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)

Using a systematically ascertained sample of 57 families, each having 2 or more members with a consensus diagnosis of schizophrenia (DSM-III-R criteria), we have carried out linkage studies of 520 loci, covering approximately 70% of the genome for susceptibility loci for schizophrenia. A two-stage strategy based on lod score thresholds from simulation studies of our sample identified regions for further exploration. In each region, a dense map of highly informative dinucleotide repeat polymorphisms (heterozygosity greater than .70) was analyzed using dominant, recessive, and "affected only" models and nonparametric sib pair identity-by-descent methods. For one region, 8p22-p21, affected sib-pair analyses gave a P value = .0001, corresponding to a lod score approximately equal to 3.00. For 8p22-p21, the maximum two-point lod score occurred using the "affected only" recessive model (ZMAX = 2.35; theta M = theta F); allowing for a constant sex difference in recombination fractions found in reference pedigrees, ZMAX = 2.78 (theta M/theta F = 3). For a second region, 3p26-p24, the maximum two-point lod score was 2.34 ("affected only" dominant model), and the affected sib-pair P value was .01. These two regions are worthy of further exploration as potential sites of susceptibility genes for schizophrenia.
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PMID:Schizophrenia: a genome scan targets chromosomes 3p and 8p as potential sites of susceptibility genes. 757 81

In our genomic scan of 265 Irish families with schizophrenia, we have thus far generated modest evidence for the presence of vulnerability genes in three chromosomal regions, i.e., 5q21-q31, 6p24-p22, and 8p22-p21. Outside of those regions, of all markers tested to date, D10S674 produced one of the highest pairwise heterogeneity lod (H-LOD) scores, 3.2 (P = 0.0004), when initially tested on a subset of 88 families. We then tested a total of 12 markers across a region of 32 centimorgans in region 10p15-p11 of all 265 families. The strongest evidence for linkage occurred assuming an intermediate phenotypic definition, and a recessive genetic model. The largest pairwise H-LOD score was found with marker D10S2443 (maximum 1.95, P = 0.005). Using multipoint H-LODs, we found a broad peak (maximum 1.91, P = 0.006) extending over the 11 centimorgans from marker D10S674 to marker D10S1426. Multipoint nonparametric linkage analysis produced a much broader peak, but with the maximum in the same location near D10S2443 (maximum z = 1.88, P = 0.03). Based on estimates from the multipoint analysis, this putative vulnerability locus appears to be segregating in 5-15% of the families studied, but this estimate should be viewed with caution. When evaluated in the context of our genome scan results, the evidence suggests the possibility of a fourth vulnerability locus for schizophrenia in these Irish families, in region 10p15-p11.
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PMID:A schizophrenia locus may be located in region 10p15-p11. 967 74

Schizophrenia is a common disorder characterized by psychotic symptoms; diagnostic criteria have been established. Family, twin and adoption studies suggest that both genetic and environmental factors influence susceptibility (heritability is approximately 71%; ref. 2), however, little is known about the aetiology of schizophrenia. Clinical and family studies suggest aetiological heterogeneity. Previously, we reported that regions on chromosomes 22, 3 and 8 may be associated with susceptibility to schizophrenia, and collaborations provided some support for regions on chromosomes 8 and 22 (refs 9-13). We present here a genome-wide scan for schizophrenia susceptibility loci (SSL) using 452 microsatellite markers on 54 multiplex pedigrees. Non-parametric linkage (NPL) analysis provided significant evidence for an SSL on chromosome 13q32 (NPL score=4.18; P=0.00002), and suggestive evidence for another SSL on chromosome 8p21-22 (NPL=3.64; P=0.0001). Parametric linkage analysis provided additional support for these SSL. Linkage evidence at chromosome 8 is weaker than that at chromosome 13, so it is more probable that chromosome 8 may be a false positive linkage. Additional putative SSL were noted on chromosomes 14q13 (NPL=2.57; P=0.005), 7q11 (NPL=2.50, P=0.007) and 22q11 (NPL=2.42, P=0.009). Verification of suggestive SSL on chromosomes 13q and 8p was attempted in a follow-up sample of 51 multiplex pedigrees. This analysis confirmed the SSL in 13q14-q33 (NPL=2.36, P=0.007) and supported the SSL in 8p22-p21 (NPL=1.95, P=0.023).
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PMID:Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. 973 35

The chromosomes 8 and 10 workshop took place at the Sixth World Congress on Psychiatric Genetics from October 6th-10th, 1998 in Bonn, Germany. Aim of the workshop was to discuss and summarize reports on potential susceptibility genes for psychiatric disorders. Linkage-findings on chromosome 8 concentrate on 8p22-p21 and include mainly schizophrenic disorders. Two areas on chromosome 10 were reported to contain potential susceptibility genes for schizophrenic as well as for affective disorders. The strongest findings were reported for 10p14-p11, while other groups communicated also linkage data for the telomeric part of the long arm to the workshop.
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PMID:Chromosomes 8 and 10 workshop. 1037 38

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

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.
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PMID:The genetics of schizophrenia and bipolar disorder: dissecting psychosis. 1574 31

Schizophrenia (SZ) is a common and severe psychiatric disorder with both environmental and genetic risk factors, and a high heritability. After over 20 years of molecular genetics research, new molecular strategies, primarily genome-wide association studies (GWAS), have generated major tangible progress. This new data provides evidence for: (1) a number of chromosomal regions with common polymorphisms showing genome-wide association with SZ (the major histocompatibility complex, MHC, region at 6p22-p21; 18q21.2; and 2q32.1). The associated alleles present small odds ratios (the odds of a risk variant being present in cases vs. controls) and suggest causative involvement of gene regulatory mechanisms in SZ. (2) Polygenic inheritance. (3) Involvement of rare (<1%) and large (>100kb) copy number variants (CNVs). (4) A genetic overlap of SZ with autism and with bipolar disorder (BP) challenging the classical clinical classifications. Most new SZ findings (chromosomal regions and genes) have generated new biological leads. These new findings, however, still need to be translated into a better understanding of the underlying biology and into causal mechanisms. Furthermore, a considerable amount of heritability still remains unexplained (missing heritability). Deep resequencing for rare variants and system biology approaches (e.g., integrating DNA sequence and functional data) are expected to further improve our understanding of the genetic architecture of SZ and its underlying biology.
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PMID:Genome-wide approaches to schizophrenia. 2043 10

Deficits in the expression of oligodendrocyte (Ol) and myelin genes have been described in numerous brain regions in schizophrenia (SZ) in association with abnormalities of cell cycle markers. We have previously reported a SZ-associated decrease in the expression of genes expressed after, but not prior to, the terminal differentiation of Ols in the posterior limb of the internal capsule (ICp). This pattern of deficits could reflect a failure of Ol precursors to exit the cell cycle and differentiate to meet the demands imposed by the high rate of apoptosis among myelinating Ols. Here we explore this hypothesis using quantitative real time PCR to examine the mRNA expression of additional genes in the ICp of the previously examined sample of 14 subjects with SZ and 15 normal controls (NCs). The genes examined in the present study were chosen because they are associated with particular phases of the cell cycle (CCND1, CCND2, p21(Cip1), p27(Kip1), and p57(Kip2)), with DNA replication and repair (PCNA), apoptosis (CASP3), or the Notch signaling pathway (JAG1, HES1, HES5, andDTX1). The Notch pathway influences whether Ol precursors continue to proliferate or exit the cell cycle. We also determined the densities of Ols in the ICp. Genes associated with maintenance of the cell cycle tended to exhibit increased expression levels in SZ relative to NCs and to be negatively correlated with the expression levels of the previously assessed mature Ol genes. In contrast, genes associated with cell cycle arrest tended to show the opposite pattern (decreased expression in SZ and positive correlations with mature Ol genes). CASP3 and PCNA expression levels were significantly decreased in SZ and positively correlated with mature Ol genes, suggesting that myelinating Ols may turnover more rapidly in normal controls than in subjects with SZ. JAG1 expression was significantly increased in SZ and exhibited positive correlations with mediators of the canonical Notch pathway but negative correlations with mature Ol genes. Ol densities were significantly decreased in SZ. These data are consistent with the hypothesis that Ol and myelin deficits in SZ involve a failure of Ol precursors to appropriately exit the cell cycle in order to differentiate and mature into myelinating Ols.
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PMID:Gene expression abnormalities and oligodendrocyte deficits in the internal capsule in schizophrenia. 2058 Aug 81

Genetic variations in the DTNBP1 gene (encoding the protein dysbindin-1) have been implicated as risk factors in the pathogenesis of schizophrenia. Previous studies have indicated that dysbindin-1 functions in the regulation of synaptic activity. Recently, dysbindin-1 has also been documented to be involved in neuronal development. In this study, we identified necdin as a binding partner of dysbindin-1 using a yeast two-hybrid screen. Dysbindin-1 recruits necdin to the cytoplasm, thereby attenuating the repressive effects of necdin on p53 transcriptional activity. Knockdown of dysbindin-1, like knockdown of p53, greatly decreases the expressions of the p53 target genes coronin 1b and rab13, which are required for neurite outgrowth. Moreover, overexpression of p53 restores the neurite outgrowth blocked by dysbindin-1 knockdown. In brains of dysbindin-1 null mice (the sandy strain), p21, Coronin 1b and Rab13 levels are reduced. Furthermore, primary cultured cortical neurons from sandy mice display neurite outgrowth defects when compared with those from wild-type mice. Thus, our data provide evidence that dysbindin-1 has an important role in neurite outgrowth through its regulation of p53's transcriptional activity.
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PMID:Dysbindin-1, a schizophrenia-related protein, facilitates neurite outgrowth by promoting the transcriptional activity of p53. 2150 52

Quetiapine is an atypical neuroleptic with a pharmacological profile distinct from classic neuroleptics that function primarily via blockade of dopamine D2 receptors. In the United States, quetiapine is currently approved for treating patients with schizophrenia, major depression and bipolar I disorder. Despite its widespread use, its cellular effects remain elusive. To address possible mechanisms, we chronically treated mice with quetiapine, haloperidol or vehicle and examined quetiapine-specific gene expression change in the frontal cortex. Through microarray analysis, we observed that several groups of genes were differentially expressed upon exposure to quetiapine compared with haloperidol or vehicle; among them, Cdkn1a, the gene encoding p21, exhibited the greatest fold change relative to haloperidol. The quetiapine-induced downregulation of p21/Cdkn1a was confirmed by real-time polymerase chain reaction and in situ hybridization. Consistent with single gene-level analyses, functional group analyses also indicated that gene sets associated with cell cycle/fate were differentially regulated in the quetiapine-treated group. In cortical cell cultures treated with quetiapine, p21/Cdkn1a was significantly downregulated in oligodendrocyte precursor cells and neurons, but not in astrocytes. We propose that cell cycle-associated intervention by quetiapine in the frontal cortex may underlie a unique efficacy of quetiapine compared with typical neuroleptics.
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PMID:Unique pharmacological actions of atypical neuroleptic quetiapine: possible role in cell cycle/fate control. 2354 17


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