UMLS:C0036341 - FACTA Search

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

From our linkage study of Irish families with a high density of schizophrenia, we have previously reported evidence for susceptibility genes in regions 5q21-31, 6p24-21, 8p22-21, and 10p15-p11. In this report, we describe the cumulative results from independent genome scans of three a priori random subsets of 90 families each, and from multipoint analysis of all 270 families in ten regions. Of these ten regions, three (13q32, 18p11-q11, and 18q22-23) did not generate scores above the empirical baseline pairwise scan results, and one (6q13-26) generated a weak signal. Six other regions produced more positive pairwise and multipoint results. They showed the following maximum multipoint H-LOD (heterogeneity LOD) and NPL scores: 2p14-13: 0.89 (P = 0.06) and 2.08 (P = 0.02), 4q24-32: 1.84 (P = 0.007) and 1.67 (P = 0.03), 5q21-31: 2.88 (P= 0.0007), and 2.65 (P = 0.002), 6p25-24: 2.13 (P = 0.005) and 3.59 (P = 0.0005), 6p23: 2.42 (P = 0.001) and 3.07 (P = 0.001), 8p22-21: 1.57 (P = 0.01) and 2.56 (P = 0.005), 10p15-11: 2.04 (P = 0.005) and 1.78 (P = 0.03). The degree of 'internal replication' across subsets differed, with 5q, 6p, and 8p being most consistent and 2p and 10p being least consistent. On 6p, the data suggested the presence of two susceptibility genes, in 6p25-24 and 6p23-22. Very few families were positive on more than one region, and little correlation between regions was evident, suggesting substantial locus heterogeneity. The levels of statistical significance were modest, as expected from loci contributing to complex traits. However, our internal replications, when considered along with the positive results obtained in multiple other samples, suggests that most of these six regions are likely to contain genes that influence liability to schizophrenia.
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PMID:Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes. 1214 Jul 77

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

Both the long and short arms of chromosome 18 have been consistently identified as potential locations for schizophrenia and bipolar affective disorder susceptibility genes. We previously described the identification of two independent pericentric inversions of chromosome 18 [inv(18)(p11.31;q21.2) and inv(18)(p11.31;q21.1)] occurring in two small families in which carriers have been diagnosed with schizophrenia and bipolar affective disorder, respectively. Using fluorescence in situ hybridization on patient metaphase chromosomes we have identified the locations of all four chromosome breakpoints in the inversion carriers. Neither pericentric inversion results in a direct gene disruption. However, each inversion breakpoint has the potential to perturb local gene expression by position effect or by the separation of important regulatory (enhancer) sequences from the core gene sequences. Five genes in the localities of the breakpoints have been identified as good candidates for the genetic basis of psychiatric illness in these families; TTMA, a novel membrane spanning protein; TCF4, a basic helix-loop-helix transcription factor; DLGAP1, an interactor of the PSD-95 synaptic protein; and ARKL1 and ARKL2, novel members of the ubiquitin ligase gene family.
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PMID:Candidate psychiatric illness genes identified in patients with pericentric inversions of chromosome 18. 1572 56

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

Chromosome 8p22-p11 has been identified as a locus for schizophrenia in several genome-wide scans, which has been confirmed by meta-analysis of published linkage data. It appears to be 1 of the most robust linkage findings in psychosis. Several attempts have been made to identify the underlying genetic variation that gives rise to this linkage peak, including systematic fine mapping using extended Icelandic pedigrees that have identified an associated haplotype (HAP(ICE)) in the gene neuregulin 1, also known as heuregulin, glial growth factor, NDF43, and ARIA. Neuregulin 1 (NRG1) is a plausible susceptibility gene because of its involvement in neurodevelopment, regulation of glutamate and other neurotransmitter receptor expression, and synaptic plasticity. Encouragingly, this finding was quickly and directly replicated in a Scottish case-control sample by the same investigators with the same approximately 300 kb associated haplotype. Although in Caucasian populations subsequent attempts at replication of this finding have been difficult to interpret, and no individual functional or causative genetic variants have yet been identified, a summary of HAP(ICE) association results in about 4,500 subjects is consistent with a small (odds ratio approximately 1.5) but significant effect of this haplotype on schizophrenia risk. In Chinese Han populations, where HAP(ICE) is not found, there is good evidence from several studies of association with other markers in the same region. Overall, there is convincing but not yet compelling evidence for a role for NRG1 in susceptibility to schizophrenia. Other genes from this region have also been implicated in schizophrenia, not by systematic mapping but by positional candidate gene analysis; these include MSTP131, frizzled-3, and the calcineurin A gamma subunit gene. Not only are these alternative explanations for the linkage seen between chromosome 8p and schizophrenia, but it is equally possible that there is more than 1 susceptibility gene at this locus.
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PMID:Association between the neuregulin 1 gene and schizophrenia: a systematic review. 1608 9

The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD=3.39) and suggestive evidence of linkage to 14q11.2 (LOD=2.87), 14q11.2-q13.2 (LOD=2.33), and 20p12.1-p11.2 (LOD=2.33). Although linkage to these regions has received little attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study--which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent--indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.
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PMID:Genomewide high-density SNP linkage analysis of 236 Japanese families supports the existence of schizophrenia susceptibility loci on chromosomes 1p, 14q, and 20p. 1638 Sep 6

Chromosome 8p22-p11 has been identified as a locus for schizophrenia in several genome-wide scans and confirmed by meta-analysis of published linkage data. Systematic fine mapping using extended Icelandic pedigrees identified an associated haplotype in the gene neuregulin 1 (NRG1), also known as heuregulin, glial growth factor, NDF43 and ARIA. A 290 kb core at risk haplotype at the 5' end of the gene (HAP(ICE)), defined by five SNPs and two microsatellite polymorphisms was found to be associated with schizophrenia in the Icelandic and Scottish populations. A number of subsequent independent studies have attempted to replicate the association, and while some have been successful, the associated haplotype is not always HAP(ICE). Furthermore, no obviously functional or pathogenic variants have been identified, and the relationship between the gene and schizophrenia has remained inconclusive. To reconcile these conflicting findings and to give a comprehensive picture of the genetic architecture of this important gene, we performed a meta-analysis of 13 published population-based and family-based association studies up to November 2005. We analysed data from the SNP markers SNP8NRG241930, SNP8NRG243177, SNP8NRG221132 and SNP8NRG221533, and the microsatellite markers 478B14-848, 420M9-1395. Across these studies, strong positive association was found for all six polymorphisms. The haplotype analysis also showed significant association in the pooled international populations (OR=1.22, 95% CI 1.15-1.3, P=8 x 10(-10)). In Asian populations, the risk haplotype was focused around the two microsatellite markers, 478B14-848, 420M9-1395 (haplotype block B), and in Caucasian populations with the remaining four SNP markers (haplotype block A). This meta-analysis supports the involvement of NRG1 in the pathogenesis of schizophrenia, but with association between two different but adjacent haplotypes blocks in the Caucasian and Asian populations.
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PMID:Meta-analysis shows strong positive association of the neuregulin 1 (NRG1) gene with schizophrenia. 1668 41

Major depressive disorder (MDD) is a common disabling psychiatric illness with an unknown etiology. Evidence from animal and human studies suggests that a disturbance in serotonergic (5-HT) activity and/or brain-derived neurotrophic factor (BDNF) signaling may be implicated in the pathogenesis of MDD. Recently, a protein, p11, has been found to increase the number of 5-HT(1B) receptors on the surface of cells and enhance 5-HT(1B) receptor function. Furthermore, mice over-expressing p11 acted as if they were undergoing treatment with antidepressants and p11 knockout mice exhibit a depression-like phenotype and reduced behavioural reactions to an antidepressant. As tissue-type plasminogen activator (tPA)/plasminogen proteolytic cascade is implicated in the cleavage of proBDNF to BDNF, and p11, a component of the Annexin II, which can greatly enhance the activation of plasmin by tPA, it is proposed that p11 may act through the tPA/plasminogen/BDNF pathway to achieve its antidepressant effect. Attempts to confirm this hypothesis may lead to new directions in the study of the pathogenesis of MDD and the development of a novel intervention for this disorder. In addition, BDNF is also implicated in several psychiatric diseases such as schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder and Alzheimer's disease; whether p11 and other components related to the tPA/plasminogen pathway may be related to the pathogenesis of these diseases needs further exploration.
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PMID:The P11, tPA/plasminogen system and brain-derived neurotrophic factor: Implications for the pathogenesis of major depression and the therapeutic mechanism of antidepressants. 1689 Mar 84

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.
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PMID:Two-stage designs to identify the effects of SNP combinations on complex diseases. 1858 17

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