Is the Dysbindin Gene (DTNBP1) a Susceptibility Gene for Schizophrenia?

Williams, Nigel

doi:10.1093/schbul/sbi061

Cited by 94 publications

(58 citation statements)

References 22 publications

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“…Most, if not all, promising candidate genes identified for schizophrenia in recent years had similar inconsistencies. [48][49][50][51][52][53] While it is possible that our findings are a false-positive, we believe that it is not very likely for several reasons. First, we performed false-positive rate evaluations with the Q-value method.…”

Section: Discussionmentioning

confidence: 78%

Association study of CSF2RB with schizophrenia in Irish family and case – control samples

et al. 2007

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Colony stimulating factor 2 receptor, beta (CSF2RB) is the shared subunit of receptors for interleukin 3 (IL3), colony stimulating factor 2 (CSF2) and IL5, and is responsible for the initiation of signal transduction triggered by ligand binding. In our previous study, we showed the evidence that the IL3 gene is associated with schizophrenia and the associations observed are sex-specific and dependent on family history (FH). In this article, we studied 10 singlenucleotide polymorphisms in the CSF2RB gene in the Irish Study of High-Density Schizophrenia Families (ISHDSF) and the Irish Case -Control Study of Schizophrenia (ICCSS), and tested allele and haplotype associations with schizophrenia. Using the pedigree disequilibrium test, we found that two markers (rs11705394 and rs7285064) reached nominal significance. In sex-stratified analyses, for both the markers the association signals were mainly derived from male subjects. In the ICCSS sample, we found that several markers (rs2072707, rs2284031 and rs909486) showed sex-specific and FH-dependent associations with schizophrenia. In multimarker haplotype analyses, both ISHDSF and ICCSS samples showed globally significant associations in multiple linkage disequilibrium (LD) blocks sharing minimal LD. Since CSF2RB is essential for IL3 signaling, the findings that both IL3 and CSF2RB showed sex-specific and FH-dependent associations suggest that the IL3 pathway is involved in schizophrenia.

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Section: Discussionmentioning

confidence: 78%

Association study of CSF2RB with schizophrenia in Irish family and case – control samples

et al. 2007

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“…5 There are two main models of the allelic architecture of schizophrenia: the common-disease/common-variant and commondisease/rare-variant hypotheses. However, current findings would indicate that the two hypotheses are not mutually exclusive, with strong support for common but low-risk alleles 6,7 and also highly penetrant but rare alleles. [8][9][10] In the course of a whole-genome linkage study of schizophrenia, we earlier identified a single pedigree (family C702) consisting of six affected male siblings, which showed genome-wide significant evidence for linkage to chromosome 17p11.2-q25.1.…”

Section: Introductionmentioning

confidence: 71%

Evidence for rare and common genetic risk variants for schizophrenia at protein kinase C, alpha

et al. 2009

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We earlier reported a genome-wide significant linkage to schizophrenia at chromosome 17 that was identified in a single pedigree (C702) consisting of six affected, male siblings with DSM-IV schizophrenia and prominent mood symptoms. In this study, we adopted several approaches in an attempt to map the putative disease locus. First, mapping the source of linkage to chromosome 17 in pedigree C702. We refined the linkage region in family C702 to a 21-marker segment spanning 11.7 Mb at 17q23-q24 by genotyping a total of 50 microsatellites across chromosome 17 in the pedigree. Analysis of data from 1028 single nucleotide polymorphisms (SNPs) across the refined linkage region identified a single region of homozygosity present in pedigree C702 but not in 2938 UK controls. This spanned B432 kb of the gene encoding protein kinase C, alpha (PRKCA), the encoded protein of which has been implicated in the pathogenesis of psychiatric disorders. Analysis of pedigree C702 by oligonucleotide-array comparative genome hybridization excluded the possibility that this region of homozygosity was because of a deletion. Mutation screening of PRKCA identified a rare, four-marker haplotype (C-HAP) in the 3 0 untranslated region of the gene, which was present in the homozygous state in all six affected members of pedigree C702. No other homozygotes were observed in genotype data for a total of 6597 unrelated Europeans (case N = 1755, control N = 3580 and parents of probands N = 1262). Second, association analysis of C702 alleles at PRKCA. The low-frequency haplotype (C-HAP) showed a trend for association in a study of unrelated schizophrenia cases and controls from the UK (661 cases, 2824 controls, P = 0.078 and odd ratio (OR) = 1.9) and significant evidence for association when the sample was expanded to include cases with bipolar (N = 710) and schizoaffective disorder (N = 50) (psychosis sample: 1421 cases, 2824 controls, P = 0.037 and OR = 1.9). Given that all the affected members of C702 are male, we also undertook sex-specific analyses. This revealed that the association was strongest in males for both schizophrenia (446 male cases, 1421 male controls, P = 0.008 and OR = 3.9) and in the broader psychosis group (730 male cases, 1421 male controls, P = 0.008 and OR = 3.6). Analysis of C-HAP in follow-up samples from Ireland and Bulgaria revealed no evidence for association in either the whole sample or in males alone, and meta-analysis of all male psychosis samples yielded no significant evidence of association (969 male cases, 1939 male controls, 311 male probands P = 0.304 and OR = 1.4). Third, association mapping of the pedigree C702 linkage region. Independent of pedigree C702, genotype data from the Affymetrix 500k GeneChip set were available for 476 patients with schizophrenia and 2938 controls from the United Kingdom. SNPs in PRKCA showed evidence for association with schizophrenia that achieved gene-wide significance (P = 0.027). Moreover, the same SNP was the most significantly associated marker out of the 1028 SNPs genotyped...

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“…Research suggests that the mGluR3 agonist NAAG might be increased in corticolimbic regions in schizophrenia as a result of downregulation of its catabolic enzyme, glutamate carboxypetidase II [41,143,144]. DTNP1: Dysbindin (DTNP1; 6p24-22) has emerged as another promising risk gene for schizophrenia [145]. Dysbindin is concentrated in the presynaptic glutamatergic terminals where it interacts with SNAP and synapsin 1 and modulates vesicular release of glutamate [146].…”

Section: Daaomentioning

confidence: 99%

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Lisman

Coyle

Green

et al. 2008

Trends in Neurosciences

899

824

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Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.

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Is the Dysbindin Gene (DTNBP1) a Susceptibility Gene for Schizophrenia?

Cited by 94 publications

References 22 publications

Association study of CSF2RB with schizophrenia in Irish family and case – control samples

Association study of CSF2RB with schizophrenia in Irish family and case – control samples

Evidence for rare and common genetic risk variants for schizophrenia at protein kinase C, alpha

Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

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