| 1 | Mol. Psychiatry 2001 May 6: 293-301 |
|---|---|
| PMID | 11326297 |
| Title | Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. |
| Abstract | Complex defects in neuronal signaling may underlie the dysfunctions that characterize schizophrenia. Using cDNA microarrays, we discovered that the transcript encoding regulator of G-protein signaling 4 (RGS4) was the most consistently and significantly decreased in the prefrontal cortex of all schizophrenic subjects examined. The expression levels of ten other RGS family members represented on the microarrays were unchanged and hierarchical data analysis revealed that as a group, 274 genes associated with G-protein signaling were unchanged. Quantitative in situ hybridization verified the microarray RGS4 data, and demonstrated highly correlated decreases in RGS4 expression across three cortical areas of ten subjects with schizophrenia. RGS4 expression was not altered in the prefrontal cortex of subjects with major depressive disorder or in monkeys treated chronically with haloperidol. Interestingly, targets for 70 genes mapped to the major schizophrenia susceptibility locus 1q21--22 were present on the microarrays, of which only RGS4 gene expression was consistently altered. The combined data indicate that a decrease in RGS4 expression may be a common and specific feature of schizophrenia, which could be due either to genetic factors or a disease- specific adaptation, both of which could affect neuronal signaling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 2 | Mol. Psychiatry 2001 May 6: 293-301 |
| PMID | 11326297 |
| Title | Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. |
| Abstract | Complex defects in neuronal signaling may underlie the dysfunctions that characterize schizophrenia. Using cDNA microarrays, we discovered that the transcript encoding regulator of G-protein signaling 4 (RGS4) was the most consistently and significantly decreased in the prefrontal cortex of all schizophrenic subjects examined. The expression levels of ten other RGS family members represented on the microarrays were unchanged and hierarchical data analysis revealed that as a group, 274 genes associated with G-protein signaling were unchanged. Quantitative in situ hybridization verified the microarray RGS4 data, and demonstrated highly correlated decreases in RGS4 expression across three cortical areas of ten subjects with schizophrenia. RGS4 expression was not altered in the prefrontal cortex of subjects with major depressive disorder or in monkeys treated chronically with haloperidol. Interestingly, targets for 70 genes mapped to the major schizophrenia susceptibility locus 1q21--22 were present on the microarrays, of which only RGS4 gene expression was consistently altered. The combined data indicate that a decrease in RGS4 expression may be a common and specific feature of schizophrenia, which could be due either to genetic factors or a disease- specific adaptation, both of which could affect neuronal signaling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 3 | Hum. Mol. Genet. 2002 Jun 11: 1373-80 |
| PMID | 12023979 |
| Title | Association and linkage analyses of RGS4 polymorphisms in schizophrenia. |
| Abstract | Gene expression analyses of postmortem cerebral cortex suggest that transcription of the regulator of G-protein signaling 4 (RGS4) is decreased in a diagnosis-specific manner in subjects with schizophrenia. To evaluate the possible role of RGS4 in the pathogenesis of schizophrenia, we conducted genetic association and linkage studies using samples ascertained independently in Pittsburgh and New Delhi and by the NIMH Collaborative Genetics Initiative. Using the transmission disequilibrium test, significant transmission distortion was observed in the Pittsburgh and NIMH samples. Among single-nucleotide polymorphisms (SNPs) spanning approximately 300 kb, significant associations involved four SNPs localized to a 10 kb region at RGS4, but the associated haplotypes differed. A trend for transmission distortion was also present in the Indian sample for haplotypes incorporating the same SNPs. Consistent with the linkage/association observed from the family-based tests, samples with affected siblings (NIMH, India) showed higher levels of allele sharing, identical by descent, at RGS4. When the US patients were contrasted to two population-based control samples, however, no significant differences were observed. To check the specificity of the transmission bias, we therefore examined US families with bipolar I disorder (BD1) probands. This sample also showed a trend for transmission distortion, and differed significantly from the population-based controls for the four-SNP haplotypes tested in the other samples. The transmission distortion is unlikely to be due to chance, but its mechanism and specificity require further study. Our results illustrate the potential power of combining gene expression profiling and genomic analyses to identify susceptibility genes for genetically complex disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 4 | Hum. Mol. Genet. 2003 Oct 12 Spec No 2: R125-33 |
| PMID | 12952866 |
| Title | Recent advances in the genetics of schizophrenia. |
| Abstract | The high heritability of schizophrenia has stimulated much work aimed at identifying susceptibility genes using positional genetics. As a result, several strong and well-established linkages have emerged. Three of the best-supported regions are 6p24-22, 1q21-22 and 13q32-34 where single studies have achieved genome-wide significance at P<0.05 and suggestive positive findings have also been reported in other samples. Other promising regions include 8p21-22, 6q21-25, 22q11-12, 5q21-q33, 10p15-p11 and 1q42. Recently, evidence implicating individual genes within some of the linked regions has been reported and more importantly replicated. Currently, the weight of evidence supports NRG1 and DTNBP1 as schizophrenia susceptibility loci, though work remains before we understand precisely how genetic variation at each locus confers susceptibility and protection. The evidence for COMT, RGS4 and G72 is promising but not yet persuasive. While it is essential that further replications are established, the respective contributions of each gene, relationships with aspects of the phenotype, the possibility of epistatic interactions between genes and functional interactions between the gene products will all need investigation. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research, and all the signs are that genetic research is poised to deliver crucial insights into the nature of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 5 | Curr Psychiatry Rep 2004 Aug 6: 303-12 |
| PMID | 15260947 |
| Title | The genes for schizophrenia: finally a breakthrough? |
| Abstract | A number of susceptibility genes for schizophrenia have recently been identified. They have engendered excitement because replicate studies have attained greater consistency than in the past. In this review, we outline gene mapping methods, and briefly review their strengths and challenges. We also evaluate peer-reviewed genetic association studies that have implicated six selected genes: catechol-O-methyl transferase (COMT), neuregulin 1 (NRG1), dysbindin (DTNBP1), regulator of G-protein signaling 4 (RGS4), and G72 and D-amino-acid oxidase (DAAO). The available supporting evidence is variable. Though credible evidence is available for all of these genes, it is strongest for NRG1 and DTNBP1. Further studies, particularly exhaustive analyses of all polymorphisms at each locus, meta-analyses, and investigations of the likely function of risk alleles (variants) are desirable. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 6 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Aug 129B: 23-6 |
| PMID | 15274033 |
| Title | Regulator of G-protein signaling 4 (RGS4) gene is associated with schizophrenia in Irish high density families. |
| Abstract | The regulator of the G-protein signaling 4 (RGS4) gene was shown to have a different expression pattern in schizophrenia patients in a microarray study. A family-based study subsequently implicated the association of this gene with schizophrenia. We replicated the study with our sample from the Irish Study of High Density schizophrenia Families (ISHDSF). Single marker transmission disequilibrium tests (TDT) for the four core SNPs showed modest association for SNP 18 (using a narrow diagnostic approach with FBAT P = 0.044; with PDT P = 0.0073) and a trend for SNP 4 (with FBAT P = 0.1098; with PDT P = 0.0249). For SNP 1 and 7, alleles overtransmitted to affected subjects were the same as previously reported. Haplotype analyses suggested that haplotype G-G-G for SNP1-4-18, which is the most abundant haplotype (42.3%) in the Irish families, was associated with the disease (narrow diagnosis, FBAT P = 0.0061, PDT P = 0.0498). This was the same haplotype implicated in the original study. While P values were not corrected for multiple testing because of the clear prior hypothesis, these results could be interpreted as supporting evidence for the association between RGS4 and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 7 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Feb 125B: 50-3 |
| PMID | 14755443 |
| Title | Confirming RGS4 as a susceptibility gene for schizophrenia. |
| Abstract | A recent study identified a putative association between variants in the regulator of G-protein signalling 4 (RGS4) and schizophrenia, Chowdari et al. [2002: Hum Mol Genet 11: 1373-1380]. RGS4 is both a positional and functional candidate gene for schizophrenia. Chowdari and colleagues identified association at this locus in a number of distinct and ethnically diverse samples, although the pattern of association was not the same in all the samples. Our study attempted to replicate this association in an independent Irish sample of schizophrenia cases and controls. We succeeded in detecting evidence of association at the RGS4 locus. The signal comes from a four-marker haplotype that is in significant excess in our case sample. The same haplotype is in excess in the Caucasian schizophrenia sample used by Chowdari et al. [2002: Hum Mol Genet 11: 1373-1380]. This study provides further support for the contribution of RGS4 to schizophrenia susceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 8 | Biol. Psychiatry 2004 Jan 55: 192-5 |
| PMID | 14732600 |
| Title | Support for RGS4 as a susceptibility gene for schizophrenia. |
| Abstract | The gene encoding the regulator of G-protein signaling 4 has recently been associated with susceptibility to schizophrenia. This finding is particularly interesting, because it was replicated within the same study and also because there are functional, positional, and expression data to support the regulator of G-protein signaling 4 as a schizophrenia candidate gene. Although the original report was highly suggestive, a limitation was that the study was conducted on rather small samples. We have examined a large case (n = 709) control (n = 710) sample for association between schizophrenia using four markers investigated in the earlier study, denoted single nucleotide polymorphisms 1, 4, 7, and 18. We were able to replicate the associations with single nucleotide polymorphisms 4 and 18 that had previously been reported individually and have also identified significant association with haplotypes constructed from single nucleotide polymorphisms 1 and 4. Our data give modest support for the hypothesis that the regulator of G-protein signaling 4 is a susceptibility gene for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 9 | Wien. Klin. Wochenschr. 2004 Dec 116: 827-33 |
| PMID | 15690966 |
| Title | [In search of susceptibility genes for schizophrenia]. |
| Abstract | After the recent discovery and replication of several schizophrenia candidate regions on multiple chromosomes, susceptibility genes for schizophrenia could be identified for the first time. Each of these discoveries resulted from association studies within chromosomal regions first identified by linkage analyses. Within the last two years, the susceptibility genes Neuregulin1, Dysbindin, D-amino-acid-oxidase (DAAO) and G72 were discovered, which, in the variant forms, reduce glutamatergic activity in brain. Therefore, they are related to the so-called "Glutamate-hypothesis", which postulates a hypofunction of the glutamatergic system. Adults with VCFS (velo-cardio-facial-syndrome), where a deletion on chromosome 22q11 can be found, show a very high incidence of schizophrenia. In addition, 2% of patients with schizophrenia exhibit this 22q11-deletion. Within the VCFS-deleted region on chromosome 22q11, the genes coding for proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT) were also found to be significantly associated with schizophrenia. Proline is a pre-stage of glutamate, and in addition, it seems to be a neuromodulator of glutamatergic transmission in the brain. COMT is one of the two enzymes degrading catecholamines such as dopamine. Therefore, it plays a large role in the cortical dopamine metabolism. Furthermore, an association of schizophrenia with the gene RGS4 (regulator-of-G-protein-signaling-4), a modulator of the function of multiple G-protein-linked neurotransmitter receptors, was identified. Gene-expression-analyses of postmortem cerebral cortex (prefrontal) indicate that the transcription of RGS4 is diminished within schizophrenics. In accordance with the fact that schizophrenia is a disease with a multifactorial etiology, it should be emphasized that the described biological risk factors can increase susceptibility, but that none of them can cause the disease alone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 10 | Wien. Klin. Wochenschr. 2004 Dec 116: 827-33 |
| PMID | 15690966 |
| Title | [In search of susceptibility genes for schizophrenia]. |
| Abstract | After the recent discovery and replication of several schizophrenia candidate regions on multiple chromosomes, susceptibility genes for schizophrenia could be identified for the first time. Each of these discoveries resulted from association studies within chromosomal regions first identified by linkage analyses. Within the last two years, the susceptibility genes Neuregulin1, Dysbindin, D-amino-acid-oxidase (DAAO) and G72 were discovered, which, in the variant forms, reduce glutamatergic activity in brain. Therefore, they are related to the so-called "Glutamate-hypothesis", which postulates a hypofunction of the glutamatergic system. Adults with VCFS (velo-cardio-facial-syndrome), where a deletion on chromosome 22q11 can be found, show a very high incidence of schizophrenia. In addition, 2% of patients with schizophrenia exhibit this 22q11-deletion. Within the VCFS-deleted region on chromosome 22q11, the genes coding for proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT) were also found to be significantly associated with schizophrenia. Proline is a pre-stage of glutamate, and in addition, it seems to be a neuromodulator of glutamatergic transmission in the brain. COMT is one of the two enzymes degrading catecholamines such as dopamine. Therefore, it plays a large role in the cortical dopamine metabolism. Furthermore, an association of schizophrenia with the gene RGS4 (regulator-of-G-protein-signaling-4), a modulator of the function of multiple G-protein-linked neurotransmitter receptors, was identified. Gene-expression-analyses of postmortem cerebral cortex (prefrontal) indicate that the transcription of RGS4 is diminished within schizophrenics. In accordance with the fact that schizophrenia is a disease with a multifactorial etiology, it should be emphasized that the described biological risk factors can increase susceptibility, but that none of them can cause the disease alone. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 11 | Mol. Psychiatry 2004 Jan 9: 14-27 |
| PMID | 14581932 |
| Title | The molecular genetics of schizophrenia: new findings promise new insights. |
| Abstract | The high heritability of schizophrenia has stimulated much work aimed at identifying susceptibility genes using positional genetics. However, difficulties in obtaining clear replicated linkages have led to the scepticism that such approaches would ever be successful. Fortunately, there are now signs of real progress. Several strong and well-established linkages have emerged. Three of the best-supported regions are 6p24-22, 1q21-22 and 13q32-34. In these cases, single studies achieved genome-wide significance at P<0.05 and suggestive positive findings have also been reported in other samples. The other promising regions include 8p21-22, 6q21-25, 22q11-12, 5q21-q33, 10p15-p11 and 1q42. The study of chromosomal abnormalities in schizophrenia has also added to the evidence for susceptibility loci at 22q11 and 1q42. Recently, evidence implicating individual genes within some of the linked regions has been reported and more importantly replicated. The weight of evidence now favours NRG1 and DTNBP1 as susceptibility loci, though work remains before we understand precisely how genetic variation at each locus confers susceptibility and protection. The evidence for catechol-O-methyl transferase, RGS4 and G72 is promising but not yet persuasive. While further replications remain the top priority, the respective contributions of each gene, relationships with aspects of the phenotype, the possibility of epistatic interactions between genes and functional interactions between the gene products will all need investigation. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research, and all the signs are that it is now poised to deliver crucial insights into the nature of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 12 | Eur. J. Neurosci. 2004 Jun 19: 3125-8 |
| PMID | 15182322 |
| Title | Regional expression of RGS4 mRNA in human brain. |
| Abstract | Regulators of G-protein signalling (RGS) proteins are a recently discovered class of proteins that modulate G-protein activity. More than 20 RGS proteins have been identified and are expressed throughout the body and brain. In particular, RGS4 appears to regulate dopamine receptor function and has been implicated in several dopamine related diseases, including schizophrenia. This study presents an extensive examination of the regional distribution of RGS4 mRNA in postmortem human brain. Using in situ hybridization, the expression levels of RGS4 mRNA were determined in human hemicoronal (Talairach sections +8 and -20) brain sections. In the rostral slice (Talairach +8) highest levels were found in the inferior frontal cortex, the superior frontal, and the cingulate cortex. Slightly lower levels were found in the insular cortex and inferior temporal cortex. The caudate, putamen and nucleus accumbens had lower levels. In the caudal slice (-20), the cortical layers showed the highest levels, with moderate levels observed in the parahippocampal gyrus, low levels in the CA-pyramidal region, and almost undetectable levels in the thalamus. In the frontal cortex a dense band was apparent near one of the inner layers of the cortex. In conclusion, RGS4 mRNA distribution in human postmortem tissue from normal persons was very dense in most cortical layers examined, with lower density in the basal ganglia and thalamus. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 13 | Br. Med. Bull. 2005 -1 73-74: 107-22 |
| PMID | 16365481 |
| Title | Psychiatric genetics--the new era: genetic research and some clinical implications. |
| Abstract | Impressive advances in the last decade have been made in the genetics and neuroscience of neuropsychiatric illness. Synergies between complex genetics, elaboration of intermediate phenotypes (Egan et al. (2004) schizophrenia. London: Blackwell) and novel applications in neuroimaging (Bookheimer et al. (2000) N Engl J Med, 343, 450-456) are revealing the effects of positively associated disease alleles on aspects of neurological function. Genes such as NRG-1, DISC1, RGS4, COMT, PRODH, DTNBP1, G72, DAAO, GRM3 (Harrison and Weinberger (2005) Mol Psychiatry, 10, 40-68) and others have been implicated in schizophrenia along with 5-HTTPR (Ogilvie et al. (1996) Lancet, 347, 731-733; Caspi et al. (2003) Science, 301, 386-389) and BDNF (Geller et al. (2004) Am J Psychiatry, 161, 1698-1700) in affective disorders. As the genetics and complex neurocircuits of these and disorders are being untangled, parallel applications in pharmacogenomics and gene-based drug metabolism are shaping a drive for personalized medicine. Genetic research and pharmacogenomics suggest that the subcategorization of individuals based on various sets of susceptibility alleles will make the treatment of neuropsychiatric and other illnesses more predictable and effective. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 14 | J. Med. Genet. 2005 Mar 42: 193-204 |
| PMID | 15744031 |
| Title | The genetics of schizophrenia and bipolar disorder: dissecting psychosis. |
| Abstract | Much work has been done to identify susceptibility genes in schizophrenia and bipolar disorder. Several well established linkages have emerged in schizophrenia. Strongly supported regions are 6p24-22, 1q21-22, and 13q32-34, while other promising regions include 8p21-22, 6q16-25, 22q11-12, 5q21-q33, 10p15-p11, and 1q42. Genomic regions of interest in bipolar disorder include 6q16-q22, 12q23-q24, and regions of 9p22-p21, 10q21-q22, 14q24-q32, 13q32-q34, 22q11-q22, and chromosome 18. Recently, specific genes or loci have been implicated in both disorders and, crucially, replicated. Current evidence supports NRG1, DTNBP1, DISC1, DAOA(G72), DAO, and RGS4 as schizophrenia susceptibility loci. For bipolar disorder the strongest evidence supports DAOA(G72) and BDNF. Increasing evidence suggests an overlap in genetic susceptibility across the traditional classification systems that dichotomised psychotic disorders into schizophrenia or bipolar disorder, most notably with association findings at DAOA(G72), DISC1, and NRG1. Future identification of psychosis susceptibility genes will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 15 | Trends Genet. 2005 Sep 21: 518-25 |
| PMID | 16009449 |
| Title | Schizophrenia: genes at last? |
| Abstract | Genetic epidemiological studies suggest that individual variation in susceptibility to schizophrenia is largely genetic, reflecting alleles of moderate to small effect in multiple genes. Molecular genetic studies have identified several potential regions of linkage and two associated chromosomal abnormalities, and evidence is accumulating in favour of several positional candidate genes. Currently, the positional candidate genes for which we consider the evidence to be strong are those encoding dysbindin (DTNBP1) and neuregulin 1 (NRG1). For other genes, disrupted in schizophrenia 1 (DISC1), D-amino-acid oxidase (DAO), D-amino-acid oxidase activator (DAOA, formerly known as G72) and regulator of G-protein signalling 4 (RGS4), the data are promising but not yet compelling. The identification of these, and other susceptibility genes, will open up new avenues for research aimed at understanding the pathogenesis of schizophrenia, and will catalyse a re-appraisal of the classification of psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 16 | Mol. Cell. Biol. 2005 May 25: 4221-8 |
| PMID | 15870291 |
| Title | Generation and characterization of Rgs4 mutant mice. |
| Abstract | RGS proteins are negative regulators of signaling through heterotrimeric G protein-coupled receptors and, as such, are in a position to regulate a plethora of biological phenomena. However, those have just begun to be explored in vivo. Here, we describe a mouse line deficient for RGS4, a gene normally expressed early on in discrete populations of differentiating neurons and later on at multiple sites of the central nervous system, the cortex in particular, where it is one of the most highly transcribed Rgs genes. RGS4(lacZ/lacZ) mice had normal neural development and were viable and fertile. Behavioral testing on mutant adults revealed subtle sensorimotor deficits but, so far, supported neither the proposed status of RGS4 as a schizophrenia susceptibility gene (by showing intact prepulse inhibition in the mutants) nor (unlike another member of the Rgs family, Rgs9) a role of RGS4 in the acute or chronic response to opioids. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 17 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Nov 139B: 23-7 |
| PMID | 16082709 |
| Title | Failure to confirm association between RGS4 haplotypes and schizophrenia in Caucasians. |
| Abstract | The regulator of G-protein signaling (RGS) and RGS-like proteins are a diverse family of over 30 molecules that function as GTPase activating proteins for Galpha subunits of the Gq and Gi families of heterotrimeric guanine nucleotide-binding proteins (G proteins). By accelerating GTPase activity, RGS proteins drive G proteins into their inactive GDP-bound forms. G-protein coupled dopamine, metabotropic glutamate, and other neurotransmitter receptors can be modulated by RGS4, the predominant form in brain. The recent finding of decreased RGS4 mRNA expression in post-mortem brains from schizophrenic patients, coupled with the map position of RGS4 to a region previously linked to schizophrenia, as well as other biological data, prompted the investigation of the gene as a disease candidate. Multiple family-based and case-control association studies have been conducted, with modest and conflicting support for particular single nucleotide polymorphism (SNP) markers and SNP marker haplotypes. The present case-control analysis of 568 patients and 689 controls, one of the largest single studies to date, failed to confirm support for association of particular RGS4 SNP alleles, or for association of any particular four, three, or two SNP haplotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 18 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Nov 139B: 23-7 |
| PMID | 16082709 |
| Title | Failure to confirm association between RGS4 haplotypes and schizophrenia in Caucasians. |
| Abstract | The regulator of G-protein signaling (RGS) and RGS-like proteins are a diverse family of over 30 molecules that function as GTPase activating proteins for Galpha subunits of the Gq and Gi families of heterotrimeric guanine nucleotide-binding proteins (G proteins). By accelerating GTPase activity, RGS proteins drive G proteins into their inactive GDP-bound forms. G-protein coupled dopamine, metabotropic glutamate, and other neurotransmitter receptors can be modulated by RGS4, the predominant form in brain. The recent finding of decreased RGS4 mRNA expression in post-mortem brains from schizophrenic patients, coupled with the map position of RGS4 to a region previously linked to schizophrenia, as well as other biological data, prompted the investigation of the gene as a disease candidate. Multiple family-based and case-control association studies have been conducted, with modest and conflicting support for particular single nucleotide polymorphism (SNP) markers and SNP marker haplotypes. The present case-control analysis of 568 patients and 689 controls, one of the largest single studies to date, failed to confirm support for association of particular RGS4 SNP alleles, or for association of any particular four, three, or two SNP haplotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 19 | Mol. Psychiatry 2005 Feb 10: 213-9 |
| PMID | 15381923 |
| Title | Genetic polymorphisms of the RGS4 and dorsolateral prefrontal cortex morphometry among first episode schizophrenia patients. |
| Abstract | Polymorphisms of the gene encoding the regulator of G-protein signaling subtype 4 (RGS4) may confer risk for schizophrenia.(1) DNA microarray studies of postmortem brain samples have shown RGS4 underexpression in the dorsolateral prefrontal cortex (DLPFC, area 9), motor and visual cortices in schizophrenia patients relative to control subjects.(2) Underexpression of RGS4 in DLPFC is pathophysiologically significant because DLPFC pathology in schizophrenia has been supported by neurocognitive,(3,4) structural(5) and functional(6,7) imaging, postmortem,(8) cellular(9,10) and molecular(11) pathological studies. For these reasons, we examined the association of DLPFC gray matter volume with RGS4 polymorphisms in a series of antipsychotic-naive first-episode schizophrenia patients and control subjects. We hypothesized that volumetric alterations of the DLPFC would be associated with RGS4 polymorphisms and that these differences would be more pronounced in patients than in controls. We observed robust volumetric differences across the genotypes in the pooled sample of patients and control subjects; when separately analyzed, we observed differences within the patient group (n = 30) but not in control subject (n = 27) group. The findings suggest that RGS4 polymorphisms may contribute to structural alterations in the DLPFC. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 20 | Mol. Psychiatry 2005 Jan 10: 40-68; image 5 |
| PMID | 15263907 |
| Title | Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. |
| Abstract | This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 21 | Am. J. Hum. Genet. 2005 Dec 77: 918-36 |
| PMID | 16380905 |
| Title | Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. |
| Abstract | Bipolar, schizophrenia, and schizoaffective disorders are common, highly heritable psychiatric disorders, for which familial coaggregation, as well as epidemiological and genetic evidence, suggests overlapping etiologies. No definitive susceptibility genes have yet been identified for any of these disorders. Genetic heterogeneity, combined with phenotypic imprecision and poor marker coverage, has contributed to the difficulty in defining risk variants. We focused on families of Ashkenazi Jewish descent, to reduce genetic heterogeneity, and, as a precursor to genomewide association studies, we undertook a single-nucleotide polymorphism (SNP) genotyping screen of 64 candidate genes (440 SNPs) chosen on the basis of previous linkage or of association and/or biological relevance. We genotyped an average of 6.9 SNPs per gene, with an average density of 1 SNP per 11.9 kb in 323 bipolar I disorder and 274 schizophrenia or schizoaffective Ashkenazi case-parent trios. Using single-SNP and haplotype-based transmission/disequilibrium tests, we ranked genes on the basis of strength of association (P<.01). Six genes (DAO, GRM3, GRM4, GRIN2B, IL2RB, and TUBA8) met this criterion for bipolar I disorder; only DAO has been previously associated with bipolar disorder. Six genes (RGS4, SCA1, GRM4, DPYSL2, NOS1, and GRID1) met this criterion for schizophrenia or schizoaffective disorder; five replicate previous associations, and one, GRID1, shows a novel association with schizophrenia. In addition, six genes (DPYSL2, DTNBP1, G30/G72, GRID1, GRM4, and NOS1) showed overlapping suggestive evidence of association in both disorders. These results may help to prioritize candidate genes for future study from among the many suspected/proposed for schizophrenia and bipolar disorders. They provide further support for shared genetic susceptibility between these two disorders that involve glutamate-signaling pathways. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 22 | Mol. Psychiatry 2005 Mar 10: 299-308 |
| PMID | 15241434 |
| Title | Influenza A virus infection causes alterations in expression of synaptic regulatory genes combined with changes in cognitive and emotional behaviors in mice. |
| Abstract | Epidemiological studies have indicated a link between certain neuropsychiatric diseases and exposure to viral infections. In order to examine long-term effects on behavior and gene expression in the brain of one candidate virus, we have used a model involving olfactory bulb injection of the neuro-adapted influenza A virus strain, WSN/33, in C57Bl/6 mice. Following this olfactory route of invasion, the virus targets neurons in the medial habenular, midline thalamic and hypothalamic nuclei as well as monoaminergic neurons in the brainstem. The mice survive and the viral infection is cleared from the brain within 12 days. When tested 14-20 weeks after infection, the mice displayed decreased anxiety in the elevated plus-maze and impaired spatial learning in the Morris water maze test. Elevated transcriptional activity of two genes encoding synaptic regulatory proteins, regulator of G-protein signaling 4 and calcium/calmodulin-dependent protein kinase IIalpha, was found in the amygdala, hypothalamus and cerebellum. It is of particular interest that the gene encoding RGS4, which has been related to schizophrenia, showed the most pronounced alteration. This study indicates that a transient influenza virus infection can cause persistent changes in emotional and cognitive functions as well as alterations in the expression of genes involved in the regulation of synaptic activities. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 23 | Genes Brain Behav. 2005 Oct 4: 444-8 |
| PMID | 16176390 |
| Title | Association analysis of the RGS4 gene in Han Chinese and Scottish populations with schizophrenia. |
| Abstract | We investigated the RGS4 as a susceptibility gene for schizophrenia in Chinese Han (184 trios and 138 sibling pairs, a total of 322 families) and Scottish (580 cases and 620 controls) populations using both a family trio and case-control design. Both the samples had statistical power greater than 70% to detect a heterozygote genotype relative risk of >1.2 for frequent RGS4-risk alleles. We genotyped four single nucleotide polymorphisms (SNPs) which have previously been associated with schizophrenia as either individually or part of haplotypes. Allele frequencies and linkage disequilibrium between the SNPs was similar in the two populations. In the Chinese sample, no individual SNPs or any of their haplotypes were associated with schizophrenia. In the Scottish population, one SNP (SNP7) was significantly over-represented in the cases compared with the controls (0.44 vs. 0.38; A allele; chi(2) 7.08, P = 0.011 after correction for correlation between markers by permutation testing). One two-marker haplotype, composed of alleles T and A of SNP4 and SNP7, respectively, showed individual significance after correction by permutation testing (chi(2) 6.8; P = 0.04). None of the full four-marker haplotypes showed association, including the G-G-G-G haplotype previously associated with schizophrenia in more than one sample and the A-T-A-A haplotype. Thus, our data do not directly replicate previous associations of RGS4, but association with SNP 7 in the Scottish population provides some support for a role in schizophrenia susceptibility. We cannot conclusively exclude RGS4, as associated haplotypes are likely to be surrogates for unknown causative alleles, whose relationship with overlying haplotypes may differ between the population groups. Differences in the association seen across the two populations could result from methodological factors such as diagnostic differences but most likely result from ethnic differences in haplotype structures within RGS4. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 24 | Genes Brain Behav. 2005 Feb 4: 45-50 |
| PMID | 15660667 |
| Title | Association and linkage analysis of RGS4 polymorphisms with schizophrenia and bipolar disorder in Brazil. |
| Abstract | Linkage and association studies in five independently ascertained samples have suggested that polymorphisms of the regulator of G-protein signaling 4 (RGS4) may confer risk for schizophrenia (SCZ). Suggestive evidence for association with bipolar disorder (BD) has also been presented. However, the associated alleles and haplotypes have differed among the samples. Data from other independent samples may clarify the putative associations. Hence, we investigated an independent, ethnically diverse Brazilian population comprising patients with SCZ (n=271) or BD1 (n=306), who were contrasted with 576 community-based controls. Parents of 49 SCZ cases and 44 BD cases were available for transmission disequilibrium tests (TDTs). Four RGS4 single-nucleotide polymorphisms (SNPs) 1, 4, 7 and 18 putatively associated with SCZ were investigated. In the SCZ samples, significant case-control differences were not observed for individual SNPs or haplotypes, though the TDT suggested transmission distortion similar to that observed in the initial report. For the BD sample, case-control comparisons revealed no significant differences for individual SNPs, but an omnibus test suggested differences in the overall distribution of haplotypes bearing all four SNPs (SNP-EM Omnibus likelihood ratio test; P=0.003). The TDT revealed over-transmission of allele A at SNP7 (P=0.016), as well as haplotypes incorporating this allele. However, global tests incorporating all haplotypes yielded only suggestive trends for association (P=0.19). In conclusion, association with SCZ was not detected in the present analyses. The failure to detect an association may be related to inadequate power or to confounds related to ethnic admixture. Suggestive associations with BD detected here require further investigation in a larger sample. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 25 | Eur. J. Hum. Genet. 2006 Jun 14: 669-80 |
| PMID | 16721403 |
| Title | Molecular genetic studies of schizophrenia. |
| Abstract | The study of schizophrenia genetics has confirmed the importance of genes in etiology, but has not so far identified the relationship between observed genetic risks and specific DNA variants, protein alterations or biological processes. In spite of many limitations, numerous regions of the human genome give consistent, although by no means unanimous, support for linkage, which is unlikely to occur by chance. Two recent shifts have been evident in the field. First, a series of studies combining linkage and association analyses in the same family sets have identified promising candidate genes (DTNBP1, NRG1, G72/G30, TRAR4). Although a consensus definition of replication for genetic association in a complex trait remains difficult to achieve, the evidence for two of these (dystrobrevin binding protein 1 (DTNBP1), NRG1) is strong. Second, a series of studies combining association with functional investigation of changes in the associated gene in schizophrenia have also identified several candidate genes (COMT, RGS4, PPP3CC, ZDHHC8, AKT1). Somewhat surprisingly, the loci implicated by these studies have proven less robust in replication, although the number of replication studies remains small in several cases. Assessment of the combined evidence for the DTNBP1 gene gives some insight into the nature of the problems remaining to be solved. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 26 | Curr Opin Psychiatry 2006 Mar 19: 158-64 |
| PMID | 16612196 |
| Title | An update on the genetics of schizophrenia. |
| Abstract | This paper reviews recent molecular genetic studies of schizophrenia and evaluates claims implicating specific genes as susceptibility loci. Molecular genetic studies have identified several potential regions of linkage and two associated chromosomal abnormalities, and the evidence is accumulating in favour of several positional candidate genes. Currently, the strongest evidence for putative schizophrenia susceptibility loci relates to the genes encoding dysbindin (DTNBP1) and neuregulin (NRG1). For other genes, disrupted in schizophrenia (DISC1), D-amino acid oxidase activator (DAOA), regulator of G-protein signalling 4 (RGS4) and V-AKT murine thymoma viral oncogene homolog 1 (AKT1) the data are promising but not yet compelling. In the most convincing cases, the risk haplotypes appear to be associated with small effect sizes and do not fully explain the linkage findings that prompted each study. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research. Despite the accumulation of significant genetic data, however, the susceptibility variants have yet to be identified and detailed follow-up studies are now required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 27 | Eur. J. Hum. Genet. 2006 Sep 14: 1037-43 |
| PMID | 16736033 |
| Title | A summary statistic approach to sequence variation in noncoding regions of six schizophrenia-associated gene loci. |
| Abstract | In order to explore the role of noncoding variants in the genetics of schizophrenia, we sequenced 27 kb of noncoding DNA from the gene loci RAC-alpha serine/threonine-protein kinase (AKT1), brain-derived neurotrophic factor (BDNF), dopamine receptor-3 (DRD3), dystrobrevin binding protein-1 (DTNBP1), neuregulin-1 (NRG1) and regulator of G-protein signaling-4 (RGS4) in 37 schizophrenia patients and 25 healthy controls. To compare the allele frequency spectrum between the two samples, we separately computed Tajima's D-value for each sample. The results showed a smaller Tajima's D-value in the case sample, pointing to an excess of rare variants as compared to the control sample. When randomly permuting the affection status of sequenced individuals, we observed a stronger decrease of Tajima's D in 2400 out of 100,000 permutations, corresponding to a P-value of 0.024 in a one-sided test. Thus, rare variants are significantly enriched in the schizophrenia sample, indicating the existence of disease-related sequence alterations. When categorizing the sequenced fragments according to their level of human-rodent conservation or according to their gene locus, we observed a wide range of diversity parameter estimates. Rare variants were enriched in conserved regions as compared to nonconserved regions in both samples. Nevertheless, rare variants remained more common among patients, suggesting an increased number of variants under purifying selection in this sample. Finally, we performed a heuristic search for the subset of gene loci, which jointly produces the strongest difference between controls and cases. This showed a more prominent role of variants from the loci AKT1, BDNF and RGS4. Taken together, our approach provides promising strategy to investigate the genetics of schizophrenia and related phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 28 | Schizophr. Res. 2006 Jun 84: 253-71 |
| PMID | 16632332 |
| Title | Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. |
| Abstract | Neurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 29 | Psychiatr Hung 2006 -1 21: 404-12 |
| PMID | 17438657 |
| Title | [Gene polymorphism and gene expression in schizophrenia]. |
| Abstract | The author reviews relevant data on the neuropathology and molecular genetics of schizophrenia. Anatomical alterations are localized mainly in the hippocampus, dorsal thalamus and dorsolateral prefrontal cortex, and involve the morphology and molecular structure of the neurons and synapses. Several susceptibility genes [including COMT, dysbindin, neuregulin, DISCI, RGS4, GRM3, G72, PPP3CC, CHRNA7, PRODH2, Aktl, 5qGABA(A)] having physiological function in the brain have been identified and this supports the view of schizophrenia as a disorder of cerebral synaptic function. NMDA receptor-mediated glutamate transmission may be particularly involved, but disturbances of dopamine and GABA signalling seem to be linked as well. Based on recent data, an agreement is emerging between the roles of the genes on the molecular and synaptic levels and the understanding of the disorder at the neural systems level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 30 | Psychiatr. Genet. 2006 Dec 16: 229-30 |
| PMID | 17106420 |
| Title | Bipolar 1 disorder is not associated with the RGS4, PRODH, COMT and GRK3 genes. |
| Abstract | Although current psychiatric nosology separates bipolar disorder and schizophrenia into non-overlapping categories, there is growing evidence of a partial aetiological overlap between them from linkage, genetic epidemiology and molecular genetics studies. Thus, it is important to determine whether genes implicated in the aetiology of schizophrenia play a role in bipolar disorder, and vice versa. In this study we investigated a total of 15 single nucleotide polymorphisms (SNPs), and all possible haplotypes, of genes that have been previously implicated in schizophrenia or bipolar disorder - RGS4, PRODH, COMT and GRK3 - in a sample of 213 cases with bipolar affective disorder type 1 and 197 controls from Scotland. We analysed the polymorphisms allele-wise, genotype-wise and, for each gene, haplotype-wise but obtained no result that reached nominal significance (p<0.05) for an association with the disease status. In conclusion, we could not find evidence of association between RGS4, PRODH, COMT and GRK3 genes and bipolar affective disorder 1 in the Scottish population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 31 | Biol. Psychiatry 2006 Jul 60: 163-76 |
| PMID | 16616896 |
| Title | Critical appraisal of DNA microarrays in psychiatric genomics. |
| Abstract | Transcriptome profiling using DNA microarrays are data-driven approaches with the potential to uncover unanticipated relationships between gene expression alterations and psychiatric disorders. Studies to date have yielded both convergent and divergent findings. Differences may be explained, at least in part, by the use of a variety of microarray platforms and analytical approaches. Consistent findings across studies suggest, however, that important relationships may exist between altered gene expression and genetic susceptibility to psychiatric disorders. For example, GAD67, RGS4, DTNBP1, NRG1, and GABRAB2 show expression alterations in the postmortem brain of subjects with schizophrenia, and these genes have been also implicated as putative, heritable schizophrenia susceptibility genes. Thus, we propose that for some genes, altered expression in the postmortem human brain may have a dual origin: polymorphisms in the candidate genes themselves or upstream genetic-environmental factors that converge to alter their expression level. We hypothesize that certain gene products, which function as "molecular hubs," commonly show altered expression in psychiatric disorders and confer genetic susceptibility for one or more diseases. Microarray gene expression studies are ideally suited to reveal these putative disease-associated molecular hubs and to identify promising candidates for genetic association studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 32 | Neuroscience 2006 Nov 142: 1163-81 |
| PMID | 16989953 |
| Title | Bacterial artificial chromosome transgenic analysis of dynamic expression patterns of regulator of G-protein signaling 4 during development. II. Subcortical regions. |
| Abstract | A large family of regulator of G protein signaling (RGS) proteins modulates signaling through G-protein-coupled receptors. Previous studies have implicated RGS4 as a vulnerability gene in schizophrenia. To begin to understand structure-function relationships, we have utilized bacterial artificial chromosome (BAC) methods to create transgenic mice that express green fluorescent protein (GFP) under the control of endogenous RGS4 enhancer elements, circumventing the lack of suitable antibodies for analysis of dynamic patterns of expression. This report follows from the accompanying mapping paper in cerebral cortex, with a focus on developmental and mature expression patterns in subcortical telencephalic, diencephalic and brainstem areas. Based on reporter distribution, the data suggest that alterations in RGS4 function will engender a complex phenotype of increased and decreased neuronal output, with developmental, regional, and cellular specificity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 33 | Eur. J. Hum. Genet. 2006 Oct 14: 1130-5 |
| PMID | 16791139 |
| Title | Association study of the G-protein signaling 4 (RGS4) and proline dehydrogenase (PRODH) genes with schizophrenia: a meta-analysis. |
| Abstract | schizophrenia is a devastating psychiatric disease that affects up to 1% of the population worldwide. Recent studies suggested that schizophrenia might result from the hypofunction of glutamatergic neurotransmission. Systematic positional, expression and functional studies have implicated the regulator of G-protein signaling 4 (RGS4) and proline dehydrogenase (PRODH) genes as promising and novel candidates for explaining schizophrenia. However, the findings of association studies tend to vary depending on the different populations on which they have been conducted. To reconcile this conflict of evidence, we combined all available population-based and family-based studies up to July 2005 involving eight polymorphisms. However, this meta-analysis did not find statistically significant evidence for association between the two glutamate-related genes and schizophrenia on the basis of either allelic or genotypic analysis. This may be the first systematic meta-analysis study based on RGS4 and PRODH. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 34 | Hum. Mol. Genet. 2006 Sep 15: 2804-12 |
| PMID | 16905560 |
| Title | RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity. |
| Abstract | Linkage, association and postmortem studies have implicated regulator of G-protein signaling 4 (RGS4), which negatively modulates signal transduction at G-protein-coupled receptors, as a candidate schizophrenia susceptibility gene. We compared RGS4 mRNA expression in the dorsolateral prefrontal cortex (DLPFC), between normal controls and patients with schizophrenia in two independent cohorts (>100 subjects each) (the CBDB/NIMH Collection and the Stanley Array Collection), and in the hippocampus in the CBDB/NIMH Collection. We also examined the effects of the four previously identified putative RGS4 risk SNPs (rs10917670, rs951436, rs951439, rs2661319) on RGS4 expression levels in these cohorts. As dopamine signaling is linked to RGS4 expression and there is evidence for statistical epistasis between COMT Val158Met polymorphism and RGS4 alleles, we also examined relationships between the COMT Val158Met genotype and RGS4 expression in the DLPFC. We did not detect a difference in RGS4 expression levels between schizophrenic patients (or bipolar disorder patients in the Stanley Collection) and controls and found no significant association between any of the RGS4 risk SNPs and RGS4 expression. However, COMT Val158Met genotype was associated with prefrontal and hippocampal RGS4 mRNA expression in an allele dose-dependent manner, with carriers of the COMT Val allele showing significantly lower expression than heterozygous individuals or subjects homozygous for the Met allele. Consistent with these genotype effects, RGS4 mRNA was inversely correlated with the COMT enzyme activity in the DLPFC. These data suggest that RGS4 mRNA expression is associated with cortical dopamine signaling and illustrate the importance of genetic and/or environmental background in gene expression studies in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 35 | Neurosci. Lett. 2006 Oct 406: 122-7 |
| PMID | 16904822 |
| Title | RGS4 polymorphisms and risk of schizophrenia: an association study in Han Chinese plus meta-analysis. |
| Abstract | Recently, several researches based on expression analysis, genetic linkage and association studies have suggested that the regulator of G-protein signaling 4 (RGS4) might be a schizophrenia susceptibility gene. However, these linkage and association studies have been conducted using different ethnic samples, and have therefore tended to produce inconsistent results. To help to clarify this inconsistency, we used non-family based samples to carry out a case-control analysis on six single nucleotide polymorphisms (SNPs) (including four widely investigated SNPs, SNP1, 4, 7, 18 and another two SNPs, rs2842030 and rs2344671) in a Chinese Han sample set comprising 288 schizophrenia patients and 288 normal controls. All genotypings were conducted by direct sequencing and all SNPs were in Hardy-Weinberg equilibrium. We found no individual SNPs or haplotypes to be associated with schizophrenia. We also performed a meta-analysis based on all published population-based association studies on the topic including our own. The results of both our case-control study in the Chinese Han population and the meta-analysis yield no significant evidence for association, which suggests that the genetic polymorphisms within RGS4 are unlikely to confer an increased susceptibility to the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 36 | Biol. Psychiatry 2006 Sep 60: 534-7 |
| PMID | 16860780 |
| Title | Making the case for a candidate vulnerability gene in schizophrenia: Convergent evidence for regulator of G-protein signaling 4 (RGS4). |
| Abstract | Both genetic and environmental factors have been associated with an increased risk for schizophrenia. These factors are not mutually exclusive; a single gene can be a genetic factor (due to a mutation in the gene sequence) and a target of a physiological response to an environmental stimulus, both with the common endpoint of altered expression of the gene. Regulator of G-protein signaling 4 (RGS4) has been implicated as such a gene from three lines of evidence. First, a subset of genetic studies revealed an association between schizophrenia and non-functional polymorphisms in the RGS4 gene. Second, across the cortical mantle the expression of RGS4 mRNA is decreased in a diagnosis-specific manner in subjects with schizophrenia. Third, neurobiological studies demonstrate that RGS4 is highly responsive to environmental stimuli and capable of modulating the function of G-protein coupled neurotransmitter receptors implicated in schizophrenia. RGS4 is an example of a molecule that may underlie increased vulnerability through either genetic or non-genetic mechanisms, which we suggest may be typical of other genes in a complex, polygenic disorder such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 37 | J Neural Transm (Vienna) 2006 Oct 113: 1563-8 |
| PMID | 16604300 |
| Title | RGS4 genotype is not associated with antipsychotic medication response in schizophrenia. |
| Abstract | The aims of the present study were to compare the allele frequencies of a common single nucleotide polymorphism located upstream of the regulator of G-protein signaling 4 (RGS4) gene (T > G, Rs 951436) in 219 Finnish patients with schizophrenia and in 389 control subjects, to analyze corresponding frequencies between two different subtypes of 93 schizophrenia patients according to their medication response, and to study the effect of this SNP on age at onset in schizophrenia. The RGS4 (T > G, Rs 951436) genotype was not associated with incidence or age at onset in schizophrenia. Neither was the RGS4 genotype associated with medication response with two different subpopulations with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 38 | Synapse 2006 Jun 59: 472-9 |
| PMID | 16565965 |
| Title | Regional alterations in RGS4 protein in schizophrenia. |
| Abstract | The regulator of G protein signaling (RGS) molecules are a class of proteins that modulate the signaling activity of G-protein coupled receptors. Regulator of G protein signaling 4 (RGS4) is of particular interest in schizophrenia since it is associated with the dopamine (DA) receptor, its expression is altered in affected CNS tissue, and polymorphisms in the RGS4 gene are being examined as risk factors for the disease (Morris et al.2004, Am J Med Genet B Neuropsychiatr Genet 125:50-53; Prasad et al.2005, Mol Psychiatry 10:213-219; Williams et al.2004, Biol Psychiatry 55:192-195). To further test for the involvement of RGS4 expression in schizophrenia, we examined a selection of different cortical and subcortical regions in human brain for alterations in RGS4 mRNA and protein expression. To evaluate the effect of antipsychotic medication on RGS4 expression levels, we compared a subset of treated and untreated cases that were off antipsychotic medication for at least 3 months prior to death. We report a significant decrease in RGS4 mRNA levels in the cingulate gyrus, superior frontal gyrus, and the insular cortex of all schizophrenia cases when compared with controls. A decrease in RGS4 mRNA was also observed in the caudate, but only in the medicated schizophrenia cases. Measurement of protein levels using Western blot demonstrated that RGS4 protein is decreased in the frontal cortex of schizophrenia cases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 39 | J. Biol. Chem. 2006 Nov 281: 34549-60 |
| PMID | 16973624 |
| Title | RGS3 and RGS4 differentially associate with G protein-coupled receptor-Kir3 channel signaling complexes revealing two modes of RGS modulation. Precoupling and collision coupling. |
| Abstract | RGS3 and RGS4 are GTPase-activating proteins expressed in the brain and heart that accelerate the termination of G(i/o)- and G(q)-mediated signaling. We report here the determinants mediating selective association of RGS4 with several G protein-coupled receptors (GPCRs) that form macromolecular complexes with neuronal G protein-gated inwardly rectifying potassium (Kir3 or GIRK) channels. Kir3 channels are instrumental in regulating neuronal firing in the central and peripheral nervous system and pacemaker activity in the heart. By using an epitope-tagged degradation-resistant RGS4 mutant, RGS4(C2V), immunoprecipitation of several hemagglutinin-tagged G(i/o)-coupled and G(q)-coupled receptors expressed in Chinese hamster ovary (CHO-K1) cells readily co-precipitated both Kir3.1/Kir3.2a channels and RGS4(C2V). In contrast to RGS4(C2V), the closely related and functionally active RGS3 "short" isoform (RGS3s) did not interact with any of the GPCR-Kir3 channel complexes examined. Deletion and chimeric RGS constructs indicate both the N-terminal domain and the RGS domain of RGS4(C2V) are necessary for association with m2 receptor-Kir3.1/Kir3.2a channel complexes, where the GPCR was found to be the major target for RGS4(C2V) interaction. The functional impact of RGS4(C2V) "precoupling" to the GPCR-Kir3 channel complex versus RGS3s "collision coupling" was a 100-fold greater potency in the acceleration of G protein-dependent Kir3 channel-gating kinetics with no attenuation in current amplitude. These findings demonstrate that RGS4, a highly regulated modulator and susceptibility gene for schizophrenia, can directly associate with multiple GPCR-Kir3 channel complexes and may affect a wide range of neurotransmitter-mediated inhibitory and excitatory events in the nervous and cardiovascular systems. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 40 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Jun 141B: 418-20 |
| PMID | 16526029 |
| Title | Evaluation of RGS4 as a candidate gene for schizophrenia. |
| Abstract | Several studies have suggested that the regulator of G-protein signaling 4 (RGS4) may be a positional and functional candidate gene for schizophrenia. Three single nucleotide polymorphisms (SNP) located at the promoter region (SNP4 and SNP7) and the intron 1 (SNP18) of RGS4 have been verified in different ethnic groups. Positive results have been reported in these SNPs with different numbers of SNP combinatory haplotypes. In this study, these three SNP markers were genotyped in 218 schizophrenia pedigrees of Taiwan (864 individuals) for association analysis. Among these three SNPs, neither SNP4, SNP7, SNP18 has shown significant association with schizophrenia in single locus association analysis, nor any compositions of the three SNP haplotypes has shown significantly associations with the DSM-IV diagnosed schizophrenia. Our results fail to support the RGS4 as a candidate gene for schizophrenia when evaluated from these three SNP markers. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 41 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Apr 141B: 296-300 |
| PMID | 16508931 |
| Title | Failure to confirm genetic association between schizophrenia and markers on chromosome 1q23.3 in the region of the gene encoding the regulator of G-protein signaling 4 protein (RGS4). |
| Abstract | The chromosome 1q23.3 region, which includes the RGS4 gene has been implicated in genetic susceptibility to schizophrenia by two linkage studies with lod scores of 6.35 and 3.20 and with positive lod between 2.00 and 3.00 scores in several other studies. Reduced post mortem RGS4 gene expression in the brain of schizophrenics was reported as well as positive allelic association between markers at the RGS4 gene locus and schizophrenia. We have attempted to replicate the finding of allelic association with schizophrenia in a UK based sample of 450 subjects with schizophrenia and 450 supernormal controls. We genotyped the same SNP marker alleles investigated in the earlier studies and also a di-nucleotide (GT)14 repeat microsatellite marker, which was 7 kb distal to RGS4. In the new UK sample there was no evidence for allelic or haplotypic association between RGS4 markers and schizophrenia. This might reflect genetic heterogeneity between the population samples, genotyping or other methodological problems. The finding weakens the evidence that mutations or variation in the RGS4 gene have an effect on schizophrenia susceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 42 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Apr 141B: 296-300 |
| PMID | 16508931 |
| Title | Failure to confirm genetic association between schizophrenia and markers on chromosome 1q23.3 in the region of the gene encoding the regulator of G-protein signaling 4 protein (RGS4). |
| Abstract | The chromosome 1q23.3 region, which includes the RGS4 gene has been implicated in genetic susceptibility to schizophrenia by two linkage studies with lod scores of 6.35 and 3.20 and with positive lod between 2.00 and 3.00 scores in several other studies. Reduced post mortem RGS4 gene expression in the brain of schizophrenics was reported as well as positive allelic association between markers at the RGS4 gene locus and schizophrenia. We have attempted to replicate the finding of allelic association with schizophrenia in a UK based sample of 450 subjects with schizophrenia and 450 supernormal controls. We genotyped the same SNP marker alleles investigated in the earlier studies and also a di-nucleotide (GT)14 repeat microsatellite marker, which was 7 kb distal to RGS4. In the new UK sample there was no evidence for allelic or haplotypic association between RGS4 markers and schizophrenia. This might reflect genetic heterogeneity between the population samples, genotyping or other methodological problems. The finding weakens the evidence that mutations or variation in the RGS4 gene have an effect on schizophrenia susceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 43 | Biol. Psychiatry 2006 Jul 60: 152-62 |
| PMID | 16631129 |
| Title | Evaluation of a susceptibility gene for schizophrenia: genotype based meta-analysis of RGS4 polymorphisms from thirteen independent samples. |
| Abstract | Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotide polymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles. In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807). The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations. Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 44 | Hum. Mol. Genet. 2006 Sep 15: 2804-12 |
| PMID | 16905560 |
| Title | RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity. |
| Abstract | Linkage, association and postmortem studies have implicated regulator of G-protein signaling 4 (RGS4), which negatively modulates signal transduction at G-protein-coupled receptors, as a candidate schizophrenia susceptibility gene. We compared RGS4 mRNA expression in the dorsolateral prefrontal cortex (DLPFC), between normal controls and patients with schizophrenia in two independent cohorts (>100 subjects each) (the CBDB/NIMH Collection and the Stanley Array Collection), and in the hippocampus in the CBDB/NIMH Collection. We also examined the effects of the four previously identified putative RGS4 risk SNPs (rs10917670, rs951436, rs951439, rs2661319) on RGS4 expression levels in these cohorts. As dopamine signaling is linked to RGS4 expression and there is evidence for statistical epistasis between COMT Val158Met polymorphism and RGS4 alleles, we also examined relationships between the COMT Val158Met genotype and RGS4 expression in the DLPFC. We did not detect a difference in RGS4 expression levels between schizophrenic patients (or bipolar disorder patients in the Stanley Collection) and controls and found no significant association between any of the RGS4 risk SNPs and RGS4 expression. However, COMT Val158Met genotype was associated with prefrontal and hippocampal RGS4 mRNA expression in an allele dose-dependent manner, with carriers of the COMT Val allele showing significantly lower expression than heterozygous individuals or subjects homozygous for the Met allele. Consistent with these genotype effects, RGS4 mRNA was inversely correlated with the COMT enzyme activity in the DLPFC. These data suggest that RGS4 mRNA expression is associated with cortical dopamine signaling and illustrate the importance of genetic and/or environmental background in gene expression studies in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 45 | Schizophr Bull 2006 Apr 32: 203-8 |
| PMID | 16469939 |
| Title | Can RGS4 polymorphisms be viewed as credible risk factors for schizophrenia? A critical review of the evidence. |
| Abstract | There has been a recent explosion in the list of putative susceptibility genes for schizophrenia (SZ). These genes have been identified on the basis of presumed pathogenesis, linkage, and genetic association studies. While several promising candidates have arisen, identification of a conclusive genetic risk factor has remained elusive. The proof would be most compelling if it stemmed from all three of these domains. In this review, we consider such evidence in relation to the regulator of G-protein signaling 4 (RGS4), a gene localized to chromosome 1q23. Disorder-specific changes in RGS4 mRNA levels have been observed in post-mortem brain samples; linkage has been reported at chromosome 1q23; and several association studies have concluded that significant associations exist. The latter are supported by a recently conducted meta-analysis. Thus, there is suggestive evidence in each of these domains implicating a role for RGS4 in SZ susceptibility. However, analogous to other promising susceptibility candidates, the nature of the genetic association, the precise polymorphism(s) conferring risk, and the functional implications of sequence variation at this gene are unclear. We review the published data and place them in the context of suggested criteria for establishing a candidate gene as a credible susceptibility factor for disorders with non-Mendelian patterns of inheritance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 46 | Schizophr Bull 2007 Nov 33: 1343-53 |
| PMID | 17329232 |
| Title | eIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia? |
| Abstract | Bipolar disorder and schizophrenia share common chromosomal susceptibility loci and many risk-promoting genes. Oligodendrocyte cell loss and hypomyelination are common to both diseases. A number of environmental risk factors including famine, viral infection, and prenatal or childhood stress may also predispose to schizophrenia or bipolar disorder. In cells, related stressors (starvation, viruses, cytokines, oxidative, and endoplasmic reticulum stress) activate a series of eIF2-alpha kinases, which arrest protein synthesis via the eventual inhibition, by phosphorylated eIF2-alpha, of the translation initiation factor eIF2B. Growth factors increase protein synthesis via eIF2B activation and counterbalance this system. The control of protein synthesis by eIF2-alpha kinases is also engaged by long-term potentiation and repressed by long-term depression, mediated by N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors. Many genes reportedly associated with both schizophrenia and bipolar disorder code for proteins within or associated with this network. These include NMDA (GRIN1, GRIN2A, GRIN2B) and metabotropic (GRM3, GRM4) glutamate receptors, growth factors (BDNF, NRG1), and many of their downstream signaling components or accomplices (AKT1, DAO, DAOA, DISC1, DTNBP1, DPYSL2, IMPA2, NCAM1, NOS1, NOS1AP, PIK3C3, PIP5K2A, PDLIM5, RGS4, YWHAH). They also include multiple gene products related to the control of the stress-responsive eIF2-alpha kinases (IL1B, IL1RN, MTHFR, TNF, ND4, NDUFV2, XBP1). Oligodendrocytes are particularly sensitive to defects in the eIF2B complex, mutations in which are responsible for vanishing white matter disease. The convergence of natural and genetic risk factors on this area in bipolar disorder and schizophrenia may help to explain the apparent vulnerability of this cell type in these conditions. This convergence may also help to reconcile certain arguments related to the importance of nature and nurture in the etiology of these psychiatric disorders. Both may affect common stress-related signaling pathways that dictate oligodendrocyte viability and synaptic plasticity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 47 | Psychiatry Clin. Neurosci. 2007 Feb 61: 3-19 |
| PMID | 17239033 |
| Title | Molecular genetics of bipolar disorder and depression. |
| Abstract | In this review, all papers relevant to the molecular genetics of bipolar disorder published from 2004 to the present (mid 2006) are reviewed, and major results on depression are summarized. Several candidate genes for schizophrenia may also be associated with bipolar disorder: G72, DISC1, NRG1, RGS4, NCAM1, DAO, GRM3, GRM4, GRIN2B, MLC1, SYNGR1, and SLC12A6. Of these, association with G72 may be most robust. However, G72 haplotypes and polymorphisms associated with bipolar disorder are not consistent with each other. The positional candidate approach showed an association between bipolar disorder and TRPM2 (21q22.3), GPR50 (Xq28), Citron (12q24), CHMP1.5 (18p11.2), GCHI (14q22-24), MLC1 (22q13), GABRA5 (15q11-q13), BCR (22q11), CUX2, FLJ32356 (12q23-q24), and NAPG (18p11). Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation. From gene expression analysis, PDLIM5, somatostatin, and the mtDNA 3243 mutation were found to be related to bipolar disorder. Whereas most previous positive findings were not supported by subsequent studies, DRD1 and IMPA2 have been implicated in follow-up studies. Several candidate genes in the circadian rhythm pathway, BmaL1, TIMELESS, and PERIOD3, are reported to be associated with bipolar disorder. Linkage studies show many new linkage loci. In depression, the previously reported positive finding of a gene-environmental interaction between HTTLPR (insertion/deletion polymorphism in the promoter of a serotonin transporter) and stress was not replicated. Although the role of the TPH2 mutation in depression had drawn attention previously, this has not been replicated either. Pharmacogenetic studies show a relationship between antidepressant response and HTR2A or FKBP5. New technologies for comprehensive genomic analysis have already been applied. HTTLPR and BDNF promoter polymorphisms are now found to be more complex than previously thought, and previous papers on these polymorphisms should be treated with caution. Finally, this report addresses some possible causes for the lack of replication in this field. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 48 | Schizophr. Res. 2007 Jan 89: 161-4 |
| PMID | 17092693 |
| Title | RGS4 is not a susceptibility gene for schizophrenia in Japanese: association study in a large case-control population. |
| Abstract | The regulator of the G-protein signaling 4 (RGS4) has been implicated in the susceptibility to schizophrenia. RGS4 interacts with ErbB3 that acts as receptors for neuregulin 1 and these proteins may play a role in the pathogenesis of schizophrenia via glutamatergic dysfunction. Recently, two meta-analysis studies provided different interpretations for the genetic association between RGS4 and schizophrenia. We attempted to confirm this association in a case-control study of 1918 Japanese patients with schizophrenia and 1909 Japanese control subjects. Four widely studied single nucleotide polymorphisms (SNPs) were genotyped, and none showed association with schizophrenia. SNP 1 (rs10917670), p=0.92; SNP 4 (rs951436), p=0.91; SNP 7 (rs951439), p=0.27; and SNP 18 (rs2661319), p=0.43. A haplotype block constructed by these SNPs spans the 5' flanking region to the 5' mid-region of the RGS4 gene. Previous meta-analysis showed that both two major haplotypes of this block were risk haplotypes. The two common haplotypes were observed in the Japanese population. However, neither haplotype was significantly associated with schizophrenia. We conclude that the common haplotypes and SNPs of the RGS4 gene identified thus far are unlikely to contribute to the genetic susceptibility to schizophrenia in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 49 | Cell. Physiol. Biochem. 2007 -1 20: 687-702 |
| PMID | 17982252 |
| Title | Molecular mechanisms of schizophrenia. |
| Abstract | schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 50 | Hum. Genet. 2007 Feb 120: 889-906 |
| PMID | 17006672 |
| Title | Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia. |
| Abstract | Catechol-O-methyltransferase (COMT) regulates dopamine degradation and is located in a genomic region that is deleted in a syndrome associated with psychosis, making it a promising candidate gene for schizophrenia. COMT also has been shown to influence prefrontal cortex processing efficiency. Prefrontal processing dysfunction is a common finding in schizophrenia, and a background of inefficient processing may modulate the effect of other candidate genes. Using the NIMH sibling study (SS), a non-independent case-control set, and an independent German (G) case-control set, we performed conditional/unconditional logistic regression to test for epistasis between SNPs in COMT (rs2097603, Val158Met (rs4680), rs165599) and polymorphisms in other schizophrenia susceptibility genes. Evidence for interaction was evaluated using a likelihood ratio test (LRT) between nested models. SNPs in RGS4, G72, GRM3, and DISC1 showed evidence for significant statistical epistasis with COMT. A striking result was found in RGS4: three of five SNPs showed a significant increase in risk [LRT P-values: 90387 = 0.05 (SS); SNP4 = 0.02 (SS), 0.02 (G); SNP18 = 0.04 (SS), 0.008 (G)] in interaction with COMT; main effects for RGS4 SNPs were null. Significant results for SNP4 and SNP18 were also found in the German study. We were able to detect statistical interaction between COMT and polymorphisms in candidate genes for schizophrenia, many of which had no significant main effect. In addition, we were able to replicate other studies, including allelic directionality. The use of epistatic models may improve replication of psychiatric candidate gene studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 51 | Neurosci Biobehav Rev 2007 -1 31: 60-78 |
| PMID | 16782199 |
| Title | Susceptibility genes for schizophrenia: characterisation of mutant mouse models at the level of phenotypic behaviour. |
| Abstract | A wealth of evidence indicates that schizophrenia is heritable. However, the genetic mechanisms involved are poorly understood. Furthermore, it may be that genes conferring susceptibility interact with one another and with non-genetic factors to modulate risk status and/or the expression of symptoms. Genome-wide scanning and the mapping of several regions linked with risk for schizophrenia have led to the identification of several putative susceptibility genes including neuregulin-1 (NRG1), dysbindin (DTNBP1), regulator of G-protein signalling 4 (RGS4), catechol-o-methyltransferase (COMT), proline dehydrogenase (PRODH) and disrupted-in-schizophrenia 1 (DISC1). Genetic animal models involving targeted mutation via gene knockout or transgenesis have the potential to inform on the role of a given susceptibility gene on the development and behaviour of the whole organism and on whether disruption of gene function is associated with schizophrenia-related structural and functional deficits. This review focuses on data regarding the behavioural phenotype of mice mutant for schizophrenia susceptibility genes identified by positional candidate analysis and the study of chromosomal abnormalities. We also consider methodological issues that are likely to influence phenotypic effects, as well as the limitations associated with existing molecular techniques. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 52 | Biol. Psychiatry 2007 May 61: 1195-9 |
| PMID | 17055463 |
| Title | Significant support for DAO as a schizophrenia susceptibility locus: examination of five genes putatively associated with schizophrenia. |
| Abstract | schizophrenia is a complex psychiatric disorder with a strong genetic component. Past linkage studies have implicated several chromosomal regions in the etiology of schizophrenia. Within these regions, several genes have been identified via candidate gene association studies as strong schizophrenia susceptibility loci, including DAO, DAOA, DISC1, DTNBP1, and RGS4. The present study attempted to replicate these association findings by analyzing a total of 120 markers across these genes in 311 schizophrenia subjects, 140 schizoaffective subjects, and 291 control subjects. Our study found no association for DAOA and DTNBP1 with schizophrenia. Although no association was seen with DAOA and DTNBP1, several other markers in the other genes resulted in significant association with schizophrenia (p < .05). However, after a conservative Bonferroni correction for multiple testing, only one marker, rs3918346, within DAO remained significant (odds ratio = 1.71, confidence interval = 1.32-2.22, p = 4 x 10(-5)). This significant association was concordant with previous DAO genetic findings. Our results significantly support DAO as a susceptibility locus for schizophrenia and offer some support for the implication of both RGS4 and DISC1 in the etiology of schizophrenia. However, we see no evidence to support either DAOA or DTNBP1 as schizophrenia disease loci. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 53 | J. Neurosci. 2007 Feb 27: 1584-93 |
| PMID | 17301167 |
| Title | Allelic variation in RGS4 impacts functional and structural connectivity in the human brain. |
| Abstract | Regulator of G-protein signaling 4 (RGS4) modulates postsynaptic signal transduction by affecting the kinetics of G alpha-GTP binding. Linkage, association, and postmortem studies have implicated the gene encoding RGS4 (RGS4) as a schizophrenia susceptibility factor. Using a multimodal neuroimaging approach, we demonstrate that genetic variation in RGS4 is associated with functional activation and connectivity during working memory in the absence of overt behavioral differences, with regional gray and white matter volume and with gray matter structural connectivity in healthy human subjects. Specifically, variation at one RGS4 single nucleotide polymorphism that has been associated previously with psychosis (rs951436) impacts frontoparietal and frontotemporal blood oxygenation level-dependent response and network coupling during working memory and results in regionally specific reductions in gray and white matter structural volume in individuals carrying the A allele. These findings suggest mechanisms in brain for the association of RGS4 with risk for psychiatric illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 54 | Schizophr. Res. 2007 Jan 89: 165-8 |
| PMID | 17071056 |
| Title | Altered expression of regulator of G-protein signalling 4 (RGS4) mRNA in the superior temporal gyrus in schizophrenia. |
| Abstract | To identify altered mRNA expression of regulator of G-protein signalling 4 (RGS4) in the superior temporal gyrus (STG) in schizophrenia mRNA expression of RGS4 was measured from post-mortem STG tissue from 13 individuals with schizophrenia and 13 matched non-psychiatric controls using relative real-time PCR. Significantly decreased expression of RGS4 mRNA in the STG in schizophrenia was identified in 10 of the 13 matched pairs. Altered expression of RGS4 in cortical regions previously implicated in schizophrenia, such as the STG further supports the notion of RGS4 as a potential genetic and functional biological marker of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 55 | Genes Brain Behav. 2007 Mar 6: 113-9 |
| PMID | 17410640 |
| Title | The PIP5K2A and RGS4 genes are differentially associated with deficit and non-deficit schizophrenia. |
| Abstract | Several putative schizophrenia susceptibility genes have recently been reported, but it is not clear whether these genes are associated with schizophrenia in general or with specific disease subtypes. In a previous study, we found an association of the neuregulin 1 (NRG1) gene with non-deficit schizophrenia only. We now report an association study of four schizophrenia candidate genes in patients with and without deficit schizophrenia, which is characterized by severe and enduring negative symptoms. Single-nucleotide polymorphisms (SNPs) were genotyped in the DTNBP1 (dysbindin), G72/G30 and RGS4 genes, and the relatively unknown PIP5K2A gene, which is located in a region of linkage with both schizophrenia and bipolar disorder. The sample consisted of 273 Dutch schizophrenia patients, 146 of whom were diagnosed with deficit schizophrenia and 580 controls. The strongest evidence for association was found for the A-allele of SNP rs10828317 in the PIP5K2A gene, which was associated with both clinical subtypes (P = 0.0004 in the entire group; non-deficit P = 0.016, deficit P = 0.002). Interestingly, this SNP leads to a change in protein composition. In RGS4, the G-allele of the previously reported SNP RGS4-1 (single and as part of haplotypes with SNP RGS4-18) was associated with non-deficit schizophrenia (P = 0.03) but not with deficit schizophrenia (P = 0.79). SNPs in the DTNBP1 and G72/G30 genes were not significantly associated in any group. In conclusion, our data provide further evidence that specific genes may be involved in different schizophrenia subtypes and suggest that the PIP5K2A gene deserves further study as a general susceptibility gene for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 56 | Gene 2007 Oct 401: 46-60 |
| PMID | 17707117 |
| Title | Full length cloning and expression analysis of splice variants of regulator of G-protein signaling RGS4 in human and murine brain. |
| Abstract | RGS4 (regulator of G protein signaling 4) protein is a GTPase-activating protein specific for Gi/o and Gq alpha subunits. It is highly expressed in brain but the mechanisms by which RGS4 expression is regulated remain unknown. RGS4 is associated with schizophrenia either through heritable genetic polymorphisms or as a co-regulated mediator of the pathology, and may play a role in other brain diseases. As a necessary step towards understanding the transcriptional regulation of RGS4, we isolated full-length splice variants of the human RGS4 and mouse RGS4 gene using bioinformatic predictions, followed by RACE, RT-PCR, and sequencing. In human brain, we found five different isoforms RGS4-1, RGS4-2, RGS4-3, RGS4-4 and RGS4-5 of which RGS4-2, RGS4-3, RGS4-4 and RGS4-5 are novel. RGS4-1 and 2 encode a 205-amino acid protein, while RGS4-3 encodes a 302 aa protein with an N-terminal extension. RGS4-4 and RGS4-5 encode truncated proteins of 93 aa and 187 aa respectively. Our results indicate that RGS4-1, RGS4-2, RGS4-3 and RGS4-4 are translated into proteins. In contrast, the mouse brain has 3 different splice variants, RGS4-1, RGS4-2 and RGS4-3 which encode the same 205 aa protein but vary in their 3'UTRs. Among the mouse isoforms, RGS4-1 and RGS4-3 are novel. Human RGS4 has four different transcription start sites and three different stop sites. We found differential expression of the human isoforms in dorsolateral prefrontal and visual cortex. All five RGS4 splice variants are expressed at high levels in human cortical areas although RGS4 isoforms 1, 2, and 3 are not expressed in the cerebellum. RGS4-2 is tissue-specific whereas RGS4-4 and RGS4-5 appear to be ubiquitously expressed. Our results suggest the intriguing possibility that RGS4 gene expression in the human brain is spatially and temporally regulated through differential transcription of isoforms from alternative promoters. This may have implications for the physiological role of RGS4 and in pathologies of the brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 57 | Mol. Pharmacol. 2007 Apr 71: 1030-9 |
| PMID | 17220354 |
| Title | RGS4 modulates serotonin signaling in prefrontal cortex and links to serotonin dysfunction in a rat model of schizophrenia. |
| Abstract | Regulator of G protein signaling 4 (RGS4) has recently been identified as one of the genes linked to the susceptibility of schizophrenia. However, the functional roles of RGS4 and how it may be involved in the pathophysiology of schizophrenia remain largely unknown. In this study, we investigated the possible impact of RGS4 on the function of serotonin and dopamine receptors, two main targets for schizophrenia treatment. Activation of serotonin 5-HT(1A) receptors or dopamine D(4) receptors down-regulates the function of NMDA receptor (NMDAR) channel, a key player controlling cognition and emotion, in pyramidal neurons of prefrontal cortex (PFC). Blocking RGS4 function significantly potentiated the 5-HT(1A) regulation of NMDAR current; conversely, overexpression of RGS4 attenuated the 5-HT(1A) effect. In contrast, the D(4) regulation of NMDAR current was not altered by RGS4 manipulation. Moreover, the 5-HT(1A) regulation of NMDA receptors was significantly enhanced in a subset of PFC pyramidal neurons from rats treated with subchronic phencyclidine, an animal model of schizophrenia, which was found to be associated with specifically decreased RGS4 expression in these cells. Thus, our study has revealed an important coupling of RGS4 to serotonin signaling in cortical neurons and provided a molecular and cellular mechanism underlying the potential involvement of RGS4 in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 58 | Biol. Psychiatry 2007 Apr 61: 873-9 |
| PMID | 16978587 |
| Title | Fine mapping by genetic association implicates the chromosome 1q23.3 gene UHMK1, encoding a serine/threonine protein kinase, as a novel schizophrenia susceptibility gene. |
| Abstract | Linkage studies by us and others have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. Based on this information, several research groups have published evidence that markers within both the RGS4 and CAPON genes, which are 700 kb apart, independently showed allelic association with schizophrenia. Tests of allelic association with both of these genes in our case control sample were negative. Therefore, we carried out further fine mapping between the RGS4 and CAPON genes. Twenty-nine SNP and microsatellite markers in the 1q23.3 region were genotyped in the United Kingdom based sample of 450 cases and 450 supernormal control subjects. We detected positive allelic association after the eighth marker was genotyped and found that three microsatellite markers (p = .011, p = .014, p = .049) and two SNPs (p = .004, p = .043) localized in the 700 kb region between the RGS4 and CAPON genes, within the UHMK1 gene, were associated with schizophrenia. Tests of significance for marker rs10494370 remained significant following Bonferroni correction (alpha = .006) for multiple tests. Tests of haplotypic association were also significant for UHMK1 (p = .009) using empirical permutation tests, which make it unnecessary to further correct for both multiple alleles and multiple markers. These results provide preliminary evidence that the UHMK1 gene increases susceptibility to schizophrenia. Further confirmation in adequately powered samples is needed. UHMK1 is a serine threonine kinase nuclear protein and is highly expressed in regions of the brain implicated in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 59 | Cell. Physiol. Biochem. 2007 -1 20: 687-702 |
| PMID | 17982252 |
| Title | Molecular mechanisms of schizophrenia. |
| Abstract | schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 60 | Mol. Psychiatry 2008 Sep 13: 873-7 |
| PMID | 18195713 |
| Title | Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. |
| Abstract | The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-alpha) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 61 | Am J Psychiatry 2008 Apr 165: 497-506 |
| PMID | 18198266 |
| Title | No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. |
| Abstract | The authors carried out a genetic association study of 14 schizophrenia candidate genes (RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF). This study tested the hypothesis of association of schizophrenia with common single nucleotide polymorphisms (SNPs) in these genes using the largest sample to date that has been collected with uniform clinical methods and the most comprehensive set of SNPs in each gene. The sample included 1,870 cases (schizophrenia and schizoaffective disorder) and 2,002 screened comparison subjects (i.e. controls), all of European ancestry, with ancestral outliers excluded based on analysis of ancestry-informative markers. The authors genotyped 789 SNPs, including tags for most common SNPs in each gene, SNPs previously reported as associated, and SNPs located in functional domains of genes such as promoters, coding exons (including nonsynonymous SNPs), 3' untranslated regions, and conserved noncoding sequences. After extensive data cleaning, 648 SNPs were analyzed for association of single SNPs and of haplotypes. Neither experiment-wide nor gene-wide statistical significance was observed in the primary single-SNP analyses or in secondary analyses of haplotypes or of imputed genotypes for additional common HapMap SNPs. Results in SNPs previously reported as associated with schizophrenia were consistent with chance expectation, and four functional polymorphisms in COMT, DRD2, and HTR2A did not produce nominally significant evidence to support previous evidence for association. It is unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects cannot be ruled out. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 62 | Hippocampus 2008 -1 18: 824-34 |
| PMID | 18493969 |
| Title | PLC-beta1 knockout mice as a model of disrupted cortical development and plasticity: behavioral endophenotypes and dysregulation of RGS4 gene expression. |
| Abstract | The complexity of the genetics underlying schizophrenia is highlighted by the multitude of molecular pathways that have been reported to be disrupted in the disorder including muscarinic, serotonergic, and glutamatergic signaling systems. It is of interest, therefore, that phospholipase C-beta1 (PLC-beta1) acts as a point of convergence for these pathways during cortical development and plasticity. These signaling pathways, furthermore, are susceptible to modulation by RGS4, one of the more promising candidate genes for schizophrenia. PLC-beta1 knockout mice were behaviorally assessed on tests including fear conditioning, elevated plus maze, and the Y maze. In situ hybridization was used to assess RGS4 expression. We found that PLC-beta1 knockout mice display abnormal anxiety profiles on some, but not all measures assessed, including decreased anxiety on the elevated plus maze. We also show memory impairment and a complete absence of acquisition of hippocampal-dependent fear conditioning. Furthermore, at a molecular level, we demonstrate dramatic changes in expression of RGS4 mRNA in selective regions of the PLC-beta1 knockout mouse brain, particularly the CA1 region of the hippocampus. These results validate the utility of the PLC-beta1 knockout mouse as a model of schizophrenia, including molecular and cellular evidence for disrupted cortical maturation and associated behavioral endophenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 63 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 606-11 |
| PMID | 18163393 |
| Title | Gene copy number variation in schizophrenia. |
| Abstract | Recent reports have highlighted the possibility that gene copy number variations play a role in the development of complex disorders and have suggested that some variations are very common in schizophrenic patients. We have carried out a comparative genomic hybridization screen using oligonucleotide probes of 891 candidate genes to look for very common copy number variance in schizophrenic patients. In addition we have developed a new approach for the detection and validation of putative copy number variation based upon established methods of allele quantification by DNA pooling and have used it to study 15 major candidates including dysbindin (DTNBP1), neuregulin (NRG1), RGS4 and DISC1. With the exception of positive control sequences, no copy number variations were found for any of the genes in any samples by the use of either technique. Our data for the genes studied are in line with the known existence and frequency of CNVs as reported by recent large scale studies and suggest that gene copy number variations are not more common in schizophrenics than controls, although large ethnic differences cannot be excluded. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 64 | Learn. Mem. 2008 Aug 15: 551-64 |
| PMID | 18685145 |
| Title | Molecular mechanisms of stress-induced prefrontal cortical impairment: implications for mental illness. |
| Abstract | The symptoms of mental illness often involve weakened regulation of thought, emotion, and behavior by the prefrontal cortex. Exposure to stress exacerbates symptoms of mental illness and causes marked prefrontal cortical dysfunction. Studies in animals have revealed the intracellular signaling pathways activated by stress exposure that induce profound prefrontal cortical impairment: Excessive dopamine stimulation of D1 receptors impairs prefrontal function via cAMP intracellular signaling, leading to disconnection of prefrontal networks, while excessive norepinephrine stimulation of alpha1 receptors impairs prefrontal function via phosphatidylinositol-protein kinase C intracellular signaling. Genetic studies indicate that the genes disrupted in serious mental illness (bipolar disorder and schizophrenia) often encode for the intracellular proteins that serve as brakes on the intracellular stress pathways. For example, disrupted in schizophrenia 1 (DISC1) normally regulates cAMP levels, while regulator of G protein signaling 4 (RGS4) and diacylglycerol kinase (DGKH)-the molecule most associated with bipolar disorder- normally serve to inhibit phosphatidylinositol-protein kinase C intracellular signaling. Patients with mutations resulting in loss of adequate function of these genes likely have weaker endogenous regulation of these stress pathways. This may account for the vulnerability to stress and the severe loss of PFC regulation of behavior, thought, and affect in these illnesses. This review highlights the signaling pathways onto which genetic vulnerability and stress converge to impair PFC function and induce debilitating symptoms such as thought disorder, disinhibition, and impaired working memory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 65 | J Psychiatr Res 2008 Mar 42: 278-88 |
| PMID | 17408693 |
| Title | Association of schizophrenia with DTNBP1 but not with DAO, DAOA, NRG1 and RGS4 nor their genetic interaction. |
| Abstract | Recent reports indicate that DAO, DAOA, DTNBP1, NRG1 and RGS4 are some of the most-replicated genes implicated in susceptibility to schizophrenia. Also, the functions of these genes could converge in a common pathway of glutamate metabolism. The aim of this study was to evaluate if each of these genes, or their interaction, was associated with schizophrenia. A case-control study was conducted in 589 Spanish patients having a diagnosis of schizophrenia, and compared with 617 equivalent control subjects. Several single nucleotide polymorphisms (SNPs) in each gene were determined in all individuals. SNP and haplotype frequencies were compared between cases and controls. The interaction between different SNPs at the same, or at different gene, loci was analyzed by the multifactor dimensionality reduction (MDR) method. We found a new schizophrenia risk and protective haplotypes in intron VII of DTNBP1; one of the most important candidate genes for this disorder, to-date. However, no association was found between DAO, DAOA, NRG1 and RGS4 and schizophrenia. The hypothesis that gene-gene interaction in these five genes could increase the risk for the disorder was not confirmed in the present study. In summary, these results may provide further support for an association between the dysbindin gene (DTNBP1) and schizophrenia, but not between the disease and DAO, DAOA, NRG1 and RGS4 or with the interaction of these genes. In the light of recent data, these results need to be interpreted with caution and future analyses with dense genetic maps are awaited. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 66 | Aust N Z J Psychiatry 2008 Aug 42: 740-5 |
| PMID | 18622782 |
| Title | Regulator of G-protein signalling 4 expression is not altered in the prefrontal cortex in schizophrenia. |
| Abstract | Regulator of G-protein signalling 4 (RGS4) modulates signal transduction through several neurotransmitter receptor systems associated with the pathology of schizophrenia. A reported decrease in RGS4 expression in the prefrontal cortex of schizophrenia patients followed by supporting evidence from association studies implicated RGS4 as a susceptibility gene for schizophrenia. Subsequent efforts to extend these findings in post-mortem brain tissue have produced conflicting results. The aim of the present study was to reconcile these discrepancies by examining RGS4 expression in the dorsolateral prefrontal and parietal cortices from subjects with schizophrenia. RGS4 mRNA and protein levels were measured in post-mortem Brodmann area (BA)9 and BA40 tissue from 19 schizophrenia patients subjects and 19 pair-matched controls using in situ hybridization and western blotting. Levels of RGS4 mRNA (F(1,73)=1.845; p >0.05) or protein (F(1,72)=3.336 x 10(-4), p >0.05) did not vary significantly with diagnosis in BA9 or BA40 from subjects with schizophrenia. Altered RGS4 expression is not universally present throughout the cortex of people with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 67 | Brain Struct Funct 2008 Sep 213: 255-71 |
| PMID | 18470533 |
| Title | Age-related changes in the expression of schizophrenia susceptibility genes in the human prefrontal cortex. |
| Abstract | The molecular basis of complex neuropsychiatric disorders most likely involves many genes. In recent years, specific genetic variations influencing risk for schizophrenia and other neuropsychiatric disorders have been reported. We have used custom DNA microarrays and qPCR to investigate the expression of putative schizophrenia susceptibility genes and related genes of interest in the normal human brain. Expression of 31 genes was measured in Brodmann's area 10 (BA10) in the prefrontal cortex of 72 postmortem brain samples spanning half a century of human aging (18-67 years), each without history of neuropsychiatric illness, neurological disease, or drug abuse. Examination of expression across age allowed the identification of genes whose expression patterns correlate with age, as well as genes that share common expression patterns and that possibly participate in common cellular mechanisms related to the emergence of schizophrenia in early adult life. The expression of GRM3 and RGS4 decreased across the entire age range surveyed, while that of PRODH and DARPP-32 was shown to increase with age. NRG1, ERBB3, and NGFR show expression changes during the years of greatest risk for the development of schizophrenia. Expression of FEZ1, GAD1, and RGS4 showed especially high correlation with one another, in addition to the strongest mean levels of absolute correlation with all other genes studied here. All microarray data are available at NCBI's Gene Expression Omnibus: GEO Series accession number GSE11546 (http://www.ncbi.nlm.nih.gov/geo) [corrected] |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 68 | J. Hum. Genet. 2008 -1 53: 739-46 |
| PMID | 18584117 |
| Title | Two-stage designs to identify the effects of SNP combinations on complex diseases. |
| Abstract | The genetic basis of complex diseases is expected to be highly heterogeneous, with many disease genes, where each gene by itself has only a small effect. Based on the nonlinear contributions of disease genes across the genome to complex diseases, we introduce the concept of single nucleotide polymorphism (SNP) synergistic blocks. A two-stage approach is applied to detect the genetic association of synergistic blocks with a disease. In the first stage, synergistic blocks associated with a complex disease are identified by clustering SNP patterns and choosing blocks within a cluster that minimize a diversity criterion. In the second stage, a logistic regression model is given for a synergistic block. Using simulated case-control data, we demonstrate that our method has reasonable power to identify gene-gene interactions. To further evaluate the performance of our method, we apply our method to 17 loci of four candidate genes for paranoid schizophrenia in a Chinese population. Five synergistic blocks are found to be associated with schizophrenia, three of which are negatively associated (odds ratio, OR < 0.3, P < 0.05), while the others are positively associated (OR > 2.0, P < 0.05). The mathematical models of these five synergistic blocks are presented. The results suggest that there may be interactive effects for schizophrenia among variants of the genes neuregulin 1 (NRG1, 8p22-p11), G72 (13q34), the regulator of G-protein signaling-4 (RGS4, 1q21-q22) and frizzled 3 (FZD3, 8p21). Using synergistic blocks, we can reduce the dimensionality in a multi-locus association analysis, and evaluate the sizes of interactive effects among multiple disease genes on complex phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 69 | Schizophr. Res. 2008 Dec 106: 208-17 |
| PMID | 18804346 |
| Title | Interaction between interleukin 3 and dystrobrevin-binding protein 1 in schizophrenia. |
| Abstract | schizophrenia is a common psychotic mental disorder that is believed to result from the effects of multiple genetic and environmental factors. In this study, we explored gene-gene interactions and main effects in both case-control (657 cases and 411 controls) and family-based (273 families, 1,350 subjects) datasets of English or Irish ancestry. Fifty three markers in 8 genes were genotyped in the family sample and 44 markers in 7 genes were genotyped in the case-control sample. The Multifactor Dimensionality Reduction Pedigree Disequilibrium Test (MDR-PDT) was used to examine epistasis in the family dataset and a 3-locus model was identified (permuted p=0.003). The 3-locus model involved the IL3 (rs2069803), RGS4 (rs2661319), and DTNBP1 (rs2619539) genes. We used MDR to analyze the case-control dataset containing the same markers typed in the RGS4, IL3 and DTNBP1 genes and found evidence of a joint effect between IL3 (rs31400) and DTNBP1 (rs760761) (cross-validation consistency 4/5, balanced prediction accuracy=56.84%, p=0.019). While this is not a direct replication, the results obtained from both the family and case-control samples collectively suggest that IL3 and DTNBP1 are likely to interact and jointly contribute to increase risk for schizophrenia. We also observed a significant main effect in DTNBP1, which survived correction for multiple comparisons, and numerous nominally significant effects in several genes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 70 | Schizophr Bull 2008 Jan 34: 118-26 |
| PMID | 17515439 |
| Title | Linkage disequilibrium patterns and functional analysis of RGS4 polymorphisms in relation to schizophrenia. |
| Abstract | The regulator of G-protein signaling 4 (RGS4, chromosome 1q23.3) plays a critical role in G-protein function. Four common single-nucleotide polymorphisms (SNPs) localized between the 5' upstream sequence and the first intron, as well as 2 haplotypes derived from these SNPs may confer liability to schizophrenia (SZ). However, the pattern of associations varies among samples. To help clarify the putative associations, we report the following analyses: (1) a comprehensive catalog of common polymorphisms, (2) linkage disequilibrium (LD) and association analyses using these SNPs, and (3) functional analysis based on dual-luciferase promoter assays. We identified 62 SNPs from a 20-kb genomic region spanning RGS4, of which 26 are common polymorphisms with a minor allele frequency (MAF) of >5%. LD analysis suggested 5 clusters of SNPs (r(2) > .8). Association analyses using the novel SNPs were consistent with the prior reports, but further localization was constrained by significant LD across the region. The 2 haplotypes reported to confer liability to SZ had significant promoter activity compared with promoterless constructs, suggesting a functional role for both haplotypes. Further analyses of promoter sequences are warranted to understand transcriptional regulation at RGS4. This information will be useful for further analysis of samples in which genetic association of RGS4 polymorphisms with SZ has been reported. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 71 | Schizophr. Res. 2008 Apr 101: 67-75 |
| PMID | 18262772 |
| Title | Association of RGS2 and RGS5 variants with schizophrenia symptom severity. |
| Abstract | Several lines of evidence indicate that Regulator of G Protein Signaling 4 (RGS4) contributes to schizophrenia vulnerability. RGS4 is one of a family of molecules that modulate signaling via G-protein coupled receptors. Five genes encoding members of this family (RGS2, RGS4, RGS5, RGS8 and RGS16) map to chromosome 1q23.3-1q31. Due to overlapping cellular functions and chromosomal proximity, we hypothesized that multiple RGS genes may contribute to schizophrenia severity and treatment responsiveness. Subjects were 750 individuals with schizophrenia who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Inferred ancestries were: 221 (30%) 'Africa only', 422 (56%) 'Europe only' and 107 (14%) 'Other'. Fifty-nine single nucleotide polymorphisms (SNPs) in or near the RGS5, RGS16, RGS8 and RGS2 genes were genotyped. Multiple linear regression was used to analyze association of markers with Positive and Negative Symptoms Scale (PANSS) total scores at baseline and throughout antipsychotic treatment. RGS5 marker rs10799902 was associated with altered baseline PANSS total score in both the Africa only (P=0.0440) and Europe only (P=0.0143) strata, although neither association survived multiple comparisons correction. A common five-marker haplotype of the RGS2 gene was associated with more severe baseline PANSS total score in the Europe only strata (global P=0.0254; haplotype-specific P=0.0196). In contrast to RGS4, none of the markers showed association with antipsychotic treatment response. RGS2 and RGS5 genotypes predicted severity of baseline symptoms in schizophrenia. Although these analyses are exploratory and replication is required, these data suggest a possible role for multiple RGS proteins in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 72 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 606-11 |
| PMID | 18163393 |
| Title | Gene copy number variation in schizophrenia. |
| Abstract | Recent reports have highlighted the possibility that gene copy number variations play a role in the development of complex disorders and have suggested that some variations are very common in schizophrenic patients. We have carried out a comparative genomic hybridization screen using oligonucleotide probes of 891 candidate genes to look for very common copy number variance in schizophrenic patients. In addition we have developed a new approach for the detection and validation of putative copy number variation based upon established methods of allele quantification by DNA pooling and have used it to study 15 major candidates including dysbindin (DTNBP1), neuregulin (NRG1), RGS4 and DISC1. With the exception of positive control sequences, no copy number variations were found for any of the genes in any samples by the use of either technique. Our data for the genes studied are in line with the known existence and frequency of CNVs as reported by recent large scale studies and suggest that gene copy number variations are not more common in schizophrenics than controls, although large ethnic differences cannot be excluded. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 73 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 606-11 |
| PMID | 18163393 |
| Title | Gene copy number variation in schizophrenia. |
| Abstract | Recent reports have highlighted the possibility that gene copy number variations play a role in the development of complex disorders and have suggested that some variations are very common in schizophrenic patients. We have carried out a comparative genomic hybridization screen using oligonucleotide probes of 891 candidate genes to look for very common copy number variance in schizophrenic patients. In addition we have developed a new approach for the detection and validation of putative copy number variation based upon established methods of allele quantification by DNA pooling and have used it to study 15 major candidates including dysbindin (DTNBP1), neuregulin (NRG1), RGS4 and DISC1. With the exception of positive control sequences, no copy number variations were found for any of the genes in any samples by the use of either technique. Our data for the genes studied are in line with the known existence and frequency of CNVs as reported by recent large scale studies and suggest that gene copy number variations are not more common in schizophrenics than controls, although large ethnic differences cannot be excluded. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 74 | Behav Brain Funct 2008 -1 4: 46 |
| PMID | 18834502 |
| Title | Association of RGS4 variants with schizotypy and cognitive endophenotypes at the population level. |
| Abstract | While association studies on schizophrenia show conflicting results regarding the importance of the regulator of the G-protein signaling 4 (RGS4) gene, recent work suggests that RGS4 may impact on the structural and functional integrity of the prefrontal cortex. We aimed to study associations of common RGS4 variants with prefrontal dependent cognitive performance and schizotypy endophenotypes at the population level. Four RGS4 single nucleotide polymorphisms (SNP1 [rs10917670], SNP4 [rs951436], SNP7 [rs951439], and SNP18 [rs2661319]) and their haplotypes were selected. Their associations with self-rated schizotypy (SPQ), vigilance, verbal, spatial working memory and antisaccade eye performance were tested with regressions in a representative population of 2,243 young male military conscripts. SNP4 was associated with negative schizotypy (higher SPQ negative factor for common T allele, p = 0.009; p = 0.031 for differences across genotypes) and a similar trend was seen also for common A allele of SNP18 (p = 0.039 for allele-load model; but p = 0.12 for genotype differences). Haplotype analyses showed a similar pattern with a dose-response for the most common haplotype (GGGG) on the negative schizotypy score with or without adjustment for age, IQ and their interaction (p = 0.011 and p = 0.024, respectively). There was no clear evidence for any association of the RGS4 variants with cognitive endophenotypes, except for an isolated effect of SNP18 on antisaccade error rate (p = 0.028 for allele-load model). Common RGS4 variants were associated with negative schizotypal personality traits amongst a large cohort of young healthy individuals. In accordance with recent findings, this may suggest that RGS4 variants impact on the functional integrity of the prefrontal cortex, thus increasing susceptibility for psychotic spectrum disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 75 | Eur. J. Hum. Genet. 2008 Oct 16: 1275-82 |
| PMID | 18414510 |
| Title | Confirmation of the genetic association between the U2AF homology motif (UHM) kinase 1 (UHMK1) gene and schizophrenia on chromosome 1q23.3. |
| Abstract | UHMK1 has previously been implicated as a susceptibility gene for schizophrenia in the 1q23.3 region by significant evidence of allelic and haplotypic association between schizophrenia and several genetic markers at UHMK1 in a London-based case-control sample. Further fine mapping of the UHMK1 gene locus in the University College London schizophrenia case-control sample was carried out with tagging SNPs. Two additional SNPs were found to be associated with schizophrenia (rs6604863 P = 0.02, rs10753578 P = 0.017). Tests of allelic and haplotypic association were then carried out in a second independent sample from Aberdeen consisting of 858 individuals with schizophrenia and 591 controls. Two of these SNPs also showed association in the Aberdeen sample (rs7513662 P = 0.0087, rs10753578 P = 0.022) and several haplotypes were associated (global permutation P = 0.0004). When the UCL and Aberdeen samples were combined three SNPs (rs7513662 P = 0.0007, rs6427680 P = 0.0252, rs6694863 P = 0.015) and several haplotypes showed association (eg HAP-A, HAP-B, HAP-C permutation P = 0.00005). The finding of allelic association with markers in the UHMK1 gene might help explain why it has not been possible, despite great effort, to satisfactorily confirm previously reported associations between schizophrenia and the genes RGS4 and NOS1AP/CAPON. These genes flank UHMK1 and all three loci are within a 700 kb region showing linkage to schizophrenia. The confirmation of association between UHMK1 and schizophrenia, rather than RGS4 and NOS1AP in the London sample, points to the possibility that previous efforts to accurately fine map a gene in the 1q23.3 region have lacked accuracy or may have suffered from methodological flaws. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 76 | J Clin Psychopharmacol 2008 Feb 28: 64-8 |
| PMID | 18204343 |
| Title | RGS4 polymorphisms predict clinical manifestations and responses to risperidone treatment in patients with schizophrenia. |
| Abstract | Polymorphisms of the gene encoding the regulator of G-protein signaling subtype 4 (RGS4) are associated with schizophrenia. This study aims to investigate the association of 4 RGS4 polymorphisms (single nucleotide polymorphisms [SNPs] 1, 4, 7, and 18), implicated in previous studies, with baseline symptoms and treatment response to risperidone in patients with schizophrenia. One hundred twenty patients with acutely exacerbated schizophrenia who had never been treated by atypical antipsychotics were recruited. They received optimal treatment of risperidone for up to 42 days in the inpatient research unit. Patients' social functions were monitored by Nurses' Observation Scale for Inpatients Evaluation and clinical manifestations, by Positive and Negative Syndrome Scale. At baseline status, the A/A genotype at SNP7 of RGS4 was associated with poorer social function when compared with the G/G genotype. After risperidone treatment, the A/A genotype at SNP1 was associated with greater improvement at social function, and the A/A genotype at SNP18 was associated with greater improvement at social function, Positive and Negative Syndrome Scale total score, and positive- and negative-symptom subscale. These findings suggest that RGS4 variances influence clinical manifestations of schizophrenia as well as the treatment response to risperidone, suggesting that RGS4 plays a role in the fundamental process of disease pathophysiology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 77 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jan 147B: 77-85 |
| PMID | 17722013 |
| Title | An association study of RGS4 polymorphisms with clinical phenotypes of schizophrenia in a Chinese population. |
| Abstract | The regulator of G-protein signaling 4 (RGS4) has been suggested as a candidate gene for schizophrenia. However, following an initial positive report, subsequent association studies between RGS4 and schizophrenia have yielded inconclusive results. Also, few studies have investigated the association of RGS4 polymorphisms with the phenotypic subgroups of schizophrenia. To further clarify the role of RGS4 in this disease, we performed a case-control study (504 cases and 531 controls of Han Chinese descent) to examine the association of RGS4 with schizophrenia and with clinical and neurocognitive profiles. The four markers (SNPs 1, 4, 7, and 18) implicated in the original association study were genotyped. We detected significant association of four-marker haplotypes with schizophrenia (UNPHASED: global P = 0.037; PHASE: global P = 0.048). The haplotype G-G-G-G, which was implicated in at least three previous studies, was the major risk haplotype (UNPHASED: P = 0.019; PHASE: P = 0.010). Regarding the clinical phenotypes, the Wechsler Adult Intelligence Test (WAIS) information subtest score was associated with SNP4 genotypes (P = 0.001). PANSS total and global psychopathology scores were also associated with SNP4, but may not reliably reflect the general severity of disease as the scores may be affected by confounders like medication response. Our study provides further support for a role of RGS4 in the pathogenesis of schizophrenia. We identified G-G-G-G as the risk haplotype in our Chinese sample. The association with information subtest score suggests an effect of RGS4 on premorbid functioning, which may be related to neurodevelopmental processes. Further independent studies are required to verify our findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 78 | Biol. Psychiatry 2008 Jan 63: 32-41 |
| PMID | 17588543 |
| Title | Ethnic stratification of the association of RGS4 variants with antipsychotic treatment response in schizophrenia. |
| Abstract | Genetic association studies, including a large meta-analysis, report association of regulator of G protein signaling 4 (RGS4) with schizophrenia in the context of heterogeneity. The central role of RGS4 in regulating signaling via Gi/o coupled neurotransmitter receptors led us to hypothesize that there may be RGS4 genotypes predictive of specific disease phenotypes and antipsychotic treatment responses. Subjects were 678 individuals with schizophrenia who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Among the 678 subjects, the inferred ancestries were 198 (29%) "Africa only," 397 (59%) "Europe only," and 83 (12%) "Other." Eight single nucleotide polymorphisms (SNPs) spanning RGS4 were genotyped. Multiple linear regression was used to analyze association of RGS4 markers with Positive and Negative Symptoms Scale (PANSS) scores at baseline and throughout antipsychotic treatment. Two consecutive markers within RGS4, rs2661319 and rs2842030, were associated with more severe baseline PANSS total score. Treatment with perphenazine was more effective than treatment with quetiapine (p = .010) or ziprasidone (p = .002) in individuals of inferred African ancestry and homozygous for the rs951439 C allele. RGS4 genotypes predicted both the severity of baseline symptoms and relative responsiveness to antipsychotic treatment. Although these analyses are exploratory and replication is required, these data provide support for RGS4 in schizophrenia pathogenesis and suggest a functional role for RGS4 in differential antipsychotic treatment efficacy of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 79 | Behav Brain Funct 2008 -1 4: 46 |
| PMID | 18834502 |
| Title | Association of RGS4 variants with schizotypy and cognitive endophenotypes at the population level. |
| Abstract | While association studies on schizophrenia show conflicting results regarding the importance of the regulator of the G-protein signaling 4 (RGS4) gene, recent work suggests that RGS4 may impact on the structural and functional integrity of the prefrontal cortex. We aimed to study associations of common RGS4 variants with prefrontal dependent cognitive performance and schizotypy endophenotypes at the population level. Four RGS4 single nucleotide polymorphisms (SNP1 [rs10917670], SNP4 [rs951436], SNP7 [rs951439], and SNP18 [rs2661319]) and their haplotypes were selected. Their associations with self-rated schizotypy (SPQ), vigilance, verbal, spatial working memory and antisaccade eye performance were tested with regressions in a representative population of 2,243 young male military conscripts. SNP4 was associated with negative schizotypy (higher SPQ negative factor for common T allele, p = 0.009; p = 0.031 for differences across genotypes) and a similar trend was seen also for common A allele of SNP18 (p = 0.039 for allele-load model; but p = 0.12 for genotype differences). Haplotype analyses showed a similar pattern with a dose-response for the most common haplotype (GGGG) on the negative schizotypy score with or without adjustment for age, IQ and their interaction (p = 0.011 and p = 0.024, respectively). There was no clear evidence for any association of the RGS4 variants with cognitive endophenotypes, except for an isolated effect of SNP18 on antisaccade error rate (p = 0.028 for allele-load model). Common RGS4 variants were associated with negative schizotypal personality traits amongst a large cohort of young healthy individuals. In accordance with recent findings, this may suggest that RGS4 variants impact on the functional integrity of the prefrontal cortex, thus increasing susceptibility for psychotic spectrum disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 80 | Behav Brain Funct 2008 -1 4: 46 |
| PMID | 18834502 |
| Title | Association of RGS4 variants with schizotypy and cognitive endophenotypes at the population level. |
| Abstract | While association studies on schizophrenia show conflicting results regarding the importance of the regulator of the G-protein signaling 4 (RGS4) gene, recent work suggests that RGS4 may impact on the structural and functional integrity of the prefrontal cortex. We aimed to study associations of common RGS4 variants with prefrontal dependent cognitive performance and schizotypy endophenotypes at the population level. Four RGS4 single nucleotide polymorphisms (SNP1 [rs10917670], SNP4 [rs951436], SNP7 [rs951439], and SNP18 [rs2661319]) and their haplotypes were selected. Their associations with self-rated schizotypy (SPQ), vigilance, verbal, spatial working memory and antisaccade eye performance were tested with regressions in a representative population of 2,243 young male military conscripts. SNP4 was associated with negative schizotypy (higher SPQ negative factor for common T allele, p = 0.009; p = 0.031 for differences across genotypes) and a similar trend was seen also for common A allele of SNP18 (p = 0.039 for allele-load model; but p = 0.12 for genotype differences). Haplotype analyses showed a similar pattern with a dose-response for the most common haplotype (GGGG) on the negative schizotypy score with or without adjustment for age, IQ and their interaction (p = 0.011 and p = 0.024, respectively). There was no clear evidence for any association of the RGS4 variants with cognitive endophenotypes, except for an isolated effect of SNP18 on antisaccade error rate (p = 0.028 for allele-load model). Common RGS4 variants were associated with negative schizotypal personality traits amongst a large cohort of young healthy individuals. In accordance with recent findings, this may suggest that RGS4 variants impact on the functional integrity of the prefrontal cortex, thus increasing susceptibility for psychotic spectrum disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 81 | Curr Opin Psychiatry 2009 Mar 22: 154-60 |
| PMID | 19553869 |
| Title | Recent advances in postmortem pathology and neurochemistry in schizophrenia. |
| Abstract | This is a review examining recent data from the study of the postmortem central nervous system (CNS) of patients with schizophrenia. Studies on the human CNS transcriptome suggest changes in pro-inflammatory pathways and myelination in schizophrenia, whereas changes in the proteome suggest that pathways involved in energy and metabolism may be particularly stressed. There appear to be complex changes in the expression of proposed candidate genes for schizophrenia such as NRG1, DISC1, RGS4 and DTNB1, and there are continued reports of alterations in central gamma-aminobutyric acidergic, dopaminergic, glutamatergic and cholinergic pathways in patients with the disorder. Data on epigenetic mechanisms and transcriptome regulation suggest that at least some changes in gene expression may be due to changes in levels of gene promoter methylation or microRNAs in the CNS of patients with schizophrenia. Postmortem CNS studies have begun to unravel changes in the epigenetic regulation of gene expression that may be central to how gene-environment interactions contribute to the onset of schizophrenia. In addition, a recent study indicates that it is possible to use biomarkers to segregate the syndrome of schizophrenia into more biologically homogeneous populations, which should decrease the biological complexity observed within that group within the schizophrenia syndrome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 82 | Biol. Psychiatry 2009 Mar 65: 541-5 |
| PMID | 19041089 |
| Title | Expression of RGS4 splice variants in dorsolateral prefrontal cortex of schizophrenic and bipolar disorder patients. |
| Abstract | Previous molecular and genetic studies have implicated RGS4 (regulator of G protein signaling 4) in schizophrenia (SCZ) and bipolar disorder (BPD), but the role of RGS4 in the pathology of the two disorders remains controversial. Recently we identified five different RGS4 splice variants in the human brain. In this study we tested whether expression of specific RGS4 splice variants is altered in the prefrontal cortex of schizophrenic and BPD subjects. Quantitative real-time polymerase chain reaction was used to detect overall RGS4 expression and the messenger RNA levels of the four RGS4 splice variants in the prefrontal cortex of schizophrenic (n = 27), BPD (n = 27), and normal (n = 27) subjects. Compared with the normal group, the expression of a specific splice variant RGS4-3 was decreased in the dorsolateral prefrontal cortex of the SCZ group, whereas overall RGS4 expression and expression of other RGS4 isoforms did not differ significantly between the control and SCZ groups. The messenger RNA levels of RGS4 isoforms did not change between the control group and the BPD group. Our results suggest the possibility that alterations in the expression of RGS4-3 contribute to the development of SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 83 | Biol. Psychiatry 2009 Mar 65: 541-5 |
| PMID | 19041089 |
| Title | Expression of RGS4 splice variants in dorsolateral prefrontal cortex of schizophrenic and bipolar disorder patients. |
| Abstract | Previous molecular and genetic studies have implicated RGS4 (regulator of G protein signaling 4) in schizophrenia (SCZ) and bipolar disorder (BPD), but the role of RGS4 in the pathology of the two disorders remains controversial. Recently we identified five different RGS4 splice variants in the human brain. In this study we tested whether expression of specific RGS4 splice variants is altered in the prefrontal cortex of schizophrenic and BPD subjects. Quantitative real-time polymerase chain reaction was used to detect overall RGS4 expression and the messenger RNA levels of the four RGS4 splice variants in the prefrontal cortex of schizophrenic (n = 27), BPD (n = 27), and normal (n = 27) subjects. Compared with the normal group, the expression of a specific splice variant RGS4-3 was decreased in the dorsolateral prefrontal cortex of the SCZ group, whereas overall RGS4 expression and expression of other RGS4 isoforms did not differ significantly between the control and SCZ groups. The messenger RNA levels of RGS4 isoforms did not change between the control group and the BPD group. Our results suggest the possibility that alterations in the expression of RGS4-3 contribute to the development of SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 84 | Cereb. Cortex 2009 Sep 19: 2145-55 |
| PMID | 19153107 |
| Title | Mapping the regulator of G protein signaling 4 (RGS4): presynaptic and postsynaptic substrates for neuroregulation in prefrontal cortex. |
| Abstract | Regulator of G protein signaling 4 (RGS4) regulates intracellular signaling via G proteins and is markedly reduced in the prefrontal cortex (PFC) of patients with schizophrenia. Characterizing the expression of RGS4 within individual neuronal compartments is thus key to understanding its actions on individual G protein-coupled receptors (GPCRs). Here we present an ultrastructural reference map of RGS4 protein in macaque PFC based on immunogold electron microscopic analysis. At the soma, all labeling was asynaptic and affiliated with subsurface cistern microdomains of pyramidal neurons. The nucleus displayed most of immunoreactivity. RGS4 levels were particularly high along proximal apical dendrites and markedly decreased with distance from the soma; clustered label was present at the bifurcation into second-order branches. In distal dendrites and in spines, the protein was found flanking or directly facing the postsynaptic density of symmetric and asymmetric synapses. Axons also expressed RGS4. In fact, the density and distribution of pre- and postsynaptic labeling was correlated with the axon ultrastructure and the type of established synapses. The data indicate that RGS4 is strategically positioned to regulate not only postsynaptic but also presynaptic signaling in response to synaptic and nonsynaptic GPCR activation, having broad yet highly selective influences on multiple aspects of PFC cellular physiology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 85 | J. Neurochem. 2010 Aug 114: 739-49 |
| PMID | 20477943 |
| Title | RGS9-2 mediates specific inhibition of agonist-induced internalization of D2-dopamine receptors. |
| Abstract | Regulator of G protein signaling 9-2 (RGS9-2), a member of the RGS family of GTPase accelerating proteins, is expressed specifically in the striatum, a brain region involved in controlling movement, motivation, mood and addiction. RGS9-2 can be found co-localized with D(2)-class dopamine receptors in medium spiny striatal neurons and altered functioning of both RGS9-2 and D(2)-like dopamine receptors have been implicated in schizophrenia, movement disorders and reward responses. Previously we showed that RGS9-2 can specifically co-localize with D(2)-dopamine receptors (D2R). Here we provide further evidence of the specificity of RGS9-2 for regulating D2R cellular functions: the expression of RGS9-2 inhibits dopamine-mediated cellular internalization of D2R, while the expression of another RGS protein, RGS4, had no effect. In addition, the agonist-mediated internalization of the G protein coupled delta opioid receptor was unaffected by RGS9-2 expression. We utilized mutant constructs of RGS9-2 to show that the RGS9-2 DEP (for Disheveled, EGL-10, Pleckstrin homology) domain and the GTPase accelerating activity of RGS9-2 were necessary for mediating specific inhibition of D2R internalization. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 86 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Apr 153B: 792-801 |
| PMID | 19937977 |
| Title | Association study of NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A with schizophrenia and symptom severity in a Hungarian sample. |
| Abstract | Genetic association studies have yielded extensive but frequently inconclusive data about genetic risk factors for schizophrenia. Clinical and genetic heterogeneity are possible factors explaining the inconsistent findings. The objective of this study was to test the association of commonly incriminated candidate genes with two clinically divergent subgroups, non-deficit (SZ-ND) and deficit-schizophrenia (SZ-D), and symptom severity, in order to test for replication of previously reported results. A homogeneous sample of 280 schizophrenia patients and 230 healthy controls of Hungarian, Caucasian descent were genotyped for polymorphisms in schizophrenia candidate genes NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A. Patients were divided into the diagnostic subgroups of SZ-ND and SZ-D using the Schedule for Deficit Syndrome (SDS), and assessed clinically by the Positive and Negative Symptom Scale (PANSS). SNP8NRG241930 in NRG1 and rs1011313 in DTNBP1 were associated with SZ-ND (P = 0.04 and 0.03, respectively). Polymorphisms in RGS4, G72/G30, and PIP5K2A were neither associated with SZ-ND nor with SZ-D. SNP8NRG241930 showed association with the PANSS cognitive and hostility/excitability factors, rs1011313 with the negative factor and SDS total score, and rs10917670 in RGS4 was associated with the depression factor. Although these results replicate earlier findings about the genetic background of SZ-ND and SZ-D only partially, our data seem to confirm previously reported association of NRG1 with schizophrenia without prominent negative symptoms. It was possible to detect associations of small-to-medium effect size between the investigated candidate genes and symptom severity. Such studies have the potential to unravel the possible connection between genetic and clinical heterogeneity in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 87 | Am J Psychiatry 2010 Dec 167: 1489-98 |
| PMID | 20889653 |
| Title | Alterations in metabotropic glutamate receptor 1? and regulator of G protein signaling 4 in the prefrontal cortex in schizophrenia. |
| Abstract | Certain cognitive deficits in individuals with schizophrenia have been linked to disturbed gamma-aminobutyric acid (GABA) and glutamate neurotrans-mission in the prefrontal cortex. Thus, it is important to understand how the mechanisms that regulate GABA and glutamate neurotransmission are altered in schizophrenia. For example, group I metabo-tropic glutamate receptors (mGluR1?, mGluR5) modulate both GABA and gluta-mate systems. In addition, regulator of G protein signaling 4 (RGS4) reduces intra-cellular signaling through several different G protein-coupled receptors, including group I mGluRs. Finally, the endocannabinoid system plays an important role in regulating GABA and glutamate neurotrans-mission. The status of endocannabinoid ligands, such as 2-arachidonoylglycerol, can be inferred in part through measures of diacylglycerol lipase and monoglyceride lipase, which synthesize and degrade 2-arachidonoylglycerol, respectively. Quantitative polymerase chain reaction was used to measure mRNA levels for group I mGluRs, RGS4, and markers of the endocannabinoid system in the prefrontal cortex Brodmann's area 9 of 42 schizophrenia subjects and matched normal comparison subjects. Similar analyses in monkeys chronically exposed to haloperidol, olanzapine, or placebo were also conducted. schizophrenia subjects had higher mRNA levels for mGluR1? and lower mRNA levels for RGS4, and these differences did not appear to be attributable to antipsychotic medications or other potential confounds. In contrast, no differences between subject groups were found in mRNA levels for endocannabinoid synthesizing and metabolizing enzymes. Together, higher mGluR1? and lower RGS4 mRNA levels may represent a disturbed "molecular hub" in schizophrenia that may disrupt the function of prefrontal cortical networks, including both GABA and glutamate systems. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 88 | Schizophr Bull 2010 Sep 36: 983-90 |
| PMID | 19282471 |
| Title | RGS4 polymorphisms associated with variability of cognitive performance in a family-based schizophrenia sample. |
| Abstract | Polymorphisms of the gene encoding the regulator of G protein signaling, subtype 4 (RGS4), may be associated with schizophrenia. Among first-episode schizophrenia patients, they are also associated with dorsolateral prefrontal cortex (DLPFC) volume. The DLPFC is a key region that regulates heritable cognitive functions implicated in schizophrenia pathogenesis. To further understand the relationship of RGS4 variants to schizophrenia, we examined their associations with cognitive functions among schizophrenia patients and their relatives. We analyzed 31 multiplex, multigenerational Caucasian families with schizophrenia recruited on the basis of 2 affected first-degree relatives. All participants underwent a computerized neurocognitive battery that evaluates accuracy and speed (response time) of performance on abstraction/mental flexibility; attention; verbal, spatial, and face memory; and spatial ability. "Tag" single-nucleotide polymorphisms (SNPs) representing common polymorphisms were genotyped. Measured genotype analyses accounting for family relationships were performed using Sequential Oligogenic Linkage Analysis Routines. SNPs rs10917670 ("SNP1") and rs951439 ("SNP7") were associated with face memory speed (P = .0003) at a significance level that survived Bonferroni correction (P = .039). The same SNPs have earlier been reported to be associated with schizophrenia. There also were uncorrected associations with rs10917670 ("SNP1") and rs951439 ("SNP7") on face memory efficiency (P = .03) and verbal memory efficiency (P = 0.02), rs28757217 on abstraction/mental flexibility speed (P = .02) and verbal memory efficiency (P = .03), SNP18 (rs2661319) on spatial memory accuracy (P = 0.02) and face memory speed (P = .03). RGS4 polymorphisms are associated with variations in cognitive functions and contribute a small but statistically significant proportion of variance in a family-based sample. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 89 | Neuropsychopharmacol Hung 2011 Dec 13: 205-10 |
| PMID | 22184188 |
| Title | Genetic predisposition to schizophrenia: what did we learn and what does the future hold? |
| Abstract | schizophrenia is a complex, devastating brain disorder with clear genetic and environmental contributions to the emergence of the disease. In the last several decades of research hundreds of millions of dollars were spent of the elusive search for schizophrenia susceptibility genes, but the results have been meager. Researchers have identified a number of genetic variants that predispose the brain to developing the disease, yet alone they can explain only a very small number of the schizophrenia occurrence. Vulnerability in DISC1, NRG1, DTNBP1, RGS4, KCNH2, COMT, AKT1 and other putative schizophrenia genes, together with copy number variants, leave unexplained the vast majority of diseased cases. Furthermore, most of the uncovered disease-associated genetic variants have been inconsistently replicated across multiple cohorts and do not lead to altered protein structure. In summary, we argue that large-scale genetic studies will not provide us with the answers we seek: we have to accept that there are no schizophrenia-predisposing genes with large effect sizes, and due to the diversity of findings, genetics-based novel therapies of schizophrenia are not realistic. The new treatments will have to come from functional studies of intracellular pathways and understanding the confluence of environmental influences and genetic predisposition, and their combined effects on developmental mechanisms and intracellular cascades. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 90 | Neuro Endocrinol. Lett. 2011 -1 32: 246-52 |
| PMID | 21712773 |
| Title | The effects of siRNA-mediated RGS4 gene silencing on the whole genome transcription profile: implications for schizophrenia. |
| Abstract | The regulator of G-protein signaling (RGS) molecules represent a class of proteins that modulate the signaling activity of G-protein coupled receptors. Regulator of G-protein signaling 4 (RGS4) is of particular interest in schizophrenia due to reported downregulation of RGS4 transcripts in schizophrenia as well as a connection between RGS4 and a number of receptors implicated in schizophrenia. The mechanism of RGS4 involvement in the pathophysiology of this illness is not clear. To elucidate thise role of RGS4 in pathophysiology of schizophrenia, we silenced RGS4 using siRNAs in human neuroblastoma cell lines and we studied the effects of differential RGS4 expression by microarray. The cell lines with downregulated expression of RGS4 showed 67 genes with changed expression (30 underexpressed and 37 overexpressed). We have detected three subgroups of genes which might be implicated in schizophrenia pathophysiology: histone genes, which suggest epigenetic mechanisms of the disease; genes for transcription factors associated with other genes relevant to schizophrenia pathology (BDNF and DISCI1) and a heterogeneous group containing genes for G-proteins (GPR50 and GPR64) and calcium binding proteins. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 91 | PLoS ONE 2011 -1 6: e19239 |
| PMID | 21541283 |
| Title | Sim1 is a novel regulator in the differentiation of mouse dorsal raphe serotonergic neurons. |
| Abstract | Mesencephalic dopaminergic neurons (mDA) and serotonergic (5-HT) neurons are clinically important ventral neuronal populations. Degeneration of mDA is associated with Parkinson's disease; defects in the serotonergic system are related to depression, obsessive-compulsive disorder, and schizophrenia. Although these neuronal subpopulations reveal positional and developmental relationships, the developmental cascades that govern specification and differentiation of mDA or 5-HT neurons reveal missing determinants and are not yet understood. We investigated the impact of the transcription factor Sim1 in the differentiation of mDA and rostral 5-HT neurons in vivo using Sim1-/- mouse embryos and newborn pups, and in vitro by gain- and loss-of-function approaches. We show a selective significant reduction in the number of dorsal raphe nucleus (DRN) 5-HT neurons in Sim1-/- newborn mice. In contrast, 5-HT neurons of other raphe nuclei as well as dopaminergic neurons were not affected. Analysis of the underlying molecular mechanism revealed that tryptophan hydroxylase 2 (Tph2) and the transcription factor Pet1 are regulated by Sim1. Moreover, the transcription factor Lhx8 and the modulator of 5-HT(1A)-mediated neurotransmitter release, RGS4, exhibit significant higher expression in ventral hindbrain, compared to midbrain and are target genes of Sim1. The results demonstrate for the first time a selective transcription factor dependence of the 5-HT cell groups, and introduce Sim1 as a regulator of DRN specification acting upstream of Pet1 and Tph2. Moreover, Sim1 may act to modulate serotonin release via regulating RGS4. Our study underscores that subpopulations of a common neurotransmitter phenotype use distinct combinations of transcription factors to control the expression of shared properties. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 92 | Psychiatr. Genet. 2012 Oct 22: 263-4 |
| PMID | 22157635 |
| Title | Lack of association between the regulator of G-protein signaling 4 (RGS4) rs951436 polymorphism and schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 93 | Psychol Med 2012 Apr 42: 757-67 |
| PMID | 21910931 |
| Title | Schizophrenia-related RGS4 gene variations specifically disrupt prefrontal control of saccadic eye movements. |
| Abstract | The gene encoding the regulator of G-protein signaling subtype 4 (RGS4), located on chromosome 1q23-3, has been proposed as a possible susceptibility gene for schizophrenia and has been specifically linked to prefrontal cortical structural and functional integrity. The effects of four core single nucleotide polymorphisms (SNPs) within the RGS4 gene on oculomotor parameters in a battery of oculomotor tasks (saccade, antisaccade, smooth eye pursuit, fixation) were investigated in a sample of 2243 young male military conscripts. The risk allele of RGS4SNP18 was found to be associated with two variables of antisaccade performance, increased error rate and variation in the correct antisaccade latency. By contrast, the same allele and also the risk allele of RGS4SNP4 led to an improvement in smooth eye pursuit performance (increased gain). Structural equation modeling confirmed that the combined gene variation of RGS4SNP4 and RGS4SNP18 was a significant predictor of antisaccade but not smooth eye pursuit performance. These results provide evidence for a specific effect of schizophrenia-related RGS4 genotype variations to prefrontal dysfunction measured by oculomotor indices of performance in normal individuals, further validating the hypothesis that RGS4 is related to prefrontal dysfunction in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 94 | PLoS ONE 2012 -1 7: e44564 |
| PMID | 22970249 |
| Title | Hypoxic induction of the regulator of G-protein signalling 4 gene is mediated by the hypoxia-inducible factor pathway. |
| Abstract | The transcriptional response to hypoxia is largely dependent on the Hypoxia Inducible Factors (HIF-1 and HIF-2) in mammalian cells. Many target genes have been characterised for these heterodimeric transcription factors, yet there is evidence that the full range of HIF-regulated genes has not yet been described. We constructed a TetON overexpression system in the rat pheochromocytoma PC-12 cell line to search for novel HIF and hypoxia responsive genes. The RGS4 gene encodes the Regulator of G-Protein Signalling 4 (RGS4) protein, an inhibitor of signalling from G-protein coupled receptors, and dysregulation of RGS4 is linked to disease states such as schizophrenia and cardiomyopathy. RGS4 was found to be responsive to HIF-2? overexpression, hypoxic treatment, and hypoxia mimetic drugs in PC-12 cells. Similar responses were observed in human neuroblastoma cell lines SK-N-SH and SK-N-BE(2)C, but not in endothelial cells, where RGS4 transcript is readily detected but does not respond to hypoxia. Furthermore, this regulation was found to be dependent on transcription, and occurs in a manner consistent with direct HIF transactivation of RGS4 transcription. However, no HIF binding site was detectable within 32 kb of the human RGS4 gene locus, leading to the possibility of regulation by long-distance genomic interactions. Further research into RGS4 regulation by hypoxia and HIF may result in better understanding of disease states such as schizophrenia, and also shed light on the other roles of HIF yet to be discovered. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 95 | Psychopharmacology (Berl.) 2012 Jun 221: 621-35 |
| PMID | 22193724 |
| Title | RGS4 overexpression in the rat dorsal striatum modulates mGluR5- and amphetamine-mediated behavior and signaling. |
| Abstract | Regulator of G-protein signaling 4 (RGS4) is a brain-enriched negative modulator of G-protein-coupled receptor signaling. Decreased availability of RGS4 in the frontal cortex and striatum has been described in animal models of schizophrenia and drug addiction. However, cellular and behavioral consequences of dysregulated RGS4-dependent receptor signaling in the brain remain poorly understood. This study aims to investigate whether RGS4, through inhibiting the function of mGluR5 receptors in the dorsal striatum (dSTR), regulates cellular and behavioral responses to acute amphetamine. After herpes simplex virus-RGS4 was infused into the dSTR, RGS4 overexpression as well as binding of recombinant RGS4 to mGluR5 was assessed. The effect of RGS4 overexpression on behavioral activity induced by the intrastriatal mGluR5 agonist, DHPG, or amphetamine was recorded. Activation of extracellular signal-regulated kinase (ERK) and Akt (protein kinase B) was measured in the dSTR tissue at the end of each behavioral experiment. RGS4 overexpressed in the dSTR coimmunoprecipitated with mGluR5 receptors and suppressed both behavioral activity and phospho-ERK levels induced by DHPG. RGS4 overexpression or the mGluR5 antagonist, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP), attenuated amphetamine-induced phospho-ERK (but not phospho-Akt) levels. RGS4 suppressed amphetamine-induced vertical activity and augmented horizontal activity over 90 min. Similarly, MTEP augmented amphetamine-induced horizontal activity, but did not affect vertical activity. The present data demonstrate that RGS4 in the dSTR attenuates amphetamine-induced ERK signaling and decreases the behavioral efficacy of acute amphetamine likely by limiting mGluR5 function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 96 | Cell. Mol. Life Sci. 2013 Mar 70: 935-50 |
| PMID | 23052218 |
| Title | Zebrafish rgs4 is essential for motility and axonogenesis mediated by Akt signaling. |
| Abstract | The schizophrenia susceptibility gene, RGS4, is one of the most intensively studied regulators of G-protein signaling members, well known to be fundamental in regulating neurotransmission. However, little is known about its role in the developing nervous system. We have isolated zebrafish RGS4 and shown that it is transcribed in the developing nervous system. RGS4 knockdown did not affect neuron number and patterning but resulted in locomotion defects and aberrant development of axons. This was confirmed using a selective RGS4 inhibitor, CCG-4986. RGS4 knockdown also attenuated the level of phosphorylated-Akt1, and injection of constitutively-activated AKT1 rescued the motility defects and axonal phenotypes in the spinal cord but not in the hindbrain and trigeminal neurons. Our in vivo analysis reveals a novel role for RGS4 in regulating axonogenesis during embryogenesis, which is mediated by another schizophrenia-associated gene, Akt1, in a region-specific manner. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 97 | Schizophr Bull 2013 May 39: 518-26 |
| PMID | 22499782 |
| Title | Brain vs behavior: an effect size comparison of neuroimaging and cognitive studies of genetic risk for schizophrenia. |
| Abstract | Genetic variants associated with increased risk for schizophrenia (SZ) are hypothesized to be more penetrant at the level of brain structure and function than at the level of behavior. However, to date the relative sensitivity of imaging vs cognitive measures of these variants has not been quantified. We considered effect sizes associated with cognitive and imaging studies of 9 robust SZ risk genes (DAOA, DISC1, DTNBP1, NRG1, RGS4, NRGN, CACNA1C, TCF4, and ZNF804A) published between January 2005-November 2011. Summary data was used to calculate estimates of effect size for each significant finding. The mean effect size for each study was categorized as small, medium, or large and the relative frequency of each category was compared between modalities and across genes. Random effects meta-analysis was used to consider the impact of experimental methodology on effect size. Imaging studies reported mostly medium or large effects, whereas cognitive investigations commonly reported small effects. Meta-analysis confirmed that imaging studies were associated with larger effects. Effect size estimates were negatively correlated with sample size but did not differ as a function of gene nor imaging modality. These observations support the notion that SZ risk variants show larger effects, and hence greater penetrance, when characterized using indices of brain structure and function than when indexed by cognitive measures. However, it remains to be established whether this holds true for individual risk variants, imaging modalities, or cognitive functions, and how such effects may be mediated by a relationship with sample size and other aspects of experimental variability. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 98 | Eur Neuropsychopharmacol 2013 Oct 23: 1182-9 |
| PMID | 23332465 |
| Title | Polymorphisms in microRNA target sites influence susceptibility to schizophrenia by altering the binding of miRNAs to their targets. |
| Abstract | Single nucleotide polymorphisms (SNPs) in 3' untranslated regions (3' UTRs) of genes may affect miRNA binding to messenger RNA and contribute to the risk of disease. Whether the SNPs that modify miRNA binding in the 3' UTR are involved in schizophrenia-related genes remains unclear. We selected 803 SNPs from the 3' UTRs of 425 candidate genes for schizophrenia. The potential target SNPs were recognized by Gibbs free energy of miRNA binding. Some SNPs were associated in the literature with schizophrenia or other related neurological diseases. A case-control study of nine SNPs not previously reported as significant in any disease was carried out in a Chinese-Han cohort. We found that rs3219151 (C>T, GABRA6) showed significant decreased risk for schizophrenia (OR=0.8121, p=0.008, p(adjust)=0.03). Further, two putative target SNPs, rs165599 (COMT) and rs10759 (RGS4) reported in several references previously, were selected for analysis by luciferase assay to determine their modification to miRNA binding. We found that miR-124 showed significantly repressed 3' UTR binding to RGS4 mRNA from the rs10759-C allele (p<0.05). Our results suggest that rs3219151 of GABRA6 was associated significantly to decrease the risk of schizophrenia, rs10759 (RGS4) was possible to increase the risk of schizophrenia by miRNA altering the binding of miRNAs to their targets influencing susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 99 | Chem. Res. Toxicol. 2013 Dec 26: 1832-9 |
| PMID | 24229325 |
| Title | Modification and functional inhibition of regulator of G-protein signaling 4 (RGS4) by 4-hydroxy-2-nonenal. |
| Abstract | Oxidative stress has been implicated as a component of various pathologies including ischemia/reperfusion injury (IRI) and neurodegenerative diseases such as Parkinson's disease (PD) and schizophrenia. Similarly, regulator of G-protein signaling 4 (RGS4) has been implicated as an important player in each of these pathologies. RGS4, like other RGS proteins, is responsible for temporally regulating G-protein coupled receptor signaling by increasing the intrinsic GTPase activity of G? subunit of the heterotrimeric signaling complex. In this study we evaluated whether modification by 4-hydroxy-2-nonenal (4HNE), a common lipid peroxidation product, inhibits RGS4. Using immunoprecipitation, we first determined RGS4 modification was occurring in cells at concentrations of 4HNE within reported physiological conditions. Following this determination, we evaluated modification of RGS4 by 4HNE by both Western blot and mass spectrometry (MS). Once it was established that covalent modification occurred only on cysteine containing constructs, tryptic digest followed by mass spectrometry analysis revealed modification occurs at cysteine residues 71, 148, and 183. In order to determine the effect 4HNE had on RGS4 activity, a steady-state colorimetric assay was used to analyze the GAP activity of ?51-RGS4 as well as the cysteine null mutant. From the data, we determined that RGS4 activity can be modulated by 4HNE through modification at cysteine residues similar to previously reported small molecule inhibition of RGS4. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 100 | Schizophr. Res. 2013 Jul 147: 262-8 |
| PMID | 23684163 |
| Title | Analysis of CpG SNPs in 34 genes: association test with suicide attempt in schizophrenia. |
| Abstract | Suicide is the act of intentionally causing one's own death. The lifetime suicide risk in schizophrenia is 4.9% and 20% to 50% of patients with SCZ will attempt suicide during their life. The other risk factors for suicidal behavior in schizophrenia include prior history of suicide attempts, active psychosis, depression and substance abuse. To date, there are no robust genetic or epigenetic predictors of suicide or suicide attempt in this specific population. We collected detailed clinical information and DNA samples from 241 schizophrenia patients and performed the genetic analyses in suicide attempters and non-attempters, among these patients. Using the structured research interview, we determined the presence of suicide attempt lifetime and then we tested 384 DNA variants in candidate genes supposed to be involved in the neurobiology of schizophrenia. We applied a novel mapping analysis using a specific bioinformatic tool that analyzed only the polymorphic CpG sites in our SNP panel. This analysis looked at the presence or absence of methylation sites affected by the SNP allele. The SNPs in the candidate genes were studied under a different perspective considering their direct contribution to the availability of methylation sites within the gene of interest. The level of potential methylation was compared using a linear model in attempters and non-attempters. Among the 384 SNPs selected from the Illumina Bead Chip only the rs2661319 in the RGS4 gene was significantly associated with suicide attempt (p = 0.002). There were 119 CpG SNPs in the aforementioned panel. The gene-wise potential methylation level of RGS4 was 55% in the attempters and 65% in the non-attempters with a p-value of 0.005. The total level of potential metylation in the overall panel (119 SNPs combined) was not associated with suicide attempt. However, when considering the potential methylation at chromosome 1, we found that suicide attempt (p = 0.036) was associated with lower methylation. The overall results showed no strong association between CpG SNPs and suicide attempt but the information regarding the CpG SNP potential methylation could be used as covariate in future methylation analysis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 101 | Psychopharmacology (Berl.) 2013 Mar 226: 177-88 |
| PMID | 23093381 |
| Title | Brain RGS4 and RGS10 protein expression in schizophrenia and depression. Effect of drug treatment. |
| Abstract | Regulator of G-protein signaling (RGS) proteins, RGS4 and RGS10, may be involved in the pathophysiology of schizophrenia. RGS4 has attracted special interest since the reports of genetic association between SNPs in RGS4 and schizophrenia. However, there is no information about the subcellular distribution of RGS4 and RGS10 proteins in psychiatric disorders. Plasma membrane RGS4 and cytosolic RGS10 protein immunoreactivity in prefrontal cortex from schizophrenic subjects (n?=?25), non-diagnosed suicides (n?=?13), and control subjects (n?=?35), matched by age, gender, and postmortem delay, was analyzed by western blot. A second group of depressed subjects (n?=?25) and control subjects (n?=?25) was evaluated. The effect of the antipsychotic or antidepressant treatments was also assessed. No significant differences in plasma membrane RGS4 and cytosolic RGS10 protein expression were observed between schizophrenic subjects, non-diagnosed suicides, and control subjects. However, RGS4 immunoreactivity was significantly higher (??=?33?±?10 %, p?RGS4 and cytosolic RGS10 proteins did not differ between depressed and matched control subjects. Expression of RGS4 and RGS10 proteins at their predominant subcellular location was studied in the postmortem brain of subjects with psychiatric disorders. The results suggest unaltered membrane RGS4 and cytosolic RGS10 proteins levels in schizophrenia and major depression. Antipsychotic treatment seems to increase membrane RGS4 immunoreactivity. Further studies are needed to elucidate RGS4 and RGS10 functional status. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 102 | Psychopharmacology (Berl.) 2013 Mar 226: 177-88 |
| PMID | 23093381 |
| Title | Brain RGS4 and RGS10 protein expression in schizophrenia and depression. Effect of drug treatment. |
| Abstract | Regulator of G-protein signaling (RGS) proteins, RGS4 and RGS10, may be involved in the pathophysiology of schizophrenia. RGS4 has attracted special interest since the reports of genetic association between SNPs in RGS4 and schizophrenia. However, there is no information about the subcellular distribution of RGS4 and RGS10 proteins in psychiatric disorders. Plasma membrane RGS4 and cytosolic RGS10 protein immunoreactivity in prefrontal cortex from schizophrenic subjects (n?=?25), non-diagnosed suicides (n?=?13), and control subjects (n?=?35), matched by age, gender, and postmortem delay, was analyzed by western blot. A second group of depressed subjects (n?=?25) and control subjects (n?=?25) was evaluated. The effect of the antipsychotic or antidepressant treatments was also assessed. No significant differences in plasma membrane RGS4 and cytosolic RGS10 protein expression were observed between schizophrenic subjects, non-diagnosed suicides, and control subjects. However, RGS4 immunoreactivity was significantly higher (??=?33?±?10 %, p?RGS4 and cytosolic RGS10 proteins did not differ between depressed and matched control subjects. Expression of RGS4 and RGS10 proteins at their predominant subcellular location was studied in the postmortem brain of subjects with psychiatric disorders. The results suggest unaltered membrane RGS4 and cytosolic RGS10 proteins levels in schizophrenia and major depression. Antipsychotic treatment seems to increase membrane RGS4 immunoreactivity. Further studies are needed to elucidate RGS4 and RGS10 functional status. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 103 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jan 48: 287-94 |
| PMID | 23085507 |
| Title | Immune system and glucose metabolism interaction in schizophrenia: a chicken-egg dilemma. |
| Abstract | Impaired glucose metabolism and the development of metabolic syndrome contribute to a reduction in the average life expectancy of individuals with schizophrenia. It is unclear whether this association simply reflects an unhealthy lifestyle or whether weight gain and impaired glucose tolerance in patients with schizophrenia are directly attributable to the side effects of atypical antipsychotic medications or disease-inherent derangements. In addition, numerous previous studies have highlighted alterations in the immune system of patients with schizophrenia. Increased concentrations of interleukin (IL)-1, IL-6, and transforming growth factor-beta (TGF-?) appear to be state markers, whereas IL-12, interferon-gamma (IFN-?), tumor necrosis factor-alpha (TNF-?), and soluble IL-2 receptor (sIL-2R) appear to be trait markers of schizophrenia. Moreover, the mononuclear phagocyte system (MPS) and microglial activation are involved in the early course of the disease. This review illustrates a "chicken-egg dilemma", as it is currently unclear whether impaired cerebral glucose utilization leads to secondary disturbances in peripheral glucose metabolism, an increased risk of cardiovascular complications, and accompanying pro-inflammatory changes in patients with schizophrenia or whether immune mechanisms may be involved in the initial pathogenesis of schizophrenia, which leads to disturbances in glucose metabolism such as metabolic syndrome. Alternatively, shared underlying factors may be responsible for the co-occurrence of immune system and glucose metabolism disturbances in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 104 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2014 Dec 165B: 635-46 |
| PMID | 25209194 |
| Title | Synergistic association of PI4KA and GRM3 genetic polymorphisms with poor antipsychotic response in south Indian schizophrenia patients with low severity of illness. |
| Abstract | Literature indicates key role of glutamatergic pathway genes in antipsychotic response among schizophrenia patients. However, molecular basis of their underlying role in antipsychotic response remained unexplained. Thus, to unravel their molecular underpinnings, we sought to investigate interactions amongst GRM3, SLC1A1, SLC1A2, SLC1A3, SLC1A4 gene polymorphisms with drug response in south Indian schizophrenia patients. We genotyped 48 SNPs from these genes in 423 schizophrenia patients stratified into low and high severity of illness groups. The SNPs and haplotypic combinations of associated SNPs were examined for their association with antipsychotic response. Multifactor-dimensionality-reduction was further used to explore gene-gene interaction among these SNPs and 53 SNPs from previously studied genes (BDNF, RGS4, SLC6A3, PI4KA, and PIP4K2A). Single SNP and haplotype analyses revealed no significant association with drug response irrespective of severity of illness. Gene-gene interaction analyses yielded promising leads, including an observed synergistic effect between PI4KA_rs165854 and GRM3_rs1468412 polymorphisms and incomplete antipsychotic response in schizophrenia patients with low severity of illness (OR = 12.4; 95%CI = 3.69-41.69). Further, this interaction was also observed in atypical monotherapy (n = 355) and risperidone (n = 260) treatment subgroups (OR = 11.21; 95%CI = 3.30-38.12 and OR = 13.5; 95%CI = 3.03-121.61 respectively). PI4KA is known to be involved in the biosynthesis of phosphatidylinositol-4, 5-bisphosphate which regulates exocytotic fusion of synaptic vesicles (glutamate, dopamine) with the plasma membrane and regulates duration of signal transduction of GPCRs. Whereas GRM3 regulates glutamate and dopamine transmission. Present findings indicate that PI4KA and GRM3 polymorphisms have potential to jointly modulate antipsychotic response. These results warrant additional replication studies to shed further light on these interactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 105 | PLoS ONE 2014 -1 9: e102556 |
| PMID | 25025909 |
| Title | Genetic variations of PIP4K2A confer vulnerability to poor antipsychotic response in severely ill schizophrenia patients. |
| Abstract | Literature suggests that disease severity and neurotransmitter signaling pathway genes can accurately identify antipsychotic response in schizophrenia patients. However, putative role of signaling molecules has not been tested in schizophrenia patients based on severity of illness, despite its biological plausibility. In the present study we investigated the possible association of polymorphisms from five candidate genes RGS4, SLC6A3, PIP4K2A, BDNF, PI4KA with response to antipsychotic in variably ill schizophrenia patients. Thus in present study, a total 53 SNPs on the basis of previous reports and functional grounds were examined for their association with antipsychotic response in 423 schizophrenia patients segregated into low and high severity groups. Additionally, haplotype, diplotype, multivariate logistic regression and multifactor-dimensionality reduction (MDR) analyses were performed. Furthermore, observed associations were investigated in atypical monotherapy (n?=?355) and risperidone (n?=?260) treated subgroups. All associations were estimated as odds ratio (OR) and 95% confidence interval (CI) and test for multiple corrections was applied. Single locus analysis showed significant association of nine variants from SLC6A3, PIP4K2A and BDNF genes with incomplete antipsychotic response in schizophrenia patients with high severity. We identified significant association of six marker diplotype ATTGCT/ATTGCT (rs746203-rs10828317-rs7094131-rs2296624-rs11013052-rs1409396) of PIP4K2A gene in incomplete responders (corrected p-value?=?0.001; adjusted-OR?=?3.19, 95%-CI?=?1.46-6.98) with high severity. These associations were further observed in atypical monotherapy and risperidone sub-groups. MDR approach identified gene-gene interaction among BDNF_rs7103411-BDNF_rs1491851-SLC6A3_rs40184 in severely ill incomplete responders (OR?=?7.91, 95%-CI?=?4.08-15.36). While RGS4_rs2842026-SLC6A3_rs2975226 interacted synergistically in incomplete responders with low severity (OR?=?4.09, 95%-CI?=?2.09-8.02). Our findings provide strong evidence that diplotype ATTGCT/ATTGCT of PIP4K2A gene conferred approximately three-times higher incomplete responsiveness towards antipsychotics in severely ill patients. These results are consistent with the known role of phosphatidyl-inositol-signaling elements in antipsychotic action and outcome. Findings have implication for future molecular genetic studies as well as personalized medicine. However more work is warranted to elucidate underlying causal biological pathway. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 106 | Prilozi 2015 -1 36: 53-67 |
| PMID | 26076775 |
| Title | Pharmacogenetics and antipsychotic treatment response. |
| Abstract | (Full text is available at http://www.manu.edu.mk/prilozi). Antipsychotic drugs are widely used in the treatment of schizophrenia and psychotic disorder. The lack of antipsychotic response and treatment-induced side-effects, such as neuroleptic syndrome, polydipsia, metabolic syndrome, weight gain, extrapyramidal symptoms, tardive dyskinesia or prolactin increase, are the two main reasons for non-compliance and increased morbidity in schizophrenic patients. During the past decades intensive research has been done in order to determine the influence of genetic variations on antipsychotics dosage, treatment efficacy and safety. The present work reviews the molecular basis of treatment response of schizophrenia. It highlights the most important findings about the impact of functional polymorphisms in genes coding the CYP450 metabolizing enzymes, ABCB1 transporter gene, dopaminergic and serotonergic drug targets (DRD2, DRD3, DRD4, 5-HT1, 5HT-2A, 5HT-2C, 5HT6) as well as genes responsible for metabolism of neurotransmitters and G signalling pathways (5-HTTLPR, BDNF, COMT, RGS4) and points their role as potential biomarkers in everyday clinical practice. Pharmacogenetic testing has predictive power in the selection of antipsychotic drugs and doses tailored according to the patient's genetic profile. In this perception pharmacogenetics could help in the improvement of treatment response by using different medicinal approaches that would avoid potential adverse effects, reduce stabilization time and will advance the prognosis of schizophrenic patients. Key words: Pharmacogenetics, antipsychotics, schizophrenia, biomarkers, CYP450, P-glycoprotein, seroto-nergic receptors, dopaminergic receptors, COMT, BDNF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 107 | Mol Neuropsychiatry 2015 Jul 1: 82-93 |
| PMID | 26405684 |
| Title | Olanzapine Reversed Brain Gene Expression Changes Induced by Phencyclidine Treatment in Non-Human Primates. |
| Abstract | The NMDA receptor antagonist phencyclidine (PCP) creates schizophrenia-like symptoms in normal controls. The effect of PCP on non-human primate brain gene expression was examined and compared to changes induced by olanzapine treatment. Experimental studies of PCP and antipsychotic drugs have direct relevance to understanding the patho-physiology and treatment of schizophrenia. Genome-wide changes in prefrontal cortex gene expression revealed alterations of 146 transcripts in the PCP treatment group compared to vehicle controls. Dysregulated genes were enriched in identified classes implicated in neurological and genetic disorders, including schizophrenia genes from the Psychiatric Genomics Consortium 108 loci as well as cell death in PCP-treated primates. Canonical pathway analysis revealed a significant overrepresentation of several groups including synaptic long-term potentiation and calcium signaling. Olanzapine coadministered with PCP normalized 34% of the 146 PCP-induced probe set expression changes, and a network of 17 olanzapine-normalized genes was identified enriched in schizophrenia candidate genes containing RGS4, SYN1 and AKT as nodes. The results of this study support the use of PCP administration in non-human primates as a glutamatergic model of schizophrenia and suggest that a large number of PCP-induced expression differences can be reversed by olanzapine. The results of this study may be informative for identification of potential candidates for pharmacogenetics and biomarker research related to the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 108 | Prilozi 2015 -1 36: 53-67 |
| PMID | 26076775 |
| Title | Pharmacogenetics and antipsychotic treatment response. |
| Abstract | (Full text is available at http://www.manu.edu.mk/prilozi). Antipsychotic drugs are widely used in the treatment of schizophrenia and psychotic disorder. The lack of antipsychotic response and treatment-induced side-effects, such as neuroleptic syndrome, polydipsia, metabolic syndrome, weight gain, extrapyramidal symptoms, tardive dyskinesia or prolactin increase, are the two main reasons for non-compliance and increased morbidity in schizophrenic patients. During the past decades intensive research has been done in order to determine the influence of genetic variations on antipsychotics dosage, treatment efficacy and safety. The present work reviews the molecular basis of treatment response of schizophrenia. It highlights the most important findings about the impact of functional polymorphisms in genes coding the CYP450 metabolizing enzymes, ABCB1 transporter gene, dopaminergic and serotonergic drug targets (DRD2, DRD3, DRD4, 5-HT1, 5HT-2A, 5HT-2C, 5HT6) as well as genes responsible for metabolism of neurotransmitters and G signalling pathways (5-HTTLPR, BDNF, COMT, RGS4) and points their role as potential biomarkers in everyday clinical practice. Pharmacogenetic testing has predictive power in the selection of antipsychotic drugs and doses tailored according to the patient's genetic profile. In this perception pharmacogenetics could help in the improvement of treatment response by using different medicinal approaches that would avoid potential adverse effects, reduce stabilization time and will advance the prognosis of schizophrenic patients. Key words: Pharmacogenetics, antipsychotics, schizophrenia, biomarkers, CYP450, P-glycoprotein, seroto-nergic receptors, dopaminergic receptors, COMT, BDNF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 109 | Front Psychiatry 2016 -1 7: 26 |
| PMID | 26973546 |
| Title | Expression of the Longest RGS4 Splice Variant in the Prefrontal Cortex Is Associated with Single Nucleotide Polymorphisms in Schizophrenia Patients. |
| Abstract | The Regulator of G protein signaling 4 (RGS4) gene is a candidate susceptibility gene for schizophrenia (SCZ). Previous studies showed that the mRNA level of the longest splice variant RGS4-1 was decreased in the dorsolateral prefrontal cortex (DLPFC) of SCZ patients compared with healthy controls. In this pilot study, we examined the possible mechanisms of RGS4-1 mRNA reduction in SCZ. We genotyped SNP1 (rs10917670), rs2661347, SNP4 (rs951436), SNP7 (rs951439), SNP18 (rs2661319), and rs10799897 (SNP9897) and tested the methylation status of CpG islands of the RGS4 gene in the postmortem DLPFC samples obtained from subjects with SCZ and bipolar disorder as well as healthy controls. RGS4-1 mRNA level was associated with five SNPs (SNP1, rs2661347, SNP4, SNP7, and SNP18) and their haplotypes but not with SNP9897. In addition, this study revealed that RGS4-1 mRNA was low in subjects with specific genotypes of SNP1, rs2661347, SNP4, SNP7, and SNP18. Lower RGS4-1 mRNA expression in the DLPFC of SCZ is associated with SNPs in the 5' regulatory region of the RGS4 gene but not with the methylation status of its CpG islands. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 110 | Eur Arch Psychiatry Clin Neurosci 2016 Feb -1: -1 |
| PMID | 26910404 |
| Title | Association between RGS4 variants and psychotic-like experiences in nonclinical individuals. |
| Abstract | The psychosis phenotype is expressed across a continuum known as schizotypy, which ranges from personality variation through subclinical symptoms to severe psychopathology. The study of subclinical manifestations in non-affected individuals minimizes confounding factors associated with the clinical phenotype and facilitates the differentiation of dimension-specific etiological mechanisms. The aim of the present study was to investigate the association between the variation in the regulator of G-protein signaling 4 (RGS4) gene, a putative candidate gene for psychosis previously associated with schizophrenia endophenotypes, and psychotic-like experiences (PLEs). In total, 808 healthy individuals completed the community assessment of psychic experiences (CAPE) to measure positive and negative PLEs and provided a DNA sample. Two RGS4 single-nucleotide polymorphisms (SNPs) (rs951436 [SNP4] and rs2661319 [SNP18]) were genotyped. Analyses of covariance (ANCOVA) were used to explore the association of positive and negative PLEs with RGS4 variation. Our results showed associations of positive and negative PLEs with the two polymorphisms studied: subjects with the T allele (SNP4) and the A allele (SNP18) had higher scores on both the positive and the negative dimensions. Haplotypic analyses supported these results, showing the highest scores in those with the TA haplotype (SNP4-SNP18). The RGS4 variants might exert gene-specific modulating effects on psychosis proneness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 111 | Eur. Psychiatry 2016 Feb 32: 42-7 |
| PMID | 26803614 |
| Title | Influence of DAOA and RGS4 genes on the risk for psychotic disorders and their associated executive dysfunctions: A family-based study. |
| Abstract | Glutamatergic neurotransmission dysfunction has classically been related to the aetiology of psychotic disorders. A substantial polygenic component shared across these disorders has been reported and molecular genetics studies have associated glutamatergic-related genes, such as d-amino acid oxidase activator (DAOA) and regulator of G-protein signalling 4 (RGS4) with the risk for psychotic disorders. Our aims were to examine: (i) the relationship between DAOA and RGS4 and the risk for psychotic disorders using a family-based association approach, and (ii) whether variations in these genes are associated with differences in patients' cognitive performance. The sample comprised 753 subjects (222 patients with psychotic disorders and 531 first-degree relatives). Six SNPs in DAOA and 5 SNPs in RGS4 were genotyped. Executive cognitive performance was assessed with Trail Making Test B (TMT-B) and Wisconsin Card Sorting Test (WCST). Genetic association analyses were conducted with PLINK, using the transmission disequilibrium test (TDT) for the family-based study and linear regression for cognitive performance analyses. The haplotype GAGACT at DAOA was under-transmitted to patients (P=0.0008), indicating its association with these disorders. With regards to cognitive performance, the DAOA haplotype GAGGCT was associated with worse scores in TMT-B (P=0.018) in SZ patients only. RGS4 analyses did not report significant results. Our findings suggest that the DAOA gene may contribute to the risk for psychotic disorders and that this gene may play a role as a modulator of executive function, probably through the dysregulation of the glutamatergic signalling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 112 | Schizophr Bull 2016 Mar 42: 396-405 |
| PMID | 26424323 |
| Title | Reciprocal Alterations in Regulator of G Protein Signaling 4 and microRNA16 in Schizophrenia. |
| Abstract | N-methyl-d-aspartate receptor (NMDAR) hypofunction in the dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathology of schizophrenia. NMDAR activity is negatively regulated by some G protein-coupled receptors (GPCRs). Signaling through these GPCRs is reduced by Regulator of G protein Signaling 4 (RGS4). Thus, lower levels of RGS4 would enhance GPCR-mediated reductions in NMDAR activity and could contribute to NMDAR hypofunction in schizophrenia. In this study, we quantified RGS4 mRNA and protein levels at several levels of resolution in the DLPFC from subjects with schizophrenia and matched healthy comparison subjects. To investigate molecular mechanisms that could contribute to altered RGS4 levels, we quantified levels of small noncoding RNAs, known as microRNAs (miRs), which regulate RGS4 mRNA integrity after transcription. RGS4 mRNA and protein levels were significantly lower in schizophrenia subjects and were positively correlated across all subjects. The RGS4 mRNA deficit was present in pyramidal neurons of DLPFC layers 3 and 5 of the schizophrenia subjects. In contrast, levels of miR16 were significantly higher in the DLPFC of schizophrenia subjects, and higher miR16 levels predicted lower RGS4 mRNA levels. These findings provide convergent evidence of lower RGS4 mRNA and protein levels in schizophrenia that may result from increased expression of miR16. Given the role of RGS4 in regulating GPCRs, and consequently the strength of NMDAR signaling, these findings could contribute to the molecular substrate for NMDAR hypofunction in DLPFC pyramidal cells in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 113 | Eur Arch Psychiatry Clin Neurosci 2016 Feb -1: -1 |
| PMID | 26910404 |
| Title | Association between RGS4 variants and psychotic-like experiences in nonclinical individuals. |
| Abstract | The psychosis phenotype is expressed across a continuum known as schizotypy, which ranges from personality variation through subclinical symptoms to severe psychopathology. The study of subclinical manifestations in non-affected individuals minimizes confounding factors associated with the clinical phenotype and facilitates the differentiation of dimension-specific etiological mechanisms. The aim of the present study was to investigate the association between the variation in the regulator of G-protein signaling 4 (RGS4) gene, a putative candidate gene for psychosis previously associated with schizophrenia endophenotypes, and psychotic-like experiences (PLEs). In total, 808 healthy individuals completed the community assessment of psychic experiences (CAPE) to measure positive and negative PLEs and provided a DNA sample. Two RGS4 single-nucleotide polymorphisms (SNPs) (rs951436 [SNP4] and rs2661319 [SNP18]) were genotyped. Analyses of covariance (ANCOVA) were used to explore the association of positive and negative PLEs with RGS4 variation. Our results showed associations of positive and negative PLEs with the two polymorphisms studied: subjects with the T allele (SNP4) and the A allele (SNP18) had higher scores on both the positive and the negative dimensions. Haplotypic analyses supported these results, showing the highest scores in those with the TA haplotype (SNP4-SNP18). The RGS4 variants might exert gene-specific modulating effects on psychosis proneness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |