Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A map of 191 single-nucleotide polymorphism (SNPs) was built across a 5-Mb segment from chromosome 13q34 that has been genetically linked to schizophrenia. DNA from 213 schizophrenic patients and 241 normal individuals from Canada were genotyped with this marker set. Two 1,400- and 65-kb regions contained markers associated with the disease. Two markers from the 65-kb region were also found to be associated to schizophrenia in a Russian sample. Two overlapping genes G72 and G30 transcribed in brain were experimentally annotated in this 65-kb region. Transfection experiments point to the existence of a 153-aa protein coded by the G72 gene. This protein is rapidly evolving in primates, is localized to endoplasmic reticulum/Golgi in transfected cells, is able to form multimers and specifically binds to carbohydrates. Yeast two-hybrid experiments with the G72 protein identified the enzyme d-amino acid oxidase (DAAO) as an interacting partner. DAAO is expressed in human brain where it oxidizes d-serine, a potent activator of N-methyl-D-aspartate type glutamate receptor. The interaction between G72 and DAAO was confirmed in vitro and resulted in activation of DAAO. Four SNP markers from DAAO were found to be associated with schizophrenia in the Canadian samples. Logistic regression revealed genetic interaction between associated SNPs in vicinity of two genes. The association of both DAAO and a new gene G72 from 13q34 with schizophrenia together with activation of DAAO activity by a G72 protein product points to the involvement of this N-methyl-d-aspartate receptor regulation pathway in schizophrenia.
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PMID:Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. 1237 53

The search for new classes of antipsychotics based on novel targets identified from linkage/linkage association in diseased cohorts and microarray approaches using tissue from affected individuals is a high priority in central nervous system research. Genes linked to schizophrenia, a disease affecting 1% of the population, have been identified on nearly every chromosome of the human genome leading to a diverse choice of targets for validation. Interestingly, while the majority of currently used antipsychotic medications act by blocking dopamine receptors, there have been few genetic studies implicating the dopamine receptor family in disease etiology. Recently, four genes have been identified that encode dysbindin, neuroregulin, D-amino acid oxidase and G72, respectively, that support previous studies suggesting that schizophrenia may result from a hypofunction of glutamatergic neurotransmission. Linkage and microarray studies have similarly supported studies implicating the alpha 7 neuronal nicotinic receptor in the etiology of schizophrenia. Microarray studies using brain tissue from schizophrenic patients have shown changes in gene expression that number in the thousands, involving a number of proteins related to synaptic structure and function (PSYN gene group) and cellular metabolism. The majority of these proteins are not traditional drug discovery targets, nor are their functional roles in schizophrenia obvious, providing a challenge to validate them from the drug target identification/drug discovery perspective. The current state-of-the-art in genome-based approaches to schizophrenia, target discovery highlights a need for a multidisciplinary, integrative, null hypothesis-based approach to sort through these novel genes as drug targets.
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PMID:Genome-based drug discovery: prioritizing disease-susceptibility/disease-associated genes as novel drug targets for schizophrenia. 1262 25

Linkage evidence suggests that chromosome 13 (13q32-33) contains susceptibility genes for both bipolar disorder and schizophrenia. Recently, genes called "G72" and "G30" were identified, and polymorphisms of these overlapping genes were reported to be associated with schizophrenia. We studied two series of pedigrees with bipolar disorder: the Clinical Neurogenetics (CNG) pedigrees (in which linkage to illness had been previously reported at 13q32-33), with 83 samples from 22 multiplex families, and the National Institute of Mental Health (NIMH) Genetics Initiative pedigrees, with 474 samples from 152 families. Sixteen single-nucleotide polymorphisms (SNPs) were genotyped at and around the G72/G30 locus, which covered a 157-kb region encompassing the entire complementary DNA sequences of G72 and G30. We performed transmission/disequilibrium testing (TDT) and haplotype analysis, since a linkage-disequilibrium block was present at this gene locus. In the CNG and NIMH data sets, the results of global TDT of the entire haplotype set were significant and consistent (P=.0004 and P=.008, respectively). In the CNG series, the associated genotypes divided the families into those with linkage and those without linkage (partitioned by the linkage evidence). Analysis of the decay of haplotype sharing gave a location estimate that included G72/G30 in its 95% confidence interval. Although statistically significant association was not detected for individual SNPs in the NIMH data set, the same haplotype was consistently overtransmitted in both series. These data suggest that a susceptibility variant for bipolar illness exists in the vicinity of the G72/G30 genes. Taken together with the earlier report, this is the first demonstration of a novel gene(s), discovered through a positional approach, independently associated with both bipolar illness and schizophrenia.
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PMID:Polymorphisms at the G72/G30 gene locus, on 13q33, are associated with bipolar disorder in two independent pedigree series. 1264 58

Recent twin studies confirm that schizophrenia is highly heritable, but attempts to locate and identify genes have proved to be difficult. This is largely because major genes appear to be rare or nonexistent. Instead, genetic liability almost certainly results from the combined effects of multiple susceptibility loci and most studies have been under-equipped to detect such effects. Nevertheless, several regions of the genome have been implicated by more than one linkage study and chromosome 22q has been implicated by linkage and by studies of patients with microdeletions. Recent work attempting to refine regions of interest using linkage dysequilibrium mapping has identified four promising and novel "positional candidates;" they are neuregulin-1 on chromosome 8p-p21, G72 located at chromosome 13q34, dysbindin at 6p22.3, and proline dehydrogenase, which is a gene that maps to chromosome 22q11. In addition, there is renewed interest in a fifth gene, catechol-O-methyltransferase, also on chromosome 22q11.
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PMID:Linkage and association studies of schizophrenia. 1268 91

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.
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PMID:Recent advances in the genetics of schizophrenia. 1295 66

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.
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PMID:The molecular genetics of schizophrenia: new findings promise new insights. 1458 32

The molecular-genetic basis of non-mendelian, genetically influenced disorders (complex disorders) is beginning to be uncovered. Recently, major progress in localization and detection of disposition genes of schizophrenia and bipolar disorder was achieved. We provide a comprehensive overview of recent results of linkage and association studies in schizophrenia and bipolar disorder. Several disposition genes for schizophrenia (DTNBP1, NRG1, G72) were identified, whereas evidence for specific disposition genes in bipolar disorder is more limited. Multiple limitations of current research strategies in the search of disposition genes of complex disorders have to be considered; alternative phenotype definitions, genome-wide association studies and parallel investigation of epigenetic misregulations might overcome these limitations.
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PMID:Genetics of schizophrenia and affective disorders. 1467 79

Markers near the nested genes G72 and G30 on chromosome 13q33 have been implicated in the etiology of schizophrenia and, recently, bipolar affective disorder (BPAD). Hattori et al (2003) reported that single-nucleotide polymorphisms (SNPs) near the G72/G30 locus were associated with BPAD in a sample of 22 pedigrees, and that SNP haplotypes were associated in a second, larger sample of triads. The present study attempts to replicate this finding in an independent case-control sample. Six SNPs near the G72/G30 locus, including the most strongly associated markers in the previous study, were tested in 139 cases and 113 ethnically matched controls. Significant association was detected between BPAD and two adjacent SNPs (smallest P=0.007; global P=0.024). Haplotype analysis produced additional support for association (smallest P=0.004; global P=0.004). Analysis of 31 unlinked microsatellite markers detected no population stratification in the cases or controls studied. Although the associated alleles and haplotypes differ from those previously reported, these new results provide further evidence, in an independent sample, for an association between BPAD and genetic variation in the vicinity of the genes G72 and G30.
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PMID:Findings in an independent sample support an association between bipolar affective disorder and the G72/G30 locus on chromosome 13q33. 1469 45

A recent study has suggested that the brain-expressed genes for G72 and D-amino-acid oxidase (DAAO) exert an influence on susceptibility to schizophrenia. Our aim was to replicate this finding in German schizophrenic patients and to assess whether G72 and DAAO might also contribute to the development of bipolar affective disorder. We genotyped seven single-nucleotide polymorphisms (SNPs) in the G72 gene and three in the DAAO gene in 599 patients (299 schizophrenic, 300 bipolar) and 300 controls. At G72, individual SNPs and a four-marker haplotype were associated with schizophrenia. The most significant SNP as well as the haplotype were also associated with bipolar affective disorder (BPAD). DAAO was associated with schizophrenia, but not with BPAD. The association of variation at G72 with schizophrenia as well as BPAD provides molecular support for the hypothesis that these two major psychiatric disorders share some of their etiologic background.
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PMID:Examination of G72 and D-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder. 1496 79

Recently, the G72 gene was reported to be associated with schizophrenia in the French Canadian and Russian populations. Here, we report the results obtained from the study of six single-nucleotide polymorphisms (SNPs: rs3916965, rs3916967, rs2391191, rs1935062, rs778293, and rs3918342), which span an 82-kb region covering the complementary DNA sequences of G72 and G30, in 537 schizophrenia cases and 538 controls of the Han Chinese. In this work, we have identified statistically significant differences in allele distributions of two markers rs3916965 (P = 0.019) and rs2391191 (P = 0.0010), and a highly significant association between haplotype AGAC of the G72/G30 locus (P = 1.7 x 10(-4)) and schizophrenia. Our data provide further evidence that markers of the G72/G30 genes are associated with schizophrenia in a non-Caucasian population.
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PMID:Association of G72/G30 with schizophrenia in the Chinese population. 1519 6


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