populations and different gender groups. Collectively, we confirmed that MAOA is a risk gene for psychiatric disorders, and our results provide useful information toward a better understanding of genetic mechanism involving MAOA underlying risk of complex psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 46 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2016 Aug 69: 131-46 |
| PMID | 26851573 |
| Title | Monoamine oxidase and agitation in psychiatric patients. |
| Abstract | Subjects with schizophrenia or conduct disorder display a lifelong pattern of antisocial, aggressive and violent behavior and agitation. Monoamine oxidase (MAO) is an enzyme involved in the degradation of various monoamine neurotransmitters and neuromodulators and therefore has a role in various psychiatric and neurodegenerative disorders and pathological behaviors. Platelet MAO-B activity has been associated with psychopathy- and aggression-related personality traits, while variants of the MAOA and MAOB genes have been associated with diverse clinical phenotypes, including aggressiveness, antisocial problems and violent delinquency. The aim of the study was to evaluate the association of platelet MAO-B activity, MAOB rs1799836 polymorphism and MAOA uVNTR polymorphism with severe agitation in 363 subjects with schizophrenia and conduct disorder. The results demonstrated significant association of severe agitation and smoking, but not diagnosis or age, with platelet MAO-B activity. Higher platelet MAO-B activity was found in subjects with severe agitation compared to non-agitated subjects. Platelet MAO-B activity was not associated with MAOB rs1799836 polymorphism. These results suggested the association between increased platelet MAO-B activity and severe agitation. No significant association was found between severe agitation and MAOA uVNTR or MAOB rs1799836 polymorphism, revealing that these individual polymorphisms in MAO genes are not related to severe agitation in subjects with schizophrenia and conduct disorder. As our study included 363 homogenous Caucasian male subjects, our data showing this negative genetic association will be a useful addition to future meta-analyses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |