1Am. J. Hum. Genet. 2002 Aug 71: 337-48
PMID12098102
TitleGenetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia.
AbstractPrior evidence has supported the existence of multiple susceptibility genes for schizophrenia. Multipoint linkage analysis of the 270 Irish high-density pedigrees that we have studied, as well as results from several other samples, suggest that at least one such gene is located in region 6p24-21. In the present study, family-based association analysis of 36 simple sequence-length-polymorphism markers and of 17 SNP markers implicated two regions, separated by approximately 7 Mb. The first region, and the focus of this report, is 6p22.3. In this region, single-nucleotide polymorphisms within the 140-kb gene DTNBP1 (dystrobrevin-binding protein 1, or dysbindin) are strongly associated with schizophrenia. Uncorrected, empirical P values produced by the program TRANSMIT were significant (P<.01) for a number of individual SNP markers, and most remained significant when the data were restricted to include only one affected offspring per nuclear family per extended pedigree; multiple three-marker haplotypes were highly significant (P=.008-.0001) under the restricted conditions. The pattern of linkage disequilibrium is consistent with the presence of more than one susceptibility allele, but this important issue is unresolved. The number of markers tested in the adjacent genes, all of which are negative, is not sufficient to rule out the possibility that the dysbindin gene is not the actual susceptibility gene, but this possibility appears to be very unlikely. We conclude that further investigation of dysbindin is warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
2Mol. Psychiatry 2003 Aug 8: 717-8
PMID12888799
TitleFamily-based association study of DTNBP1 in 6p22.3 and schizophrenia.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
3Pharmacopsychiatry 2003 Nov 36 Suppl 3: S195-202
PMID14677079
TitleGenetics of schizophrenia and affective disorders.
AbstractThe 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.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
4Am. J. Hum. Genet. 2003 Dec 73: 1438-43
PMID14618545
TitleThe DTNBP1 (dysbindin) gene contributes to schizophrenia, depending on family history of the disease.
AbstractWe have investigated the gene for dystrobrevin-binding protein 1 (DTNBP1), or dysbindin, which has been strongly suggested as a positional candidate gene for schizophrenia, in three samples of subjects with schizophrenia and unaffected control subjects of German (418 cases, 285 controls), Polish (294 cases, 113 controls), and Swedish (142 cases, 272 controls) descent. We analyzed five single-nucleotide polymorphisms (P1635, P1325, P1320, P1757, and P1578) and identified significant evidence of association in the Swedish sample but not in those from Germany or Poland. The results in the Swedish sample became even more significant after a separate analysis of those cases with a positive family history of schizophrenia, in whom the five-marker haplotype A-C-A-T-T showed a P value of.00009 (3.1% in controls, 17.8% in cases; OR 6.75; P=.00153 after Bonferroni correction). Our results suggest that genetic variation in the dysbindin gene is particularly involved in the development of schizophrenia in cases with a familial loading of the disease. This would also explain the difficulty of replicating this association in consecutively ascertained case-control samples, which usually comprise only a small proportion of subjects with a family history of disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
5Schizophr. Res. 2003 Apr 60: 167-72
PMID12591580
TitleNo evidence for association of the dysbindin gene [DTNBP1] with schizophrenia in an Irish population-based study.
AbstractA recent family-based association study identified a putative association between variants in the dystrobrevin binding protein 1 (dysbindin) gene (DTNBP1) and schizophrenia. This study used a sample of 270 Irish pedigrees multiply affected with schizophrenia. We attempted to replicate these findings in an independent Irish sample of 219 schizophrenia cases and 231 controls. No evidence was found to suggest an association between the DTNBP1 gene and schizophrenia in our sample. Possible reasons for these findings are discussed.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
6Hum. Mol. Genet. 2003 Oct 12 Spec No 2: R125-33
PMID12952866
TitleRecent advances in the genetics of schizophrenia.
AbstractThe 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
7Mol. Psychiatry 2003 May 8: 499-510
PMID12808430
TitleIdentification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families.
AbstractA recent report showed significant associations between several SNPs in a previously unknown EST cluster with schizophrenia. (1). The cluster was identified as the human dystrobrevin binding protein 1 gene (DTNBP1) by sequence database comparisons and homology with mouse DTNBP1. (2). However, the linkage disequilibrium (LD) among the SNPs in DTNBP1 as well as the pattern of significant SNP-schizophrenia association was complex. This raised several questions such as the number of susceptibility alleles that may be involved and the size of the region where the actual disease mutation(s) could be located. To address these questions, we performed different single-marker tests on the 12 previously studied and 2 new SNPs in DTNBP1 that were re-scored using an improved procedure, and performed a variety of haplotype analyses. The sample consisted of 268 Irish multiplex families selected for high density of schizophrenia. Results suggested a simple structure where the LD in the target region could be explained by 6 haplotypes that together accounted for 96% of haplotype diversity in the whole sample. From these six, a single high-risk haplotype was identified that showed a significant association with schizophrenia and explained the pattern of significant findings in the analyses with individual markers. This haplotype was 30 kb long, had a large effect, could be measured with two tag SNPs only, had a frequency of 6% in our sample, seemed to be of relatively recent origin in evolutionary terms, and was equally distributed over Ireland. Implications of these findings for follow-up and replication studies are discussed.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
8Curr Psychiatry Rep 2004 Aug 6: 303-12
PMID15260947
TitleThe genes for schizophrenia: finally a breakthrough?
AbstractA 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
9Genes Brain Behav. 2004 Aug 3: 240-8
PMID15248869
TitleThe contribution of three strong candidate schizophrenia susceptibility genes in demographically distinct populations.
AbstractHere we characterize and compare the contribution of three recently identified strong candidate schizophrenia susceptibility genes; G72, neuregulin 1 (NRG1) and dystrobrevin-binding protein 1 (DTNBP1) in two independent datasets of patients with distinct genetic backgrounds. On the basis of corrected P-values from single- and multilocus transmission distortion tests our analysis provides no support for a contribution of G72, NRG1 or DTNBP1 in the tested samples. When transmission of individual haplotypes was considered, a picture more consistent with the original studies emerged, where transmission distortions in the same direction as the original samples and involving the same core haplotypes were observed for G72 and NRG1. Interestingly, whereas the NRG1 gene analysis was dominated by the presence of over-transmitted haplotypes, the G72 gene analysis was consistently dominated in both datasets by under-transmissions. Negative transmissions involved a core haplotype complementary to the originally detected over-transmitted haplotype, suggesting the presence of a protective variant within the G72 locus.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
10Schizophr. Res. 2004 Nov 71: 185-9
PMID15374586
TitleMutation analysis of the human dystrobrevin-binding protein 1 gene in schizophrenic patients.
AbstractRecent molecular genetic studies have reported a positive association of schizophrenia with several single nucleotide polymorphisms (SNPs) and haplotypes from the human dystrobrevin-binding protein 1 (DTNBP1) gene locus on chromosome 6p. This finding suggests that the DTNBP1 gene is likely a susceptible gene for schizophrenia. Because all the SNPs showing positive association with schizophrenia locate at the intronic sequences of the DTNBP1 gene, we set out to search for mutations in the protein-coding sequences and at the 5' promoter region of the DTNBP1 gene to investigate if the DTNBP1 gene is a schizophrenia-susceptible gene. We directly sequenced the cDNA of DTNBP1 gene in 50 schizophrenic patients and the 5' promoter region of the DTNBP1 genomic DNA in 94 schizophrenia patients. No mutations were identified in either the protein-coding sequences or the 5' promoter region of the human DTNBP1 gene in this sample. Thus, in contrast to prior studies reporting positive association of the DTNBP1 gene with schizophrenia in both Irish and German population, our data indicate that the human DTNBP1 is unlikely a major susceptible gene for schizophrenia in Chinese Han patients from Taiwan.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
11Am. J. Hum. Genet. 2004 Nov 75: 891-8
PMID15362017
TitleAssociation of the DTNBP1 locus with schizophrenia in a U.S. population.
AbstractLinkage and association studies have recently implicated dystrobrevin-binding protein 1 (DTNBP1) in the etiology of schizophrenia. We analyzed seven previously tested DTNBP1 single-nucleotide polymorphisms (SNPs) in a cohort of 524 individuals with schizophrenia or schizoaffective disorder and 573 control subjects. The minor alleles of three SNPs (P1578, P1763, and P1765) were positively associated with the diagnosis of schizophrenia or schizoaffective disorder in the white subset of the study cohort (258 cases, 467 controls), with P1578 showing the most significant association (odds ratio 1.76, P =.0026). The same three SNPs were also associated in a smaller Hispanic subset (51 cases, 32 controls). No association was observed in the African American subset (215 cases, 74 controls). A stratified analysis of the white and Hispanic subsets showed association with the minor alleles of four SNPs (P1578, P1763, P1320, and P1765). Again, the most significant association was observed for P1578 (P =.0006). Haplotype analysis supported these findings, with a single risk haplotype significantly overrepresented in the white sample (P =.005). Our study provides further evidence for a role of the DTNBP1 gene in the genetic etiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
12Biol. Psychiatry 2004 May 55: 971-5
PMID15121479
TitleStrong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia in 488 parent-offspring trios from Bulgaria.
AbstractThe gene encoding the dystrobrevin binding protein (DTNBP1) has been implicated in the pathogenesis of schizophrenia by several association studies. We tried to replicate these findings in a sample of 488 parent-proband trios recruited in Bulgaria. Probands had a diagnosis of schizophrenia (n = 441) or schizoaffective disorder (n = 47).
We genotyped eight single nucleotide polymorphisms within the gene, four of which had been reported in previous studies, and four identified as informative by our group through direct screening of the gene and genotyping in a sample of cases and control subjects.
A significant excess of transmissions was observed for two of the markers, p1635 and p1757, (p =.0009 and.0013, respectively). Analysis of two-, three-, and four-marker haplotypes produced numerous positive results, with six (4% of the total combinations) at p <.001.
These results provide strong support for DTNBP1 as a susceptibility gene for schizophrenia; however, different haplotypes seem to be associated in different studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
13Schizophr. Res. 2004 Nov 71: 185-9
PMID15374586
TitleMutation analysis of the human dystrobrevin-binding protein 1 gene in schizophrenic patients.
AbstractRecent molecular genetic studies have reported a positive association of schizophrenia with several single nucleotide polymorphisms (SNPs) and haplotypes from the human dystrobrevin-binding protein 1 (DTNBP1) gene locus on chromosome 6p. This finding suggests that the DTNBP1 gene is likely a susceptible gene for schizophrenia. Because all the SNPs showing positive association with schizophrenia locate at the intronic sequences of the DTNBP1 gene, we set out to search for mutations in the protein-coding sequences and at the 5' promoter region of the DTNBP1 gene to investigate if the DTNBP1 gene is a schizophrenia-susceptible gene. We directly sequenced the cDNA of DTNBP1 gene in 50 schizophrenic patients and the 5' promoter region of the DTNBP1 genomic DNA in 94 schizophrenia patients. No mutations were identified in either the protein-coding sequences or the 5' promoter region of the human DTNBP1 gene in this sample. Thus, in contrast to prior studies reporting positive association of the DTNBP1 gene with schizophrenia in both Irish and German population, our data indicate that the human DTNBP1 is unlikely a major susceptible gene for schizophrenia in Chinese Han patients from Taiwan.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
14Malays J Med Sci 2004 Jul 11: 3-11
PMID22973121
TitleThe genetics of schizophrenia.
Abstractschizophrenia is a complex biological disorder with multifactorial mode of transmission where non-genetic determinants are also play important role. It is now clear that it involves combined effect of many genes, each conferring a small increase in liability to the illness. Thus no causal disease genes or single gene of major effects, only susceptible genes are operating. Given this complexity, it comes as no surprise of the difficulty to find susceptible genes. However, schizophrenia genes have been found at last. Recent studies on molecular genetics of schizophrenia which focused on positional and functional candidate genes postulated to be associated with schizophrenia are beginning to produce findings of great interest. These include neuregulin (NRG-1, 8p12-21), dysbindin, (DTNBP1,6p22.3), G72 (13q34) / D-amino acid oxidase (DAAO,12q24), proline dehydrogenase (PRODH-2, 22q11.21), catechol-O-methyltransferase (COMT, 22q11.21), regulator of G protein signaling (RGS-4), 5HT2A and dopamine D3 receptor (DRD3). Applications of microarrays methods were able to locate positional candidate genes related to dopaminergic, serotonergic and glutamatergic neurotransmission. New genome scan project, seen in the light of previous scans, provide support for schizophrenia candidate region on chromosome 1q, 2q, 5q, 6p, 8p, 10p, 13q,15q and 22q. Other reports described including the application of LD mapping and positional cloning technique, microarray technology and efforts to develop quantitative phenotype. More exciting finding is expected in near future with the completion of Hap Map project.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
15Mol. Psychiatry 2004 Jan 9: 14-27
PMID14581932
TitleThe molecular genetics of schizophrenia: new findings promise new insights.
AbstractThe 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
16Arch. Gen. Psychiatry 2004 Apr 61: 336-44
PMID15066891
TitleIdentification in 2 independent samples of a novel schizophrenia risk haplotype of the dystrobrevin binding protein gene (DTNBP1).
AbstractRecent research suggests that variation in the gene encoding dystrobrevin binding protein (DTNBP1) confers susceptibility to schizophrenia. Thus far, no specific risk haplotype has been identified in more than 1 study.
To confirm DTNBP1 as a schizophrenia susceptibility gene, to identify and replicate specific risk and protective haplotypes, and to explore relationships between DTNBP1 and the phenotype.
Genetic association study based on mutation detection and case-control analysis.
All subjects were unrelated and ascertained from general (secondary care) psychiatric inpatient and outpatient services.
The Cardiff, Wales, sample included 708 white subjects from the United Kingdom and Ireland (221 females) who met DSM-IV criteria for schizophrenia and were individually matched for age, sex, and ethnicity to 711 blood donor controls (233 females). Mean +/- SD age at first psychiatric contact for cases was 23.6 +/- 7.7 years; mean age at ascertainment was 41.8 +/- 13.5 years. The Dublin, Ireland, sample included 219 white subjects from the Republic of Ireland who met DSM-III-R criteria for schizophrenia or schizoaffective disorder and 231 controls. The mean age of the Irish cases was 46.0 +/- 8.5 years; mean age at first psychiatric contact was 25.2 +/- 12.4 years.
Evidence for association between the DTNBP1 locus and schizophrenia.
In the Cardiff sample, there was no evidence for association with previously implicated haplotypes but strong evidence for association with multiple novel haplotypes. Maximum evidence was found for a novel 3-marker haplotype (global P<.001), composed of 1 risk haplotype (P =.01) and 2 protective haplotypes, 1 common (P =.006) and 1 rare (P<.001). Specific risk and protective haplotypes were replicated in the Dublin sample (P =.02,.047, and.006, respectively). The only phenotypic variable associated with any haplotype was between the common protective haplotype and higher educational achievement (P =.02, corrected for multiple tests).
DTNBP1 is a susceptibility gene for schizophrenia. Specific risk and protective haplotypes were identified and replicated. Association with educational achievement may suggest protection mediated by IQ, although this needs to be confirmed in an independent data set.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
17Hum. Mol. Genet. 2004 Nov 13: 2699-708
PMID15345706
TitleEvidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia.
AbstractGenetic variation in dysbindin (DTNBP1: dystrobrevin-binding protein 1) has recently been shown to be associated with schizophrenia. The dysbindin gene is located at chromosome 6p22.3, one of the most promising susceptibility loci in schizophrenia linkage studies. We attempted to replicate this association in a Japanese sample of 670 patients with schizophrenia and 588 controls. We found a nominally significant association with schizophrenia for four single nucleotide polymorphisms and stronger evidence for association in a multi-marker haplotype analysis (P = 0.00028). We then explored functions of dysbindin protein in primary cortical neuronal culture. Overexpression of dysbindin induced the expression of two pre-synaptic proteins, SNAP25 and synapsin I, and increased extracellular basal glutamate levels and release of glutamate evoked by high potassium. Conversely, knockdown of endogenous dysbindin protein by small interfering RNA (siRNA) resulted in the reduction of pre-synaptic protein expression and glutamate release, suggesting that dysbindin might influence exocytotic glutamate release via upregulation of the molecules in pre-synaptic machinery. The overexpression of dysbindin increased phosphorylation of Akt protein and protected cortical neurons against neuronal death due to serum deprivation and these effects were blocked by LY294002, a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor. SiRNA-mediated silencing of dysbindin protein diminished Akt phosphorylation and facilitated neuronal death induced by serum deprivation, suggesting that dysbindin promotes neuronal viability through PI3-kinase-Akt signaling. Genetic variants associated with impairments of these functions of dysbindin could play an important role in the pathogenesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
18Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Aug 129B: 55-8
PMID15274041
TitleThe dysbindin gene in major depression: an association study.
AbstractThe pathophysiological mechanisms, as well as the molecular loci of antidepressant drug action have not yet been established, but recent models proposed that several adaptive mechanisms in signal transduction cascades beyond the receptor and reuptake systems are involved in antidepressant action and play an important role in the etiology of affective disorders. In this context, the dysbindin gene (dystrobrevin-binding-protein 1, DTNBP1), which was recently reported to be associated with schizophrenia seems to be an interesting candidate gene for affective disorders. Dysbindin is widely expressed in the human brain and binds to the dystrophin-associated protein complex (DPC) which appears to be involved in signal transduction pathways, which have been repeatedly investigated and described as altered or disturbed in affective disorders [McLeod et al. [2003: Psychopharmacol Bull 35:24-41]; Brambilla et al. [2003: Mol Psychiatry 8:721-737]]. Therefore, we investigated whether five SNPs in the dysbindin gene could be susceptibility factors in the ethiology of major depression or for the response to antidepressant treatment in a sample of 293 patients compared to 220 healthy controls. Applying single SNP evaluation, as well as haplotype analysis we could not detect an association between the dysbindin polymorphisms and major depression or the response to antidepressant treatment. In conclusion, our results suggest that SNPs in the dysbindin gene are unlikely to play a major role in the pathophysiology of major depression or are in linkage disequilibrium (LD) with a neighboring mutation or gene. Further analysis are needed to confirm these results.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
19Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Jul 128B: 65-70
PMID15211634
TitleLinkage disequlibrium in the DTNBP1 (dysbindin) gene region and on chromosome 1p36 among psychotic patients from a genetic isolate in Israel: findings from identity by descent haplotype sharing analysis.
AbstractSeveral genes have been reported recently to be associated with schizophrenia and bipolar disorder. Because of the complexity of the inheritance of these disorders, there is an urgent need to replicate these findings and to search for additional candidate genes. The study of genetic isolates is a powerful technique that may overcome some of the obstacles caused by genetic heterogeneity and ambiguity of phenotype definition. Identity by descent (IBD) haplotype sharing analysis in these populations may be used to detect mutations within shared haplotypes in smaller samples of affected individuals. In this study, we used IBD haplotype sharing analysis to replicate positive linkage and association findings in psychotic disorders, and to identify other regions of interest. Fifty-two patients with major psychiatric disorders from a genetically isolated village in Israel were studied. By studying eight Y chromosome markers, we were able to confirm the oral tradition of members of this isolate regarding a common paternal origin. Three hundred fifty nine microsatellite markers on 9 candidate chromosomes were genotyped, and haplotypes were reconstructed using information from family members. Two highly significant (P < 0.0001) peaks of haplotype sharing were found. One was for psychotic patients with any diagnosis at the location of dysbindin, a gene previously associated with schizophrenia. The other peak was for patients with schizophrenia on chromosome 1p36. Thus, this study both replicates an earlier finding and points to a novel region of interest, which might be unique to this population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
20Arch. Gen. Psychiatry 2004 Jun 61: 544-55
PMID15184234
TitleHuman dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain.
AbstractThe schizophrenia-susceptibility gene dysbindin (DTNBP1 on 6p22.3) encodes a neuronal protein that binds to beta-dystrobrevin and may be part of the dystrophin protein complex. Little is known about dysbindin expression in normal or schizophrenic brain.
To determine whether brain regions implicated in schizophrenia express dysbindin and whether abnormal levels of dysbindin messenger RNA (mRNA) may be found in this disorder and to test whether sequence variations in the dysbindin gene in the promoter region, 5' and 3' untranslated regions, or introns would affect dysbindin mRNA levels.
In patients with schizophrenia and controls, we compared dysbindin, synaptophysin, spinophilin, and cyclophilin mRNA levels in the dorsolateral prefrontal cortex and dysbindin mRNA levels in the midbrain by in situ hybridization. We genotyped brain DNA at 11 single nucleotide polymorphisms to determine whether genetic variation in the dysbindin gene affects cortical dysbindin mRNA levels.
Quantitative assessment of dysbindin mRNA levels across various brain regions and comparative studies of dysbindin mRNA levels in brains of patients with schizophrenia compared with normal controls.
Dysbindin mRNA was detected in the frontal cortex, temporal cortex, hippocampus, caudate, putamen, nucleus accumbens, amygdala, thalamus, and midbrain of the adult brain. Patients with schizophrenia had statistically significantly reduced dysbindin mRNA levels in multiple layers of the dorsolateral prefrontal cortex, whereas synaptophysin, spinophilin, and cyclophilin mRNA levels were unchanged. Dysbindin mRNA levels were quantitatively reduced in the midbrain of patients with schizophrenia, but not statistically significantly. Cortical dysbindin mRNA levels varied statistically significantly according to dysbindin genotype.
Dysbindin mRNA is expressed widely in the brain, and its expression is reduced in schizophrenia. Variation in dysbindin mRNA levels may be determined in part by variation in the promoter and the 5' and 3' untranslated regions. These data add to the evidence that dysbindin is an etiologic factor in schizophrenia risk.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
21J. Clin. Invest. 2004 May 113: 1353-63
PMID15124027
TitleDysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia.
AbstractEleven studies now report significant associations between schizophrenia and certain haplotypes of single-nucleotide polymorphisms in the gene encoding dysbindin-1 at 6p22.3. Dysbindin-1 is best known as dystrobrevin-binding protein 1 (DTNBP1) and may thus be associated with the dystrophin glycoprotein complex found at certain postsynaptic sites in the brain. Contrary to expectations, however, we found that when compared to matched, nonpsychiatric controls, 73-93% of cases in two schizophrenia populations displayed presynaptic dysbindin-1 reductions averaging 18-42% (P = 0.027-0.0001) at hippocampal formation sites lacking neuronal dystrobrevin (i.e., beta-dystrobrevin). The reductions, which were not observed in the anterior cingulate of the same schizophrenia cases, occurred specifically in terminal fields of intrinsic, glutamatergic afferents of the subiculum, the hippocampus proper, and especially the inner molecular layer of the dentate gyrus (DGiml). An inversely correlated increase in vesicular glutamate transporter-1 (VGluT-1) occurred in DGiml of the same schizophrenia cases. Those changes occurred without evidence of axon terminal loss or neuroleptic effects on dysbindin-1 or VGluT-1. Our findings indicate that presynaptic dysbindin-1 reductions independent of the dystrophin glycoprotein complex are frequent in schizophrenia and are related to glutamatergic alterations in intrinsic hippocampal formation connections. Such changes may contribute to the cognitive deficits common in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
22Arch. Gen. Psychiatry 2004 Jun 61: 544-55
PMID15184234
TitleHuman dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain.
AbstractThe schizophrenia-susceptibility gene dysbindin (DTNBP1 on 6p22.3) encodes a neuronal protein that binds to beta-dystrobrevin and may be part of the dystrophin protein complex. Little is known about dysbindin expression in normal or schizophrenic brain.
To determine whether brain regions implicated in schizophrenia express dysbindin and whether abnormal levels of dysbindin messenger RNA (mRNA) may be found in this disorder and to test whether sequence variations in the dysbindin gene in the promoter region, 5' and 3' untranslated regions, or introns would affect dysbindin mRNA levels.
In patients with schizophrenia and controls, we compared dysbindin, synaptophysin, spinophilin, and cyclophilin mRNA levels in the dorsolateral prefrontal cortex and dysbindin mRNA levels in the midbrain by in situ hybridization. We genotyped brain DNA at 11 single nucleotide polymorphisms to determine whether genetic variation in the dysbindin gene affects cortical dysbindin mRNA levels.
Quantitative assessment of dysbindin mRNA levels across various brain regions and comparative studies of dysbindin mRNA levels in brains of patients with schizophrenia compared with normal controls.
Dysbindin mRNA was detected in the frontal cortex, temporal cortex, hippocampus, caudate, putamen, nucleus accumbens, amygdala, thalamus, and midbrain of the adult brain. Patients with schizophrenia had statistically significantly reduced dysbindin mRNA levels in multiple layers of the dorsolateral prefrontal cortex, whereas synaptophysin, spinophilin, and cyclophilin mRNA levels were unchanged. Dysbindin mRNA levels were quantitatively reduced in the midbrain of patients with schizophrenia, but not statistically significantly. Cortical dysbindin mRNA levels varied statistically significantly according to dysbindin genotype.
Dysbindin mRNA is expressed widely in the brain, and its expression is reduced in schizophrenia. Variation in dysbindin mRNA levels may be determined in part by variation in the promoter and the 5' and 3' untranslated regions. These data add to the evidence that dysbindin is an etiologic factor in schizophrenia risk.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
23Br. Med. Bull. 2005 -1 73-74: 107-22
PMID16365481
TitlePsychiatric genetics--the new era: genetic research and some clinical implications.
AbstractImpressive 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
24J. Med. Genet. 2005 Mar 42: 193-204
PMID15744031
TitleThe genetics of schizophrenia and bipolar disorder: dissecting psychosis.
AbstractMuch 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
25Trends Genet. 2005 Sep 21: 518-25
PMID16009449
TitleSchizophrenia: genes at last?
AbstractGenetic 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
26J Autism Dev Disord 2005 Dec 35: 831-8
PMID16283082
TitleDysbindin (DTNBP1, 6p22.3) is associated with childhood-onset psychosis and endophenotypes measured by the Premorbid Adjustment Scale (PAS).
AbstractStraub et al. (2002) recently identified the 6p22.3 gene dysbindin (DTNBP1) through positional cloning as a schizophrenia susceptibility gene. We studied a rare cohort of 102 children with onset of psychosis before age 13. Standardized ratings of early development, medication response, neuropsychological and cognitive performance, premorbid dysfunction and clinical follow-up were obtained. Fourteen SNPs were genotyped in the gene DTNBP1. Family-based pairwise and haplotype transmission disequilibrium test (TDT) analysis with the clinical phenotype, and quantitative transmission disequilibrium test (QTDT) explored endophenotype relationships. One SNP was associated with diagnosis (TDT p=.01). The QTDT analyses showed several significant relationships. Four adjacent SNPs were associated (p values=.0009-.003) with poor premorbid functioning. These findings support the hypothesis that this and other schizophrenia susceptibility genes contribute to early neurodevelopmental impairment.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
27Schizophr Bull 2005 Oct 31: 800-5
PMID16166606
TitleIs the dysbindin gene (DTNBP1) a susceptibility gene for schizophrenia?
AbstractOver recent years the gene DTNBP1 (chromosome 6p24-22) has emerged as one of the most promising candidate genes for schizophrenia. In this article, we review the current genetic evidence that implicates DTNBP1 as a schizophrenia-susceptibility gene. While there is now impressive support from genetic association studies, it is important to remain aware that the actual DTNBP1 susceptibility variants have not been identified. While functional analyses have allowed us to speculate their likely function, only when they are identified will we be able to confidently specify the type of altered gene function that is relevant to schizophrenia pathogenesis. This we hope will then open up new vistas for neurobiological research, allowing us to study the exact contribution of DTNBP1 in schizophrenia, its relationships with various aspects of the phenotype, and the potential of epistatic interactions with other genes, as well as functional interactions between the gene products.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
28J Neural Transm (Vienna) 2005 Sep 112: 1263-7
PMID16133786
TitleUntranslated region haplotype in dysbindin gene: analysis in schizophrenia.
AbstractGenome-scans performed in schizophrenia families have provided evidence for region 6p24-21 where variability may confer susceptibility to schizophrenia. Recent studies have implicated that gene DTNBP1 (dysbindin) in this region is strongly associated with schizophrenia. In a family based association study we investigated three markers located in the untranslated region of the DTNBP1 gene: rs909706, rs1047631 and rs742106. The sample size of our study is 117 families. No biased transmission towards the disorder was detected by haplotype analysis using TRANSMIT.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
29Hum. Mol. Genet. 2005 Jul 14: 1947-54
PMID15917270
TitleHaplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression.
AbstractThe DTNBP1 gene, encoding dysbindin, is now generally considered to be a susceptibility gene for schizophrenia. However, the confidence with which this hypothesis can be held has to be tempered by the poor reproducibility between studies in terms of the exact nature of the associated haplotypes, by the failure so far to identify any specific susceptibility variants and by the absence of any demonstrated function associated with any of the risk haplotypes. In the present study, we show that a defined schizophrenia risk haplotype tags one or more cis-acting variants that results in a relative reduction in DTNBP1 mRNA expression in human cerebral cortex. Subsidiary analyses suggest that risk haplotypes identified in other sample groups of white European ancestry also index lower DTNBP1 expression, whereas putative 'protective' haplotypes index high DTNBP1 expression. Our data indicate that variation in the DTNBP1 gene confers susceptibility to schizophrenia through reduced expression, and that this, therefore, represents a primary aetiological mechanism in the disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
30Am. J. Hum. Genet. 2005 Dec 77: 918-36
PMID16380905
TitleBipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios.
AbstractBipolar, 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
31Biol. Psychiatry 2005 Apr 57: 696-701
PMID15820225
TitleBipolar disorder and polymorphisms in the dysbindin gene (DTNBP1).
AbstractSeveral studies support the dysbindin (dystrobrevin binding protein 1) gene (DTNBP1) as a susceptibility gene for schizophrenia. We previously reported that variation at a specific 3-locus haplotype influences susceptibility to schizophrenia in a large United Kingdom (UK) Caucasian case-control sample.
Using similar methodology to our schizophrenia study, we have investigated this same 3-locus haplotype in a large, well-characterized bipolar sample (726 Caucasian UK DSM-IV bipolar I patients; 1407 ethnically matched controls).
No significant differences were found in the distribution of the 3-locus haplotype in the full sample. Within the subset of bipolar I cases with predominantly psychotic episodes of mood disturbance (n = 133) we found nominally significant support for association at this haploptype (p < .042) and at SNP rs2619538 (p = .003), with a pattern of findings similar to that in our schizophrenia sample. This finding was not significant after correction for multiple testing.
Our data suggest that variation at the polymorphisms examined does not make a major contribution to susceptibility to bipolar disorder in general. They are consistent with the possibility that DTNBP1 influences susceptibility to a subset of bipolar disorder cases with psychosis. However, our subset sample is small and the hypothesis requires testing in independent, adequately powered samples.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
32Am J Psychiatry 2005 Oct 162: 1824-32
PMID16199828
TitleRelationship between a high-risk haplotype in the DTNBP1 (dysbindin) gene and clinical features of schizophrenia.
AbstractThe purpose of this study was to determine whether a haplotype in the dystrobrevin binding protein 1 (DTNBP1) gene previously associated with schizophrenia not only increases the susceptibility to psychotic illness but also to a more or less clinically specific form of psychotic illness.
In the Irish Study of High-Density schizophrenia Families, subjects with psychotic illness (N=755) were given lifetime ratings of clinical features according to the Operational Criteria Checklist for Psychotic Illness. Exploratory and confirmatory factor analyses were used to extract five factors-hallucinations, delusions, negative, manic, and depressive symptoms-and to create factor-derived scores. The family-based transmission disequilibrium test operationalized in the program TRANSMIT was used to determine whether a high-risk haplotype in the DTNBP1 gene was overtransmitted to subjects in the upper 20th and 40th percentiles for each factor score. These results were compared to baseline overtransmission by examining the empirical distribution of chi-square statistics in groups of 5,000 replicates in which 20% and 40% of ill subjects were randomly selected. This analysis was done for both narrow and broad definitions of psychotic illness.
Subjects in the upper 40th percentile for the negative symptom factor--in both the narrowly (p=0.004) and broadly (p=0.01) defined illness groups--were more likely to inherit the high-risk haplotype than would be expected by chance. No other significant relationships between clinical features and high-risk haplotype transmission were observed.
The etiologically relevant variation in DTNBP1, which is in presumptive linkage disequilibrium with the high-risk haplotype, may predispose individuals to a form of psychotic illness associated with high levels of negative symptoms. This finding supports previous evidence suggesting that genetic factors influence the clinical heterogeneity of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
33Mol. Psychiatry 2005 Nov 10: 1037-44
PMID16044171
TitleIdentifying potential risk haplotypes for schizophrenia at the DTNBP1 locus in Han Chinese and Scottish populations.
AbstractThe dystrobrevin-binding protein 1 (DTNBP1) gene on chromosome 6p has emerged as a potential susceptibility gene for schizophrenia. Although a number of attempts to replicate the original association finding have been successful, they have not identified any obvious pathogenic variants or a single at risk haplotype common to all populations studied. In the present study we attempted further replication in an independent sample of 638 nuclear families from the Han Chinese population of Sichuan Province, SW China. We also examined 580 Scottish schizophrenic cases and 620 controls. We genotyped 10 single-nucleotide polymorphisms (SNPs) in DTNBP1 that were used in the original report of association, plus rs2619538 (SNP 'A') in the putative promoter region, which has also been associated with schizophrenia. In the Chinese trios we found that two SNPs (P1635 and P1765) were significantly overtransmitted, but with alleles opposite to those reported in the original studies. SNPs P1757 and P1765 formed a common haplotype, which also showed significant overtransmission. In the Scottish cases and controls, no individual markers were significantly associated with schizophrenia. A single haplotype, which included rs2619538 and P1583, and one rare haplotype, composed of P1320 and P1757, were significantly associated with schizophrenia, but no previously reported haplotypes were associated. Based on the data from the Chinese population, our results provide statistical support for DTNBP1 as a susceptibility gene for schizophrenia, albeit with haplotypes different from those of the original study. However, our lack of replication in the Scottish samples also indicates that caution is warranted when evaluating the robustness of the evidence for DTNBP1 as genetic risk factor for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
34Mol. Psychiatry 2005 Nov 10: 1037-44
PMID16044171
TitleIdentifying potential risk haplotypes for schizophrenia at the DTNBP1 locus in Han Chinese and Scottish populations.
AbstractThe dystrobrevin-binding protein 1 (DTNBP1) gene on chromosome 6p has emerged as a potential susceptibility gene for schizophrenia. Although a number of attempts to replicate the original association finding have been successful, they have not identified any obvious pathogenic variants or a single at risk haplotype common to all populations studied. In the present study we attempted further replication in an independent sample of 638 nuclear families from the Han Chinese population of Sichuan Province, SW China. We also examined 580 Scottish schizophrenic cases and 620 controls. We genotyped 10 single-nucleotide polymorphisms (SNPs) in DTNBP1 that were used in the original report of association, plus rs2619538 (SNP 'A') in the putative promoter region, which has also been associated with schizophrenia. In the Chinese trios we found that two SNPs (P1635 and P1765) were significantly overtransmitted, but with alleles opposite to those reported in the original studies. SNPs P1757 and P1765 formed a common haplotype, which also showed significant overtransmission. In the Scottish cases and controls, no individual markers were significantly associated with schizophrenia. A single haplotype, which included rs2619538 and P1583, and one rare haplotype, composed of P1320 and P1757, were significantly associated with schizophrenia, but no previously reported haplotypes were associated. Based on the data from the Chinese population, our results provide statistical support for DTNBP1 as a susceptibility gene for schizophrenia, albeit with haplotypes different from those of the original study. However, our lack of replication in the Scottish samples also indicates that caution is warranted when evaluating the robustness of the evidence for DTNBP1 as genetic risk factor for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
35Am J Psychiatry 2006 May 163: 940-1; author reply 941-2
PMID16648345
TitleAre high-risk haplotypes in DTNBP1 and NRG1 resistance genes for schizophrenia?
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
36Eur. J. Hum. Genet. 2006 Jun 14: 669-80
PMID16721403
TitleMolecular genetic studies of schizophrenia.
AbstractThe 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
37Dialogues Clin Neurosci 2006 -1 8: 79-84
PMID16640117
TitleClinical impact of recently detected susceptibility genes for schizophrenia.
AbstractAfter years of frustration, the search for genes impacting on schizophrenia is now undergoing some exciting developments. Several proposals of susceptibility genes have been able to be supported by replications. Thus, there are now at least three very strong candidates: the gene for dysbindin (DTNBP1), the gene for neuregulin-1 (NRG1), and a less well-understood gene locus, G72/G30, which are likely to influence manifestations of schizophrenia. Other "hot" candidates such as the disrupted-in-schizophrenia 1 gene (DISC1) and the gene coding for protein kinase B (AKT1) might also prove to be susceptibility genes in the next future. The clinical implications of these findings are not yet fully visible. However, some first insights are possible: most of the genetic findings lack diagnostic specificity, and are also reproduced in bipolar disorder. Strong associations are also obtained on a symptomatic level, not only on a diagnostic level. The pathophysiological role of these hot candidate genes is currently under intensive study.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
38Curr Opin Psychiatry 2006 Mar 19: 158-64
PMID16612196
TitleAn update on the genetics of schizophrenia.
AbstractThis 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
39Biol. Psychiatry 2006 Jul 60: 163-76
PMID16616896
TitleCritical appraisal of DNA microarrays in psychiatric genomics.
AbstractTranscriptome 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
40J Neural Transm (Vienna) 2006 Sep 113: 1337-46
PMID16463116
TitleEffect of antipsychotic drugs on DISC1 and dysbindin expression in mouse frontal cortex and hippocampus.
AbstractAltered expression of Disrupted-In-schizophrenia-1 (DISC1) and dysbindin (DTNBP1), susceptibility genes for schizophrenia, in schizophrenic brain has been reported; however, the possible effect of antipsychotics on the expression levels of these genes has not yet been studied. We measured the mRNA expression levels of these genes in frontal cortex and hippocampus of mice chronically treated with typical and atypical antipsychotics by a real-time quantitative RT-PCR method. We found that atypical antipsychotics, olanzapine and risperidone, in a clinically relevant dose increased DISC1 expression levels in frontal cortex, while a typical antipsychotic, haloperidol, did not. No significant effect on dysbindin expression levels was observed in either brain region. These data suggest that prior evidence of decreased expression of dysbindin in postmortem brain of schizophrenics is not likely to be a simple artifact of antemortem drug treatment. Our results also suggest a potential role of DISC1 in the therapeutic mechanisms of certain atypical antipsychotics.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
41Neurosci. Res. 2006 Oct 56: 154-8
PMID16876895
TitleAssociation study of the dysbindin (DTNBP1) gene in schizophrenia from the Japanese population.
AbstractDysbindin (DTNBP1: dystrobrevin binding protein 1), located on 6p22.3, is a candidate susceptibility gene for schizophrenia. Several studies, mostly in Caucasians, have provided evidence for an association between schizophrenia and the gene, although no common polymorphism or haploytpe has been established. In Asian populations, two studies investigated a limited number of single nucleotide polymorphisms (SNPs) of dysbindin and observed support for the association. In the present study, we investigated 12 SNPs of dysbindin, including those examined in previous Asian studies, and the corresponding haplotypes in a Japanese people with schizophrenia. As a result, no significant difference was observed between patients and controls in allelic frequencies or genotypic distributions of the 12 SNPs. Permutation test however showed significant differences in frequencies of the estimated 10-marker haplotypes between patients and controls (global p = 0.006). The present study may provide further support for an association between dysbindin and schizophrenia in Asian populations. The results might be similar to a previous Asian study, but specific haplotypes suggested for the association differed between the studies. Studies with more markers and subjects may be required before firm conclusions can be reached.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
42Am J Psychiatry 2006 Mar 163: 532-4
PMID16513878
TitleDysbindin genotype and negative symptoms in schizophrenia.
AbstractConverging evidence has demonstrated an association between variants in the dysbindin gene (DTNBP1) and schizophrenia. Recently, a DTNBP1 risk haplotype, associated with both schizophrenia and neurocognitive dysfunction, has been identified. Because neurocognitive dysfunction is commonly accompanied by negative symptoms (avolition, alogia, and affective flattening) in schizophrenia, the authors hypothesized that the presence of the risk haplotype would be significantly associated with negative symptoms.
The authors tested for an association between a DTNBP1 risk haplotype and a lifetime history of negative symptoms in 181 Caucasian patients with schizophrenia.
A significant association was found between the presence of the risk haplotype and negative symptoms.
These data suggest that the effect of DTNBP1 genetic variation may be associated with negative symptoms in patients with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
43Hum. Mol. Genet. 2006 May 15: 1563-8
PMID16415041
TitleGenetic variation in DTNBP1 influences general cognitive ability.
AbstractHuman intelligence is a trait that is known to be significantly influenced by genetic factors, and recent linkage data provide positional evidence to suggest that a region on chromosome 6p, previously associated with schizophrenia, may be linked to variation in intelligence. The gene for dysbindin-1 (DTNBP1) is located at 6p and has also been implicated in schizophrenia, a neuropsychiatric disorder characterized by cognitive dysfunction. We report an association between DTNBP1 genotype and general cognitive ability (g) in two independent cohorts, including 213 patients with schizophrenia or schizo-affective disorder and 126 healthy volunteers. These data suggest that DTNBP1 genetic variation influences human intelligence.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
44J Neural Transm (Vienna) 2006 Sep 113: 1337-46
PMID16463116
TitleEffect of antipsychotic drugs on DISC1 and dysbindin expression in mouse frontal cortex and hippocampus.
AbstractAltered expression of Disrupted-In-schizophrenia-1 (DISC1) and dysbindin (DTNBP1), susceptibility genes for schizophrenia, in schizophrenic brain has been reported; however, the possible effect of antipsychotics on the expression levels of these genes has not yet been studied. We measured the mRNA expression levels of these genes in frontal cortex and hippocampus of mice chronically treated with typical and atypical antipsychotics by a real-time quantitative RT-PCR method. We found that atypical antipsychotics, olanzapine and risperidone, in a clinically relevant dose increased DISC1 expression levels in frontal cortex, while a typical antipsychotic, haloperidol, did not. No significant effect on dysbindin expression levels was observed in either brain region. These data suggest that prior evidence of decreased expression of dysbindin in postmortem brain of schizophrenics is not likely to be a simple artifact of antemortem drug treatment. Our results also suggest a potential role of DISC1 in the therapeutic mechanisms of certain atypical antipsychotics.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
45J Neural Transm (Vienna) 2006 Sep 113: 1337-46
PMID16463116
TitleEffect of antipsychotic drugs on DISC1 and dysbindin expression in mouse frontal cortex and hippocampus.
AbstractAltered expression of Disrupted-In-schizophrenia-1 (DISC1) and dysbindin (DTNBP1), susceptibility genes for schizophrenia, in schizophrenic brain has been reported; however, the possible effect of antipsychotics on the expression levels of these genes has not yet been studied. We measured the mRNA expression levels of these genes in frontal cortex and hippocampus of mice chronically treated with typical and atypical antipsychotics by a real-time quantitative RT-PCR method. We found that atypical antipsychotics, olanzapine and risperidone, in a clinically relevant dose increased DISC1 expression levels in frontal cortex, while a typical antipsychotic, haloperidol, did not. No significant effect on dysbindin expression levels was observed in either brain region. These data suggest that prior evidence of decreased expression of dysbindin in postmortem brain of schizophrenics is not likely to be a simple artifact of antemortem drug treatment. Our results also suggest a potential role of DISC1 in the therapeutic mechanisms of certain atypical antipsychotics.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
46Eur. J. Hum. Genet. 2006 Sep 14: 1037-43
PMID16736033
TitleA summary statistic approach to sequence variation in noncoding regions of six schizophrenia-associated gene loci.
AbstractIn 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
47Schizophr Bull 2006 Jan 32: 9-16
PMID16319375
TitleGenes for schizophrenia and bipolar disorder? Implications for psychiatric nosology.
AbstractIt has been conventional for psychiatric research, including the search for predisposing genes, to proceed under the assumption that schizophrenia and bipolar disorder are separate disease entities with different underlying etiologies. These represent Emil Kraepelin's traditional dichotomous classification of the so-called "functional" psychoses and form the basis of modern diagnostic practice. However, findings emerging from many fields of psychiatric research do not fit well with this model. In particular, the pattern of findings emerging from genetic studies shows increasing evidence for an overlap in genetic susceptibility across the traditional classification categories-including association findings at DAOA(G72), DTNBP1 (dysbindin), COMT, BDNF, DISC1, and NRG1. The emerging evidence suggests the possibility of relatively specific relationships between genotype and psychopathology. For example, DISC1 and NRG1 may confer susceptibility to a form of illness with mixed features of schizophrenia and mania. The elucidation of genotype-phenotype relationships is at an early stage, but current findings highlight the need to consider alternative approaches to classification and conceptualization for psychiatric research rather than continuing to rely heavily on the traditional Kraepelinian dichotomy. As psychosis susceptibility genes are identified and characterized over the next few years, this 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
48Hum. Mol. Genet. 2006 Oct 15: 3041-54
PMID16980328
TitleDysbindin-1 is a synaptic and microtubular protein that binds brain snapin.
AbstractVariations in the gene encoding the novel protein dysbindin-1 (DTNBP1) are among the most commonly reported genetic variations associated with schizophrenia. Recent studies show that those variations are also associated with cognitive functioning in carriers with and without psychiatric diagnoses, suggesting a general role for dysbindin-1 in cognition. Such a role could stem from the protein's known ability to affect neuronal glutamate release. How dysbindin-1 might affect glutamate release nevertheless remains unknown without the discovery of the protein's neuronal binding partners and its subcellular locus of action. We demonstrate here that snapin is a binding partner of dysbindin-1 in vitro and in the brain. Tissue fractionation of whole mouse brains and human hippocampal formations revealed that both dysbindin-1 and snapin are concentrated in tissue enriched in synaptic vesicle membranes and less commonly in postsynaptic densities. It is not detected in presynaptic tissue fractions lacking synaptic vesicles. Consistent with that finding, immunoelectron microscopy showed that dysbindin-1 is located in (i) synaptic vesicles of axospinous terminals in the dentate gyrus inner molecular layer and CA1 stratum radiatum and in (ii) postsynaptic densities and microtubules of dentate hilus neurons and CA1 pyramidal cells. The labeled synapses are often asymmetric with thick postsynaptic densities suggestive of glutamatergic synapses, which are likely to be derived from dentate mossy cells and CA3 pyramidal cells. The function of dysbindin-1 in presynaptic, postsynaptic and microtubule locations may all be related to known functions of snapin.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
49Biochem. J. 2006 May 395: 587-98
PMID16448387
TitleReinvestigation of the dysbindin subunit of BLOC-1 (biogenesis of lysosome-related organelles complex-1) as a dystrobrevin-binding protein.
AbstractDysbindin was identified as a dystrobrevin-binding protein potentially involved in the pathogenesis of muscular dystrophy. Subsequently, genetic studies have implicated variants of the human dysbindin-encoding gene, DTNBP1, in the pathogeneses of Hermansky-Pudlak syndrome and schizophrenia. The protein is a stable component of a multisubunit complex termed BLOC-1 (biogenesis of lysosome-related organelles complex-1). In the present study, the significance of the dystrobrevin-dysbindin interaction for BLOC-1 function was examined. Yeast two-hybrid analyses, and binding assays using recombinant proteins, demonstrated direct interaction involving coiled-coil-forming regions in both dysbindin and the dystrobrevins. However, recombinant proteins bearing the coiled-coil-forming regions of the dystrobrevins failed to bind endogenous BLOC-1 from HeLa cells or mouse brain or muscle, under conditions in which they bound the Dp71 isoform of dystrophin. Immunoprecipitation of endogenous dysbindin from brain or muscle resulted in robust co-immunoprecipitation of the pallidin subunit of BLOC-1 but no specific co-immunoprecipitation of dystrobrevin isoforms. Within BLOC-1, dysbindin is engaged in interactions with three other subunits, named pallidin, snapin and muted. We herein provide evidence that the same 69-residue region of dysbindin that is sufficient for dystrobrevin binding in vitro also contains the binding sites for pallidin and snapin, and at least part of the muted-binding interface. Functional, histological and immunohistochemical analyses failed to detect any sign of muscle pathology in BLOC-1-deficient, homozygous pallid mice. Taken together, these results suggest that dysbindin assembled into BLOC-1 is not a physiological binding partner of the dystrobrevins, likely due to engagement of its dystrobrevin-binding region in interactions with other subunits.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
50Am. J. Hum. Genet. 2006 Nov 79: 903-9
PMID17033966
TitleAnalysis of high-resolution HapMap of DTNBP1 (Dysbindin) suggests no consistency between reported common variant associations and schizophrenia.
AbstractDTNBP1 was first identified as a putative schizophrenia-susceptibility gene in Irish pedigrees, with a report of association to common genetic variation. Several replication studies have reported confirmation of an association to DTNBP1 in independent European samples; however, reported risk alleles and haplotypes appear to differ between studies, and comparison among studies has been confounded because different marker sets were employed by each group. To facilitate evaluation of existing evidence of association and further work, we supplemented the extensive genotype data, available through the International HapMap Project (HapMap), about DTNBP1 by specifically typing all associated single-nucleotide polymorphisms reported in each of the studies of the Centre d'Etude du Polymorphisme Humain (CEPH)-derived HapMap sample (CEU). Using this high-density reference map, we compared the putative disease-associated haplotype from each study and found that the association studies are inconsistent with regard to the identity of the disease-associated haplotype at DTNBP1. Specifically, all five "replication" studies define a positively associated haplotype that is different from the association originally reported. We further demonstrate that, in all six studies, the European-derived populations studied have haplotype patterns and frequencies that are consistent with HapMap CEU samples (and each other). Thus, it is unlikely that population differences are creating the inconsistency of the association studies. Evidence of association is, at present, equivocal and unsatisfactory. The new dense map of the region may be valuable in more-comprehensive follow-up studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
51Neurosci. Lett. 2006 Oct 407: 101-6
PMID16959423
TitleThe dysbindin gene (DTNBP1) and schizophrenia: no support for an association in the Korean population.
AbstractThe dysbindin gene (DTNBP1) is located in chromosome 6p22.3, one of the regions of positive linkage for schizophrenia. A strong genetic association between DTNBP1 and schizophrenia has been replicated through many recent studies. In particular, dysbindin protein has been found to play a role in the glutamate neural transmission in the brain. In this study, we attempted to replicate the previously reported positive association between DTNBP1 and schizophrenia in the Korean population. Our sample included 194 patients with schizophrenia based on DSM-IV and 351 normal controls. We genotyped five SNPs including SNP A in promoter region of DTNBP1. The allele and genotype association were analyzed and the simulated haplotype was investigated as well. As the result, we could not find a significant association of DTNBP1 with schizophrenia in this Korean sample. Additional analysis of the subgroup of schizophrenia having familial loading of major psychiatric disorders did not show association, either. In summary, DTNBP1 is not likely to be a major susceptibility gene for schizophrenia in this Korean population. This result of no association also implies possible genetic heterogeneity of schizophrenia. Further studies with more dense SNPs of the whole gene sequence for various populations will be necessary to understand the genetic contribution of DTNBP1 for the development of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
52Twin Res Hum Genet 2006 Aug 9: 531-9
PMID16899160
TitleAssociation study of the dystrobrevin-binding gene with schizophrenia in Australian and Indian samples.
AbstractNumerous studies have reported association between variants in the dystrobrevin binding protein 1 (dysbindin) gene (DTNBP1) and schizophrenia. However, the pattern of results is complex and to date, no specific risk marker or haplotype has been consistently identified. The number of single nucleotide polymorphisms (SNPs) tested in these studies has ranged from 5 to 20. We attempted to replicate previous findings by testing 16 SNPs in samples of 41 Australian pedigrees, 194 Australian cases and 180 controls, and 197 Indian pedigrees. No globally significant evidence for association was observed in any sample, despite power calculations indicating sufficient power to replicate several previous findings. Possible explanations for our results include sample differences in background linkage disequilibrium and/or risk allele effect size, the presence of multiple risk alleles upon different haplotypes, or the presence of a single risk allele upon multiple haplotypes. Some previous associations may also represent false positives. Examination of Caucasian HapMap phase II genotype data spanning the DTNBP1 region indicates upwards of 40 SNPs are required to satisfactorily assess all nonredundant variation within DTNBP1 and its potential regulatory regions for association with schizophrenia. More comprehensive studies in multiple samples will be required to determine whether specific DTNBP1 variants function as risk factors for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
53Neuropsychopharmacology 2006 Sep 31: 2002-10
PMID16407900
TitleDTNBP1 (dysbindin) gene variants modulate prefrontal brain function in healthy individuals.
AbstractDTNBP1 (dysbindin) is one of the several putative schizophrenia genes supported by association, neuroanatomical, and cellular studies. These suggest an involvement of DTNBP1 in the prefrontal cortex and cognitive functions mediated by interaction with neurotransmitter systems, in particular glutamate. The influence of DTNBP1 gene variation on prefrontal brain function at the systemic neurophysiological level, though, has not been characterized. The NoGo-anteriorization (NGA) as an event-related potential (ERP) measure elicited during the continuous performance test (CPT) has been established as a valid neurophysiological parameter for prefrontal brain function in healthy individuals and patients with schizophrenias. In the present study, we therefore investigated the influence of eight dysbindin gene variants on the NGA as a marker of prefrontal brain function in 48 healthy individuals. Two DTNBP1 polymorphisms previously linked to schizophrenia (P1765 and P1320) were found associated with changes in the NGA. Post hoc analysis showing an influence of genetic variation at these loci on the Go centroid and frontal amplitudes suggest that this might be due to modification of the execution of motor processes by the prefrontal cortex. This is the first report on a role of DTNBP1 gene variation for prefrontal brain function at a systemic neurophysiological level in healthy humans. Future studies will have to address the relevance of this observation for patients with schizophrenias.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
54Neuropsychopharmacology 2006 Sep 31: 2002-10
PMID16407900
TitleDTNBP1 (dysbindin) gene variants modulate prefrontal brain function in healthy individuals.
AbstractDTNBP1 (dysbindin) is one of the several putative schizophrenia genes supported by association, neuroanatomical, and cellular studies. These suggest an involvement of DTNBP1 in the prefrontal cortex and cognitive functions mediated by interaction with neurotransmitter systems, in particular glutamate. The influence of DTNBP1 gene variation on prefrontal brain function at the systemic neurophysiological level, though, has not been characterized. The NoGo-anteriorization (NGA) as an event-related potential (ERP) measure elicited during the continuous performance test (CPT) has been established as a valid neurophysiological parameter for prefrontal brain function in healthy individuals and patients with schizophrenias. In the present study, we therefore investigated the influence of eight dysbindin gene variants on the NGA as a marker of prefrontal brain function in 48 healthy individuals. Two DTNBP1 polymorphisms previously linked to schizophrenia (P1765 and P1320) were found associated with changes in the NGA. Post hoc analysis showing an influence of genetic variation at these loci on the Go centroid and frontal amplitudes suggest that this might be due to modification of the execution of motor processes by the prefrontal cortex. This is the first report on a role of DTNBP1 gene variation for prefrontal brain function at a systemic neurophysiological level in healthy humans. Future studies will have to address the relevance of this observation for patients with schizophrenias.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
55Schizophr. Res. 2007 Mar 91: 27-36
PMID17300918
TitleThe role of DTNBP1, NRG1, and AKT1 in the genetics of schizophrenia in Finland.
AbstractSeveral putative schizophrenia susceptibility genes have recently been identified. Significant associations between schizophrenia and neuregulin 1 (NRG1) and dysbindin (DTNBP1) were first reported in 2002 and studies in several populations have since independently reported positive associations to these gene regions. Further, both tentative functional and genetic data have implicated the role of AKT1 in the genetic background of this disorder. However, findings have not been consistent in all populations. We investigated the allelic diversity of these three genes NRG1, DTNBP1 and AKT1 in a representative nation-wide study sample of 441 Finnish schizophrenia families consisting of 865 affected individuals, in order to assess their role in one of the largest population-based study samples. DTNBP1 and AKT1 failed to show evidence of association, whereas two SNPs in the 3' region of the NRG1 gene yielded suggestive evidence of association (p=0.012 and p=0.048) in family-based association analyses. Thus, our study does not indicate that AKT1 or DTNBP1 play a role in the etiology of schizophrenia in the Finnish population. Furthermore, results do not support a major role for NRG1, but we cannot completely exclude a minor role of this gene in the Finnish population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
56Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jul 144B: 701-3
PMID17192893
TitleEffect of 5-haplotype of dysbindin gene (DTNBP1) polymorphisms for the susceptibility to bipolar I disorder.
AbstractWe investigated a possible association between dysbindin gene (DTNBP1) variants and bipolar I disorder (BID). Five SNPs within DTNBP1 (rs3213207, rs1011313, rs2005976, rs760761, and rs2619522) were genotyped for 151 patients with BID and 478 controls. We observed a significant protective association of the haplotype A-C-G-T-A (all SNPs, P = 0.00016) and particularly G-T-A (the last three SNP, P = 0.00007) within DTNBP1 variants investigated. Single marker and subgroup (e.g., psychotic features, age at onset, family history, etc.) analyses showed no significant association. Although the association was due to a small number of subjects, specific DTNBP1 haplotypes, previously associated with schizophrenia, may be also associated with BID. Adequately powered studies from different ethnicities will be necessary to confirm our findings.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
57Cell. Physiol. Biochem. 2007 -1 20: 687-702
PMID17982252
TitleMolecular mechanisms of schizophrenia.
Abstractschizophrenia 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
58J. Neurosci. 2007 Nov 27: 12390-5
PMID17989303
TitleEvidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization.
AbstractThe schizophrenia susceptibility gene dystrobrevin-binding protein 1 (DTNBP1) encodes dysbindin, which along with its binding partner Muted is an essential component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin expression is reduced in schizophrenic brain tissue, but the molecular mechanisms by which this contributes to pathogenesis and symptomatology are unknown. We studied the effects of transfection of DTNBP1 siRNA on cell surface levels of dopamine D2 receptor (DRD2) in human SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. DTNBP1 siRNA decreased dysbindin protein, increased cell surface DRD2 and blocked dopamine-induced DRD2 internalization. MUTED siRNA produced similar effects. In contrast, decreased dysbindin did not change dopamine D1 receptor (DRD1) levels, or its basal or dopamine-induced internalization. The DRD2 agonist quinpirole reduced phosphorylation of CREB (cAMP response element-binding protein) in dysbindin downregulated cells, demonstrating enhanced intracellular signaling caused by the upregulation of DRD2. This is the first demonstration of a schizophrenia susceptibility gene exerting a functional effect on DRD2 signaling, a pathway that has long been implicated in the illness. We propose a molecular mechanism for pathogenesis in which risk alleles in DTNBP1, or other factors that also downregulate dysbindin, compromise the ability of BLOC-1 to traffic DRD2 toward degradation, but has little effect on DRD1 trafficking. Impaired trafficking of DRD2 decreases dopamine-induced internalization, and with more receptors retained on the cell surface, dopamine stimulation produces excess intracellular signaling. Such an increase in DRD2 signaling relative to DRD1 would contribute to the imbalances in dopaminergic neurotransmission characteristic of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
59Neurosci. Lett. 2007 Jun 421: 47-51
PMID17548156
TitleHigh dopamine turnover in the brains of Sandy mice.
Abstractschizophrenia is a chronic mental disorder and patients with this disease show positive and negative symptoms, cognitive dysfunction, and deficits in the processing of emotion. From previous studies, dopaminergic neurons are believed to be related to schizophrenic symptoms. Dysbindin (DTNBP1: dystrobrevin binding protein 1) gene is a susceptibility gene for schizophrenia, but the involvement of this gene in the dopaminergic tone remains unknown. In this paper, we studied regional contents of dopamine and its metabolite in the Sandy (Sdy) mouse which expresses no dysbindin protein. The brains of Sdy and wild-type (WT) mice were dissected into ten regions and dopamine (DA) and homovanillic acid (HVA) in each region were determined. DA contents were significantly lower in the cortex, hippocampus, and hypothalamus of Sdy mice than WT mice, while HVA contents showed no differences between the strains. Western blot analysis revealed there were no differences in the amount of tyrosine hydroxylase (TH) in the midbrain (MB) of both strains. The ratios of DA to HVA, which is an index of DA turnover, were higher in the cortex and the hippocampus, but not in the hypothalamus. These data demonstrate that DA turnover in the specific regions of the brain of the Sdy mouse was increased, and the Sdy mouse is a possible useful candidate animal for studying the pathogenic mechanism of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
60Proc. Biol. Sci. 2007 Nov 274: 2801-10
PMID17785269
TitleAdaptive evolution of genes underlying schizophrenia.
Abstractschizophrenia poses an evolutionary-genetic paradox because it exhibits strongly negative fitness effects and high heritability, yet it persists at a prevalence of approximately 1% across all human cultures. Recent theory has proposed a resolution: that genetic liability to schizophrenia has evolved as a secondary consequence of selection for human cognitive traits. This hypothesis predicts that genes increasing the risk of this disorder have been subject to positive selection in the evolutionary history of humans and other primates. We evaluated this prediction using tests for recent selective sweeps in human populations and maximum-likelihood tests for selection during primate evolution. Significant evidence for positive selection was evident using one or both methods for 28 of 76 genes demonstrated to mediate liability to schizophrenia, including DISC1, DTNBP1 and NRG1, which exhibit especially strong and well-replicated functional and genetic links to this disorder. Strong evidence of non-neutral, accelerated evolution was found for DISC1, particularly for exon 2, the only coding region within the schizophrenia-associated haplotype. Additionally, genes associated with schizophrenia exhibited a statistically significant enrichment in their signals of positive selection in HapMap and PAML analyses of evolution along the human lineage, when compared with a control set of genes involved in neuronal activities. The selective forces underlying adaptive evolution of these genes remain largely unknown, but these findings provide convergent evidence consistent with the hypothesis that schizophrenia represents, in part, a maladaptive by-product of adaptive changes during human evolution.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
61Mol. Psychiatry 2007 Jan 12: 74-86
PMID17043677
TitleDisrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia.
AbstractDisrupted in schizophrenia 1 (DISC1) is a schizophrenia risk gene associated with cognitive deficits in both schizophrenics and the normal ageing population. In this study, we have generated a network of protein-protein interactions (PPIs) around DISC1. This has been achieved by utilising iterative yeast-two hybrid (Y2H) screens, combined with detailed pathway and functional analysis. This so-called 'DISC1 interactome' contains many novel PPIs and provides a molecular framework to explore the function of DISC1. The network implicates DISC1 in processes of cytoskeletal stability and organisation, intracellular transport and cell-cycle/division. In particular, DISC1 looks to have a PPI profile consistent with that of an essential synaptic protein, which fits well with the underlying molecular pathology observed at the synaptic level and the cognitive deficits seen behaviourally in schizophrenics. Utilising a similar approach with dysbindin (DTNBP1), a second schizophrenia risk gene, we show that dysbindin and DISC1 share common PPIs suggesting they may affect common biological processes and that the function of schizophrenia risk genes may converge.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
62Schizophr. Res. 2007 Nov 96: 112-8
PMID17604607
TitleAssociation study between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia: a meta-analysis.
AbstractPositional, functional and association studies have strongly implicated the dystrobrevin binding protein 1 gene (DTNBP1) as a promising novel candidate gene for schizophrenia. Since the first association study was reported, there have been many attempts to replicate it. However the results have been mixed and these subsequent studies have produced negative as well as positive results. To reconcile these conflicting findings and to give a comprehensive picture of the relationship of DTNBP1 and schizophrenia, the current meta-analysis combined all published association studies involving nine polymorphisms up to May 2006. The results (12 studies including 3429 cases, 3376 controls and 721 trios) showed that there were five single nucleotide polymorphisms (SNPs) with p values < 0.05, however, sensitivity analyses showed that only one SNP was consistent across all nine studies (four of the five SNPs became non-significant after removal of one study), indicating that one study may cause the association findings for each of these four SNPs. In conclusion, there is only a weak association of one SNP in DTNBP1 with schizophrenia, which is not significant after multiple testing.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
63Behav Brain Funct 2007 -1 3: 19
PMID17445278
TitleAssociation between the DTNBP1 gene and intelligence: a case-control study in young patients with schizophrenia and related disorders and unaffected siblings.
AbstractThe dystrobrevin-binding protein 1 (DTNBP1) gene is a susceptibility gene for schizophrenia. There is growing evidence that DTNPB1 contributes to intelligence and cognition. In this study, we investigated association between single nucleotide polymorphisms (SNPs) in the DTNBP1 gene and intellectual functioning in patients with a first episode of schizophrenia or related psychotic disorder (first-episode psychosis, FEP), their healthy siblings, and unrelated controls.
From all subjects IQ measurements were obtained (verbal IQ [VIQ], performance IQ [PIQ], and full scale IQ [FSIQ]). Seven SNPs in the DTNBP1 gene were genotyped using single base primer extension and analyzed by matrix-assisted laser deionization mass spectrometry (MALDI-TOF).
Mean VIQ, PIQ, and FSIQ scores differed significantly (p < 0.001) between patients, siblings, and controls. Using a family-based and a case-control design, several single SNPs were significantly associated with IQ scores in patients, siblings, and controls.
Although preliminary, our results provide evidence for association between the DTNBP1 gene and intelligence in patients with FEP and their unaffected siblings. Genetic variation in the DTNBP1 gene may increase schizophrenia susceptibility by affecting intellectual functioning.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
64Schizophr. Res. 2007 Jul 93: 391-8
PMID17407805
TitleNo association evidence between schizophrenia and dystrobrevin-binding protein 1 (DTNBP1) in Taiwanese families.
AbstractSeveral linkage studies have shown significant linkage of schizophrenia to chromosome 6p region, which includes the positional candidate genes, Dystrobrevin-binding protein 1 (DTNBP1). The aim was to examine the association evidence of the candidate gene in 693 Taiwanese families with at least two affected siblings of schizophrenia. We genotyped nine SNPs of this gene with average intermarker distance of 17 kb. Intermarker linkage disequilibrium was calculated with GOLD. Single locus and haplotype association analyses were performed with TRANSMIT program. We found no significant association between schizophrenia and DTNBP1 either through single locus or haplotype analyses. We failed to replicate the association evidence between DTNBP1 and schizophrenia and this gene may not play a major role in the etiology of schizophrenia in this Taiwanese family sample.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
65Neuromuscul. Disord. 2007 Feb 17: 123-34
PMID17251025
TitleDystrobrevins in muscle and non-muscle tissues.
AbstractThe alpha- and beta-dystrobrevins belong to the family of dystrophin-related and dystrophin-associated proteins. As constituents of the dystrophin-associated protein complex, alpha-dystrobrevin was believed to have a role predominantly in muscles and beta-dystrobrevin in non-muscle tissues. Recent reports described novel localisations and molecular characteristics of alpha-dystrobrevin isoforms in non-muscle tissues (developing and adult). While single and double knockout studies have revealed distinct functions of dystrobrevin in some tissues, these also suggested a strong compensatory mechanism, where dystrobrevins displaying overlapping tissue expression pattern and structure/function similarity can substitute each other. No human disease has been unequivocally associated within mutations of dystrobrevin genes. However, some significant exceptions to these overlapping expression patterns, mainly in the brain, suggest that dystrobrevin mutations might underlie some specific motor, behavioural or cognitive defects. Dystrobrevin binding partner DTNBP1 (dysbindin) is a probable susceptibility gene for schizophrenia and bipolar affective disorder in some populations. As dysbindin abnormality is linked to Hermansky-Pudlak syndrome, dystrobrevins and/or their binding partners may also be required for proper function of other non-muscle tissues.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
66Schizophr. Res. 2007 Jan 89: 169-72
PMID17074466
TitleDTNBP1 genotype influences cognitive decline in schizophrenia.
AbstractIntellectual decline is common in schizophrenia and predicts functional outcome. While many patients undergo intellectual decline that typically predates the onset of symptoms, few studies have investigated the underlying mechanism through which this occurs. The current study assessed the relationship between intellectual decline in schizophrenia and genetic variation in dysbindin-1 (DTNBP1).
We assessed cognitive decline in 183 Caucasian patients with schizophrenia using a proxy measure of premorbid IQ with which current general cognitive ability (g) was compared. We then tested for a relationship between the risk haplotype identified in previous work (CTCTAC) and intellectual decline.
We found that carriers of the CTCTAC haplotype, demonstrated a significantly greater decline in IQ as compared with non-carriers (p=0.05).
These data suggest that DTNBP1 influences the severity of intellectual decline in schizophrenia and may represent one underlying cause for heterogeneity in cognitive course.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
67Neurosci. Lett. 2007 Jun 421: 47-51
PMID17548156
TitleHigh dopamine turnover in the brains of Sandy mice.
Abstractschizophrenia is a chronic mental disorder and patients with this disease show positive and negative symptoms, cognitive dysfunction, and deficits in the processing of emotion. From previous studies, dopaminergic neurons are believed to be related to schizophrenic symptoms. Dysbindin (DTNBP1: dystrobrevin binding protein 1) gene is a susceptibility gene for schizophrenia, but the involvement of this gene in the dopaminergic tone remains unknown. In this paper, we studied regional contents of dopamine and its metabolite in the Sandy (Sdy) mouse which expresses no dysbindin protein. The brains of Sdy and wild-type (WT) mice were dissected into ten regions and dopamine (DA) and homovanillic acid (HVA) in each region were determined. DA contents were significantly lower in the cortex, hippocampus, and hypothalamus of Sdy mice than WT mice, while HVA contents showed no differences between the strains. Western blot analysis revealed there were no differences in the amount of tyrosine hydroxylase (TH) in the midbrain (MB) of both strains. The ratios of DA to HVA, which is an index of DA turnover, were higher in the cortex and the hippocampus, but not in the hypothalamus. These data demonstrate that DA turnover in the specific regions of the brain of the Sdy mouse was increased, and the Sdy mouse is a possible useful candidate animal for studying the pathogenic mechanism of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
68Mol. Psychiatry 2007 Jan 12: 74-86
PMID17043677
TitleDisrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia.
AbstractDisrupted in schizophrenia 1 (DISC1) is a schizophrenia risk gene associated with cognitive deficits in both schizophrenics and the normal ageing population. In this study, we have generated a network of protein-protein interactions (PPIs) around DISC1. This has been achieved by utilising iterative yeast-two hybrid (Y2H) screens, combined with detailed pathway and functional analysis. This so-called 'DISC1 interactome' contains many novel PPIs and provides a molecular framework to explore the function of DISC1. The network implicates DISC1 in processes of cytoskeletal stability and organisation, intracellular transport and cell-cycle/division. In particular, DISC1 looks to have a PPI profile consistent with that of an essential synaptic protein, which fits well with the underlying molecular pathology observed at the synaptic level and the cognitive deficits seen behaviourally in schizophrenics. Utilising a similar approach with dysbindin (DTNBP1), a second schizophrenia risk gene, we show that dysbindin and DISC1 share common PPIs suggesting they may affect common biological processes and that the function of schizophrenia risk genes may converge.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
69Behav Brain Funct 2007 -1 3: 50
PMID17888175
TitleFailure to confirm allelic and haplotypic association between markers at the chromosome 6p22.3 dystrobrevin-binding protein 1 (DTNBP1) locus and schizophrenia.
AbstractPrevious linkage and association studies may have implicated the Dystrobrevin-binding protein 1 (DTNBP1) gene locus or a gene in linkage disequilibrium with DTNBP1 on chromosome 6p22.3 in genetic susceptibility to schizophrenia.
We used the case control design to test for of allelic and haplotypic association with schizophrenia in a sample of four hundred and fifty research subjects with schizophrenia and four hundred and fifty ancestrally matched supernormal controls. We genotyped the SNP markers previously found to be significantly associated with schizophrenia in the original study and also other markers found to be positive in subsequent studies.
We could find no evidence of allelic, genotypic or haplotypic association with schizophrenia in our UK sample.
The results suggest that the DTNBP1 gene contribution to schizophrenia must be rare or absent in our sample. The discrepant allelic association results in previous studies of association between DTNBP1 and schizophrenia could be due population admixture. However, even positive studies of European populations do not show any consistent DTNBP1 alleles or haplotypes associated with schizophrenia. Further research is needed to resolve these issues. The possible confounding of linkage with association in family samples already showing linkage at 6p22.3 might be revealed by testing genes closely linked to DTNBP1 for allelic association and by restricting family based tests of association to only one case per family.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
70Schizophr Bull 2007 Nov 33: 1343-53
PMID17329232
TitleeIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia?
AbstractBipolar 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
71Neurosci Biobehav Rev 2007 -1 31: 60-78
PMID16782199
TitleSusceptibility genes for schizophrenia: characterisation of mutant mouse models at the level of phenotypic behaviour.
AbstractA 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
72Biol. Psychiatry 2007 May 61: 1195-9
PMID17055463
TitleSignificant support for DAO as a schizophrenia susceptibility locus: examination of five genes putatively associated with schizophrenia.
Abstractschizophrenia 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
73Genes Brain Behav. 2007 Mar 6: 113-9
PMID17410640
TitleThe PIP5K2A and RGS4 genes are differentially associated with deficit and non-deficit schizophrenia.
AbstractSeveral 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
74Biol. Psychiatry 2007 Oct 62: 784-92
PMID17336946
TitleImpact of schizophrenia candidate genes on schizotypy and cognitive endophenotypes at the population level.
AbstractAspects of cognitive function and schizotypy have been proposed as potential endophenotypes for schizophrenia. It is unknown whether the expression of these endophenotypes at the population level is modulated by the genetic variability of candidate susceptibility genes for schizophrenia.
We examined the potential impact of 18 single nucleotide polymorphisms (SNPs) within the DTNBP1, NRG1, DAOA/G32, and DAAO genes, on cognition and self-rated schizotypy, in a representative population of 2243 young male military conscripts. Single SNP and haplotype associations were evaluated.
The DTNBP1 SNPs rs2619522 and rs760761 exhibited several single marker associations, the minor alleles being associated with lower attention capacity but also a decrease in positive and paranoid schizotypy scores. The DTNBP1 haplotype load had borderline associations with nonverbal IQ, paranoid schizotypy, and sustained attention. For individual NRG1 polymorphisms, isolated but weak signals of association were noted with sustained attention and working memory but not schizotypy. The risk allele of functional SNP8NRG243177 was associated with reduced spatial working memory capacity. An isolated effect of DAAO haplotype variability was noted on negative and disorganization schizotypy. No convincing association of DAOA/G32 variability was detected.
The DTNBP1 and, less so, NRG1 and DAAO variants might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
75Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jan 144B: 45-51
PMID16967465
TitlePositive association of schizophrenia to JARID2 gene.
AbstractDysbindin (DTNBP1) is a positional candidate gene for 6p22.3-linked schizophrenia (SZ). However, so far, no disease-causing alleles have been identified. DTNBP1 is immediately adjacent to JARID2, a member of the ARID (AT-rich interaction domain) family of transcription modulators. We have previously suggested that proteins which bind to AT-rich domains could play a role in SZ pathogenesis. Consequently, we explored the possibility that JARID2 itself could be a candidate gene for 6p22.3-linked SZ. We used a case control design to analyze single nucleotide polymorphisms (SNPs) and insertion/deletion variants affecting AT-rich domains in both the DTNBP1 and JARID2 genes. Three of the DTNBP1 SNPs analyzed had previously been shown to be associated with SZ. We did not detect any significant difference in allele, genotype or haplotype distribution for any of these DTNBP1 markers. However, we did detect a significant difference in allele distribution for a tetranucleotide repeat polymorphism in the JARID2 gene that affects an AT-rich domain. A significant increase in short alleles (less than 11 repeats) was found in patients with SZ (chi(2) = 7.02; P = 0.008). No other JARID2 marker displayed statistically significant allele and genotype distributions. Our findings suggest that JARID2 should be viewed as a candidate gene for 6p22.3-linked SZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
76Hum. Hered. 2007 -1 64: 97-106
PMID17476109
TitleDTNBP1 (Dystrobrevin binding protein 1) and schizophrenia: association evidence in the 3' end of the gene.
AbstractDysbindin (DTNBP1) has been identified as a susceptibility gene for schizophrenia (SZ) through a positional approach. However, a variety of single nucleotide polymorphisms (SNPs) and haplotypes, in different parts of the gene, have been reported to be associated in different samples, and a precise molecular mechanism of disease remains to be defined. We have performed an association study with two well-characterized family samples not previously investigated at the DTNBP1 locus.
We examined 646 subjects in 136 families with SZ, largely of European ancestry (EA), genotyping 26 SNPs in DTNBP1.
Three correlated markers (rs875462, rs760666, and rs7758659) at the 3' region of DTNBP1 showed evidence for association to SZ (p = 0.004), observed in both the EA (p = 0.031) and the African American (AA) subset (p = 0.045) with the same over-transmitted allele. The most significant haplotype in our study was rs7758659-rs3213207 (global p = 0.0015), with rs3213207 being the most frequently reported associated marker in previous studies. A non-conservative missense variant (Pro272Ser) in the 3' region of DTNBP1 that may impair DTNBP1 function was more common in SZ probands (8.2%) than in founders (5%) and in dbSNP (2.1%), but did not reach statistical significance.
Our results provide evidence for an association of SZ with SNPs at the 3' end of DTNBP1 in the samples studied.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
77Neurosci. Lett. 2007 May 418: 272-5
PMID17433541
TitleDysbindin gene variants are associated with bipolar I disorder in a Korean population.
AbstractThe dysbindin gene (DTNBP1) has been associated with schizophrenia in several populations. Because the clinical characteristics of schizophrenia and bipolar disorder overlap in many respects and findings from genetic studies have suggested common genes between them, we conducted a case control association study of bipolar disorder in Korea to investigate the genetic association between DTNBP1 and bipolar disorder. In total, 163 patients with bipolar disorder and 350 controls were evaluated. We genotyped three single nucleotide polymorphisms of DTNBP1 (SNP A, P1763, and P1320) and analyzed the allele, genotype, and haplotype associations with bipolar disorder. We found significant genotypic associations with P1763 and P1320, but no association with SNP A in the bipolar I group. When we included bipolar II and schizoaffective disorder in the affected phenotype, the significance decreased. A positive association was observed between the SNP A-P1763 haplotype and the bipolar I phenotype. This haplotype association was lost when we either broadened our phenotype or included P1320 in a haplotype. The positive results of the present study lost significance after a Bonferroni correction for multiple testing. These findings are consistent with previous findings that showed a positive association of DTNBP1 with bipolar disorders. Moreover, our results suggest that DTNBP1 may contribute more to bipolar I disorder than bipolar II disorder or schizoaffective disorder. Further comprehensive studies will be required to clarify these association, however, it seems likely that DTNBP1 is a susceptibility gene for bipolar disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
78Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jul 144B: 647-59
PMID17290445
TitleAssociation study of dysbindin gene with clinical and outcome measures in a representative cohort of Italian schizophrenic patients.
AbstractThere is evidence suggesting that Dysbindin (DTNBP1) is a susceptibility gene for schizophrenia in Caucasian, Chinese, and Japanese populations. We sought to determine if dysbindin was associated with schizophrenia and its symptoms in a representative group of schizophrenic patients from a Community-Based Mental Health Service (CMHS) in Verona, Italy. A prevalence cohort of schizophrenic patients (n = 141) was assessed at baseline and then 3 and 6 years later. Eighty patients and 106 healthy controls were genotyped for polymorphisms in dysbindin. We tested if diagnosis, clinical symptoms as measured by the Brief Psychiatric Rating Scale (BPRS), and functioning as measured by the Global Assessment of Functioning Scale (GAF), were associated with the presence of certain dysbindin polymorphisms. Finally, using the longitudinal clinical data, we tested if patients carrying dysbindin high-risk haplotypes had a more unfavorable longitudinal clinical outcome. A trend towards statistical association (P = 0.058) between schizophrenia and rs2619538 was found. Using GENECOUNTING software, we found that rs2619538-P1583 (P = 0.048), P1320-P1757 (P = 0.034), and rs2619538-P1583-P1578 (P = 0.040) haplotypes occurred more often in cases compared to controls before correction for multiple testing. The rs2619538-P1583 haplotype was more likely to be transmitted to subjects with more severe and persistent psychopathology. These preliminary results are compatible with the view that DTNBP1 is a susceptibility factor for schizophrenia, and is associated with worse psychopathology.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
79Cell. Physiol. Biochem. 2007 -1 20: 687-702
PMID17982252
TitleMolecular mechanisms of schizophrenia.
Abstractschizophrenia 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
80J. Neurosci. 2007 Nov 27: 12390-5
PMID17989303
TitleEvidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization.
AbstractThe schizophrenia susceptibility gene dystrobrevin-binding protein 1 (DTNBP1) encodes dysbindin, which along with its binding partner Muted is an essential component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin expression is reduced in schizophrenic brain tissue, but the molecular mechanisms by which this contributes to pathogenesis and symptomatology are unknown. We studied the effects of transfection of DTNBP1 siRNA on cell surface levels of dopamine D2 receptor (DRD2) in human SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. DTNBP1 siRNA decreased dysbindin protein, increased cell surface DRD2 and blocked dopamine-induced DRD2 internalization. MUTED siRNA produced similar effects. In contrast, decreased dysbindin did not change dopamine D1 receptor (DRD1) levels, or its basal or dopamine-induced internalization. The DRD2 agonist quinpirole reduced phosphorylation of CREB (cAMP response element-binding protein) in dysbindin downregulated cells, demonstrating enhanced intracellular signaling caused by the upregulation of DRD2. This is the first demonstration of a schizophrenia susceptibility gene exerting a functional effect on DRD2 signaling, a pathway that has long been implicated in the illness. We propose a molecular mechanism for pathogenesis in which risk alleles in DTNBP1, or other factors that also downregulate dysbindin, compromise the ability of BLOC-1 to traffic DRD2 toward degradation, but has little effect on DRD1 trafficking. Impaired trafficking of DRD2 decreases dopamine-induced internalization, and with more receptors retained on the cell surface, dopamine stimulation produces excess intracellular signaling. Such an increase in DRD2 signaling relative to DRD1 would contribute to the imbalances in dopaminergic neurotransmission characteristic of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
81Biol. Psychiatry 2007 Oct 62: 784-92
PMID17336946
TitleImpact of schizophrenia candidate genes on schizotypy and cognitive endophenotypes at the population level.
AbstractAspects of cognitive function and schizotypy have been proposed as potential endophenotypes for schizophrenia. It is unknown whether the expression of these endophenotypes at the population level is modulated by the genetic variability of candidate susceptibility genes for schizophrenia.
We examined the potential impact of 18 single nucleotide polymorphisms (SNPs) within the DTNBP1, NRG1, DAOA/G32, and DAAO genes, on cognition and self-rated schizotypy, in a representative population of 2243 young male military conscripts. Single SNP and haplotype associations were evaluated.
The DTNBP1 SNPs rs2619522 and rs760761 exhibited several single marker associations, the minor alleles being associated with lower attention capacity but also a decrease in positive and paranoid schizotypy scores. The DTNBP1 haplotype load had borderline associations with nonverbal IQ, paranoid schizotypy, and sustained attention. For individual NRG1 polymorphisms, isolated but weak signals of association were noted with sustained attention and working memory but not schizotypy. The risk allele of functional SNP8NRG243177 was associated with reduced spatial working memory capacity. An isolated effect of DAAO haplotype variability was noted on negative and disorganization schizotypy. No convincing association of DAOA/G32 variability was detected.
The DTNBP1 and, less so, NRG1 and DAAO variants might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
82Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Jul 144B: 647-59
PMID17290445
TitleAssociation study of dysbindin gene with clinical and outcome measures in a representative cohort of Italian schizophrenic patients.
AbstractThere is evidence suggesting that Dysbindin (DTNBP1) is a susceptibility gene for schizophrenia in Caucasian, Chinese, and Japanese populations. We sought to determine if dysbindin was associated with schizophrenia and its symptoms in a representative group of schizophrenic patients from a Community-Based Mental Health Service (CMHS) in Verona, Italy. A prevalence cohort of schizophrenic patients (n = 141) was assessed at baseline and then 3 and 6 years later. Eighty patients and 106 healthy controls were genotyped for polymorphisms in dysbindin. We tested if diagnosis, clinical symptoms as measured by the Brief Psychiatric Rating Scale (BPRS), and functioning as measured by the Global Assessment of Functioning Scale (GAF), were associated with the presence of certain dysbindin polymorphisms. Finally, using the longitudinal clinical data, we tested if patients carrying dysbindin high-risk haplotypes had a more unfavorable longitudinal clinical outcome. A trend towards statistical association (P = 0.058) between schizophrenia and rs2619538 was found. Using GENECOUNTING software, we found that rs2619538-P1583 (P = 0.048), P1320-P1757 (P = 0.034), and rs2619538-P1583-P1578 (P = 0.040) haplotypes occurred more often in cases compared to controls before correction for multiple testing. The rs2619538-P1583 haplotype was more likely to be transmitted to subjects with more severe and persistent psychopathology. These preliminary results are compatible with the view that DTNBP1 is a susceptibility factor for schizophrenia, and is associated with worse psychopathology.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
83Mol. Psychiatry 2008 Sep 13: 873-7
PMID18195713
TitleSerious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk.
AbstractThe 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
84Schizophr. Res. 2008 Jan 98: 105-10
PMID17961984
TitleReduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients.
AbstractGenetic and molecular studies indicate that dysbindin-1 plays a role in the pathophysiology of schizophrenia. We examined dysbindin-1 mRNA in the hippocampal formation of patients with schizophrenia and found reduced expression in dentate granule and polymorph cells and in hippocampal field CA3, but not in CA1. Furthermore, there were positive correlations between dysbindin-1 mRNA and expression of synaptic markers known to be reduced in schizophrenia. Our results indicate that previously reported dysbindin-1 protein reductions may be due in part to decreased dysbindin-1 mRNA and that reduced dysbindin-1 may contribute to hippocampal formation synaptic pathology in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
85Z Kinder Jugendpsychiatr Psychother 2008 Jan 36: 17-26
PMID18476600
Title[Genetic findings in schizophrenia].
Abstractschizophrenia is characterized by a great heterogeneity of symptoms and functional deficits, especially of cognition. Different phenotypes are thought to result from the interaction of genetic predisposition and environmental factors. Pathophysiological models range from the dopamine and glutamate hypotheses to the hypothesis of free radicals and the hypotheses of neurodevelopment as opposed to neurodegeneration. In addition to the neurobiological approaches, linkage studies and subsequent finemappings deliver evidence with regard to genes potentially involved in schizophrenia. The most important candidate genes, such as dysbindin (DTNBP1), neuregulin (NRG1) and DISC-1 (disrupted-in schizophrenia-1), are thought to influence neurotransmission, as well as the development and maintenance of the structure of neuronal networks. The list of potential candidates includes numerous other genes as well. In conclusion, multiple genetic, neurobiological, and exogenous factors are assumed to interact in the pathogenesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
86Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 606-11
PMID18163393
TitleGene copy number variation in schizophrenia.
AbstractRecent 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
87Biochem. Biophys. Res. Commun. 2008 Aug 373: 298-302
PMID18555792
TitleBehavioral abnormalities and dopamine reductions in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia.
AbstractGenetic susceptibility plays an important role in the pathogenesis of schizophrenia. Genetic evidence for an association between the dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) and schizophrenia has been repeatedly reported in various populations worldwide. Thus, we performed behavioral analyses on homozygous sandy (sdy) mice, which lack dysbindin-1 owing to a deletion in the DTNBP1 gene. Our results showed that sdy mice were less active and spent less time in the center of an open field apparatus. Consistent with the latter observation, sdy mice also displayed evidence of heightened anxiety-like response and deficits in social interaction. Compared to wild-type mice, sdy mice displayed lower levels of dopamine, but not glutamate, in the cerebral cortex, hippocampus, and hypothalamus. These findings indicate that sdy mice display a number of behavioral abnormalities associated with schizophrenia and suggest that these abnormalities may be mediated by reductions in forebrain dopamine transmission.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
88J. Cell Biol. 2008 Jun 181: 791-801
PMID18504299
TitleDTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release.
Abstractschizophrenia is one of the most debilitating neuropsychiatric disorders, affecting 0.5-1.0% of the population worldwide. Its pathology, attributed to defects in synaptic transmission, remains elusive. The dystrobrevin-binding protein 1 (DTNBP1) gene, which encodes a coiled-coil protein, dysbindin, is a major susceptibility gene for schizophrenia. Our previous results have demonstrated that the sandy (sdy) mouse harbors a spontaneously occurring deletion in the DTNBP1 gene and expresses no dysbindin protein (Li, W., Q. Zhang, N. Oiso, E.K. Novak, R. Gautam, E.P. O'Brien, C.L. Tinsley, D.J. Blake, R.A. Spritz, N.G. Copeland, et al. 2003. Nat. Genet. 35:84-89). Here, using amperometry, whole-cell patch clamping, and electron microscopy techniques, we discovered specific defects in neurosecretion and vesicular morphology in neuroendocrine cells and hippocampal synapses at the single vesicle level in sdy mice. These defects include larger vesicle size, slower quantal vesicle release, lower release probability, and smaller total population of the readily releasable vesicle pool. These findings suggest that dysbindin functions to regulate exocytosis and vesicle biogenesis in endocrine cells and neurons. Our work also suggests a possible mechanism in the pathogenesis of schizophrenia at the synaptic level.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
89Neurosci. Lett. 2008 Aug 440: 150-4
PMID18562100
TitleDTNBP1 haplotype influences baseline assessment scores of schizophrenic in-patients.
AbstractDysbindin gene (DTNBP1) has been associated with schizophrenia, but literature findings are inconsistent, and further analyses are required. This study is aimed to investigate if a set of DTNBP1 variations might influence clinic psychotic phenotype or treatment response in a sample of 240 Korean schizophrenic in-patients. Four variants have been selected (rs3213207; rs1011313; rs16876759; rs2619522) on the basis of previous findings of association with schizophrenia, bipolar disorder and antidepressant response. Single marker analysis gave marginal results. Haplotype analysis identified a significant association between A-A (rs3213207(A/G), rs1011313(A/G)) haplotype and lower PANSS total and positive scores at baseline (p=0.01; 0.02) and at discharge (p=0.008; 0.005). Covariate analysis revealed a more stable significant association between A-A haplotype and baseline scores. These results suggest a protective effect of A-A haplotype on psychotic positive symptoms at baseline.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
90Prog. Neuropsychopharmacol. Biol. Psychiatry 2008 Feb 32: 375-9
PMID17964051
TitleIs there protective haplotype of dysbindin gene (DTNBP1) 3 polymorphisms for major depressive disorder.
AbstractDysbindin gene has been repeatedly associated with psychiatric disorders and schizophrenia in particular. This study aimed to investigate the variants of dysbindin gene in major depressive disorder (MDD). One hundred and eighty eight patients with MDD and 350 controls were investigated for 4 variants within the dysbindin gene (rs3213207 A/G, rs1011313 C/T, rs760761 C/T, and rs2619522 A/C). Haplotype analyses revealed a significant association with MDD (p=0.0007, protective A-C-T-A and A-C-C-C haplotypes), in particular the effect was due to the rs760761 (C/T) and rs2619522 (A/C) haplotype (p=0.000026). These results suggest a protective effect of some dysbindin gene haplotypes on the development of MDD. Coupled with previous findings on schizophrenia, our finding suggests that dysbindin gene variants may have a role in the susceptibility to MDD. Adequately powered further studies in different ethnic groups are warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
91Curr Psychiatry Rep 2008 Apr 10: 164-70
PMID18474210
TitleGenetics of clinical features and subtypes of schizophrenia: a review of the recent literature.
AbstractSince its earliest descriptions, schizophrenia has been thought to be clinically heterogeneous. Symptomatic features and subtypes tend to aggregate in families, suggesting that genetic factors contribute to individual differences in illness presentation. Over the past 5 years, evidence from genetic linkage and association studies has mounted to suggest that some susceptibility genes are etiologic factors for more or less specific illness subtypes. Furthermore, modifier genes may affect clinical features dimensionally only after a given patient is already affected with the illness. In this paper, we review recent findings supporting the existence of such "modifier" genes. To date, DTNBP1 has provided the greatest evidence of illness modification, as associations with negative and cognitive symptoms and worse outcome have been published in independent samples. Future directions include using whole-genome association studies to search for genetic modifiers of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
92Biol. Psychiatry 2008 Sep 64: 438-42
PMID18466879
TitleAssociation of a nonsynonymous variant of DAOA with visuospatial ability in a bipolar family sample.
AbstractBipolar disorder and schizophrenia are hypothesized to share some genetic background.
In a two-phase study, we evaluated the effect of five promising candidate genes for psychotic disorders, DAOA, COMT, DTNBP1, NRG1, and AKT1, on bipolar spectrum disorder, psychotic disorder, and related cognitive endophenotypes in a Finnish family-based sample ascertained for bipolar disorder.
In initial screening of 362 individuals from 63 families, we found only marginal evidence for association with the diagnosis-based dichotomous classification. Those associations did not strengthen when we genotyped the complete sample of 723 individuals from 180 families. We observed a significant association of DAOA variants rs3916966 and rs2391191 with visuospatial ability (Quantitative Transmission Disequilibrium Test [QTDT]; p = 4 x 10(-6) and 5 x 10(-6), respectively) (n = 159) with the two variants in almost complete linkage disequilibrium. The COMT variant rs165599 also associated with visuospatial ability, and in our dataset, we saw an additive effect of DAOA and COMT variants on this neuropsychological trait.
The ancestral allele (Arg) of the nonsynonymous common DAOA variant rs2391191 (Arg30Lys) was found to predispose to impaired performance. The DAOA gene may play a role in predisposing individuals to a mixed phenotype of psychosis and mania and to impairments in related neuropsychological traits.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
93Am J Psychiatry 2008 Apr 165: 497-506
PMID18198266
TitleNo significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics.
AbstractThe 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
94Biol. Psychiatry 2008 Mar 63: 449-57
PMID17825267
TitleAKT1 is associated with schizophrenia across multiple symptom dimensions in the Irish study of high density schizophrenia families.
AbstractThe phosphatidylinositol 3-kinase (PI3K)-AKT signal transduction pathway is critical to cell growth and survival. In vitro functional studies indicate that the candidate schizophrenia susceptibility gene DTNBP1 influences AKT signaling to promote neuronal viability. The AKT1 gene has also been implicated in schizophrenia by association studies and decreased protein expression in the brains of schizophrenic patients.
The association of DTNBP1 in the Irish Study of High Density schizophrenia Families (ISHDSF) prompted our investigation of AKT1 for association with disease in this sample. Eight single nucleotide polymorphisms spanning AKT1 were analyzed for association with schizophrenia across four definitions of affection and according to Operational Criteria Checklist of Psychotic Illness (OPCRIT) symptom scales. We examined expression of AKT1 messenger RNA from postmortem brain tissue of schizophrenic, bipolar, and control individuals.
No single marker showed significant association, but the risk haplotype previously found over-transmitted to Caucasian schizophrenic patients was significantly under-transmitted in the ISHDSF (.01 < p < .05), across all OPCRIT symptom dimensions. Exploratory haplotype analysis confirmed association with schizophrenia toward the 5' end of AKT1 (.008 < p < .049, uncorrected). We found significantly decreased RNA levels in prefrontal cortex of schizophrenic individuals, consistent with reduced AKT1 protein levels reported in schizophrenic brain.
The replication of association of AKT1 gene variants in a further Caucasian family sample adds support for involvement of AKT signaling in schizophrenia, perhaps encompassing a broader clinical phenotype that includes mood dysregulation. We show that AKT signaling might be compromised in schizophrenic and bipolar patients via reduced RNA expression of specific AKT isoforms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
95Nat. Genet. 2008 Jul 40: 827-34
PMID18583979
TitleSystematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database.
AbstractIn an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
96Psychiatr. Genet. 2008 Oct 18: 219-25
PMID18797396
TitleAssociation study of candidate variants from brain-derived neurotrophic factor and dystrobrevin-binding protein 1 with neuroticism, anxiety, and depression.
AbstractAssociation of the valine/methionine variant at codon 66 (Val66Met) of brain derived neurotrophic factor (BDNF) has been reported inconsistently across a spectrum of psychiatric disorders. Haplotypes of six tagging single nucleotide polymorphisms (SNPs) of a 37-kb region of dystrobrevin-binding protein 1 (DTNBP1) were found to be associated with schizophrenia. These haplotypes have not been studied extensively for other psychiatric disorders but are plausible candidates for anxiety and depression disorders. Here, association between variants of BDNF and DTNBP1, and multiple anxiety and depression phenotypes is explored.
Study participants were selected as sibling pairs that were either concordant or discordant for extreme neuroticism scores from a total sample of 18 742 Australian twin individuals and their siblings. All participants completed detailed Composite International Diagnostic Interview from which diagnoses of Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV depression and anxiety disorders were determined. Six hundred and seventy-four participants had a diagnosis of anxiety and/or depression from 492 families. The BDNF Val66Met and six DTNBP1 (rs3213207, rs1011313, rs2619528, rs760761, rs1018381, rs2619538) SNPs were genotyped on samples from study participants (n=2045 from 987 families) and, where possible, their parents (n=787). Family-based association tests were conducted between the individual SNPs and the DTNBP1 six SNP haplotypes and anxiety, depression, and neuroticism.
We found no convincing evidence for association between any of the variants studied and anxiety, depression, or neuroticism.
This study sample is relatively large but our results do not support an association between BDNF Val66Met and anxiety, depression, or neuroticisim. DTNBP1 haplotypes, which have been found to be risk factors for schizophrenia, are unlikely to be risk factors for anxiety and depression.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
97Pharmacogenet. Genomics 2008 Sep 18: 751-9
PMID18698228
TitleModel-based gene selection shows engrailed 1 is associated with antipsychotic response.
Abstractschizophrenia is an highly heritable complex disorder with a significant impact on public health. A variety of antipsychotics are available for treatment of the disorder and individual response to treatment is variable. To date, only a limited number of potential candidate genes have been examined for genetic association with treatment response. As there is lack of understanding of disease etiology and variation in treatment response, a large number of additional genes are potential targets for investigation. A variety of strategies for selecting candidate genes for further investigation are available and in most cases information used is weighed and ranked intuitively by the investigator. We sought to find genes that may influence treatment response in a less biased manner, after integrating heterogeneous data sources related to schizophrenia.
A method to select liability and treatment response candidate genes for schizophrenia using multiple data sets was constructed. The method successfully selected DTNBP1, a strong candidate gene for schizophrenia. We then evaluated novel genes picked by the method. Thirty-six single nucleotide polymorphisms in two genes engrailed 1 (EN1) and secretin receptor (SCTR) were genotyped in the Clinical Antipsychotic Trials of Intervention Effectiveness study sample. Outcomes analyzed were the Positive and Negative Syndrome Scale and six different neurocognitive measures.
Several of the seven single nucleotide polymorphisms genotyped in the EN1 gene were associated with schizophrenia symptoms (smallest P value=0.0061) and the effects of antipsychotics on symptoms (smallest P value=2.4x10). The estimated probabilities of being a false discovery were 0.14 for symptoms and 0.0012 for drug response.
These findings show that EN1 may influence individual variation in response to antipsychotics. In addition, model-based data integration of schizophrenia-related data seems to improve the prior probability of selecting genes that have an effect on antipsychotics response.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
98Arch. Gen. Psychiatry 2008 Jan 65: 53-61
PMID18180429
TitleFamily-based association study of lithium-related and other candidate genes in bipolar disorder.
AbstractAssociation studies in bipolar disorder have been focused on a relatively narrow pool of candidate genes based on a limited understanding of the underlying pathophysiologic features. Recent developments suggest that a broader pool of genes may be associated with this disorder.
To examine the association between genes related to the lithium mechanism of action, as well as other positional and functional candidates, with bipolar I disorder.
We examined a dense set of haplotype-tagging single-nucleotide polymorphisms using a gene-based test of association.
Three hundred seventy-nine parent-affected offspring trios.
No genes specifically chosen to probe the action of lithium were associated with bipolar disorder. However, gene-based analysis of sialyltransferase 4A (SIAT4A), tachykinin receptor 1 (TACR1), and gamma-aminobutyric acid(A) beta2 receptor subunit (GABRB2) yielded evidence of association (empirical P value, <.005). Among 3 genes associated with schizophrenia or bipolar disorder in multiple previous studies, including dysbindin (DTNBP1), neuregulin (NRG1), and disrupted-in-schizophrenia 1 (DISC1), only DISC1 showed evidence of association in this cohort. In a secondary analysis of these 6 genes among parent-proband trios with a history of psychosis, evidence of the association with SIAT4A was strengthened.
These results suggest novel candidates and 1 gene (DISC1) previously associated with schizophrenia that merit further study in bipolar disorder. However, polymorphisms in major lithium-signaling genes do not appear to contribute substantially to bipolar liability.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
99Schizophr. Res. 2008 Mar 100: 281-90
PMID18234478
TitleDifferential RNA expression between schizophrenic patients and controls of the dystrobrevin binding protein 1 and neuregulin 1 genes in immortalized lymphocytes.
AbstractThe dystrobrevin binding protein 1 (DTNBP1) and neuregulin 1 (NRG1) genes have been related to schizophrenia (SZ) and bipolar disorder (BP) by several whole-genome linkage and associations studies. Few expression studies in post-mortem brains have also reported a lower or a higher expression of DTNBP1 and NRG1, respectively, in SZ. Since the difficulty to access post-mortem brains, we evaluated RNA expression of DTNBP1 and NRG1 in immortalized lymphocytes of SZ patients and unrelated-family controls. An antipsychotic stimulation was also used to challenge the genetic background of the subjects and enhance differential expression. Immortalized lymphocytes of twelve SZ and twelve controls were grown individually in the presence or not of the antipsychotic olanzapine (Zyprexa; EliLilly). RNA was extracted and pooled in four groups of three SZ and four groups of three controls, and used to probe Agilent 18K microchips. Mean gene expression values were contrasted between SZ and control groups using a T-test. For DTNBP1, RNA expression was lower in SZ than in controls before (-28%; p=0.02) and after (-30%; p=0.01) olanzapine stimulation. Similarly, NRG1 GGF2 isoform showed a lower expression in SZ before (-29%; p=0.04) and after (-33%; p=0.02) olanzapine stimulation. In contrast, NRG1 GGF isoform showed no significant difference between SZ and controls (-7%; p=0.61, +3%; p=0.86, respectively), but was slightly repressed by olanzapine in controls (-8%; p=0.008) but not in SZ (+1%; p=0.91). These results are in agreement with those observed in post-mortem brain when the isoforms involved are considered.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
100Hum. Mol. Genet. 2008 Apr 17: 1169-74
PMID18182443
TitleCis- and trans- loci influence expression of the schizophrenia susceptibility gene DTNBP1.
AbstractSusceptibility to complex disease appears to be partly mediated by heritable differences in gene expression. Where cis-acting effects on a gene's expression influence disease susceptibility, other genes containing polymorphism with a trans-acting effect on expression of that gene may also be expected to modulate risk. Use of the expression of an identified disease gene as an endophenotype for quantitative linkage analysis may therefore provide a powerful method for mapping loci that modulate disease susceptibility. We performed genome-wide linkage analysis on expression of dystrobrevin binding protein 1 (DTNBP1), a well-supported susceptibility gene for schizophrenia, in large CEPH pedigrees. We observed genome-wide significant evidence for linkage at the DTNBP1 locus on chromosome 6p22, and demonstrated that this reflects variable cis-acting effects on DTNBP1 expression. In addition, we observed genome-wide suggestive evidence for linkage of DTNBP1 expression to chromosome 8p, suggesting a locus that exerts a trans-acting effect on DTNBP1 expression. The region of linkage to DTNBP1 expression on chromosome 8 is contiguous with linkage findings based upon the clinical schizophrenia phenotype, and contains another well-supported schizophrenia susceptibility gene, neuregulin-1 (NRG1). Our data provide complementary evidence for chromosome 8p as a susceptibility locus for schizophrenia, and suggest that genetic variation within this region may influence risk, at least in part, through effects on DTNBP1 expression.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
101Schizophr. Res. 2008 Dec 106: 208-17
PMID18804346
TitleInteraction between interleukin 3 and dystrobrevin-binding protein 1 in schizophrenia.
Abstractschizophrenia 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
102Mol Brain 2008 -1 1: 11
PMID18945333
TitleImpaired long-term memory retention and working memory in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia.
Abstractschizophrenia is a complex genetic disorder caused by multiple genetic and environmental factors. The dystrobrevin-binding protein 1 (DTNBP1: dysbindin-1) gene is a major susceptibility gene for schizophrenia. Genetic variations in DTNBP1 are associated with cognitive functions, general cognitive ability and memory function, and clinical features of patients with schizophrenia including negative symptoms and cognitive decline. Since reduced expression of dysbindin-1 has been observed in postmortem brains of patients with schizophrenia, the sandy (sdy) mouse, which has a deletion in the DTNBP1 gene and expresses no dysbindin-1 protein, could be an animal model of schizophrenia. To address this issue, we have carried out a comprehensive behavioral analysis of the sdy mouse in this study.
In a rotarod test, sdy mice did not exhibit motor learning whilst the wild type mice did. In a Barnes circular maze test both sdy mice and wild type mice learned to selectively locate the escape hole during the course of the training period and in the probe trial conducted 24 hours after last training. However, sdy mice did not locate the correct hole in the retention probe tests 7 days after the last training trial, whereas wild type mice did, indicating impaired long-term memory retention. A T-maze forced alternation task, a task of working memory, revealed no effect of training in sdy mice despite the obvious effect of training in wild type mice, suggesting a working memory deficit.
Sdy mouse showed impaired long-term memory retention and working memory. Since genetic variation in DTNBP1 is associated with both schizophrenia and memory function, and memory function is compromised in patients with schizophrenia, the sdy mouse may represent a useful animal model to investigate the mechanisms of memory dysfunction in the disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
103Schizophr. Res. 2008 Dec 106: 218-28
PMID18774265
TitleDysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia.
Abstractschizophrenia (SCZ) is a complex trait with a high heritability. The DTNBP1 gene (encoding dysbindin) is one of the leading susceptible genes of SCZ. This risk gene has been reported to be associated with clinical symptoms such as negative symptoms and cognitive deficits. Although reduction of dysbindin expression in schizophrenic brain tissue has been reported, how this contributes to its symptomatology remains uncertain. The sandy (sdy) mouse, which harbors a spontaneously occurring deletion in the DTNBP1 gene and expresses no dysbindin protein, provides a unique tool to study the role of dysbindin in SCZ. Our recent findings reveal that the sdy mice exhibit specific defects of neurosecretion and synaptic morphology in hippocampal neurons. We here further described that sdy manifested schizophrenia-like behaviors such as social withdrawal and cognitive deficits. In sdy hippocampus, the steady-state level of snapin (a SNAP25-binding protein and a synaptic priming regulator) was reduced due to loss of dysbindin. We further characterized that a 30-residue peptide in dysbindin (90-119 amino acids) mediated the interaction with snapin. Our results suggest that the destabilization of snapin in sdy mice may lead to abnormal neurotransmission and therefore abnormal behaviors. This further defines the sdy mutant as a potential model in schizophrenia research.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
104Neurosci. Lett. 2008 Jan 431: 146-9
PMID18162312
TitleA dysbindin risk haplotype associated with less severe manic-type symptoms in psychosis.
AbstractDelineating relationships between susceptibility genes and clinical symptoms may be an important step in understanding the genetics of psychosis. Recent data suggests that the gene dysbindin (DTNBP1) may confer susceptibility across psychotic disorders and may particularly be associated with negative symptoms, i.e. affective flattening, alogia and avolition. We have previously published evidence of association with a dysbindin risk haplotype derived from alleles C-A-T at SNPs P1655 (rs2619539), P1635 (rs3213207) and SNP66961 (rs2619538) in two independent schizophrenia (SZ) case-control samples. The C-A-T haplotype impacts at the level of gene function and phenotype: the haplotype indexes lower cortical expression of the dysbindin gene in post-mortem SZ brain samples and haplotype carriers show greater deficits in spatial working memory and early visual processing than non-carrier SZ patients. The aim of this study was to establish if the C-A-T dysbindin risk haplotype is associated with a specific clinical symptom profile. We investigated the relationship between the haplotype and PANSS-derived symptom factors in 262 individuals with schizophrenia/schizoaffective disorder using principal components analysis (PCA) and analysis of variance (ANOVA). Dysbindin risk carriers scored significantly less than non-carriers on the 'hostility/excitability' factor (F 1,196=8.468; p=.004), with a trend for higher negative symptom scores. This suggests that risk variation at the dysbindin gene may contribute to a more prototypical SZ presentation with less severe excitement/manic symptoms and more negative symptoms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
105Biol. Psychiatry 2008 Mar 63: 484-9
PMID17945199
TitleEarly visual processing deficits in dysbindin-associated schizophrenia.
AbstractVariation at the dysbindin gene (DTNBP1) has been associated with increased risk for schizophrenia in numerous independent samples and recently with deficits in general and domain-specific cognitive processing. The relationship between dysbindin risk variants and sensory-level deficits in schizophrenia remains to be explored. We investigated P1 performance, a component of early visual processing on which both patients and their relatives show deficits, in carriers and noncarriers of a known dysbindin risk haplotype.
Event-related potential responses to simple visual isolated-check stimuli were measured using high-density electrical scalp recordings in 26 individuals meeting DSM-IV criteria for schizophrenia, comprising 14 patients who were carriers of the dysbindin risk haplotype and 12 patients who were nonrisk haplotype carriers.
Carriers of the dysbindin risk haplotype demonstrated significantly reduced P1 amplitudes compared with noncarriers. A large effect size of d = .89 was calculated for the difference in P1 amplitude over scalp sites where the deficit was maximal.
The P1 deficits associated with a dysbindin risk haplotype previously identified in our sample presents functional confirmation of its deleterious effect on brain activity. Building on evidence of dysbindin's role in higher cognitive function, these early visual processing deficits suggest a generalized role for dysbindin in brain function and is likely to be part of the mechanism by which illness susceptibility is mediated.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
106Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 606-11
PMID18163393
TitleGene copy number variation in schizophrenia.
AbstractRecent 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
107Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jul 147B: 606-11
PMID18163393
TitleGene copy number variation in schizophrenia.
AbstractRecent 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
108Eur Arch Psychiatry Clin Neurosci 2008 Jun 258 Suppl 2: 37-40
PMID18516516
TitleCommon risk genes for affective and schizophrenic psychoses.
AbstractThe familial-genetic relationship between affective and schizophrenic disorders is receiving a re-emergence of interest. The reasons are a series of cross-diagnostic molecular-genetic discoveries: specific alleles in the genes for dysbindin (DTNBP1), neuregulin (NRG1) and DAOA (G72/G30) reveal associations for each of both groups of disorders in the same direction in some but not all reported studies. These findings cannot just be false positives because of confirming metaanalyses. Furthermore there is some pathophysiological support: the mentioned genes are involved in biochemical pathways, which are contributing to both disorders partly in a similar and partly in a different manner. The new levels of evidence enrich the classical continuity/discontinuity debate on the relationship between both groups of disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
109Neurosci. Lett. 2008 Aug 440: 150-4
PMID18562100
TitleDTNBP1 haplotype influences baseline assessment scores of schizophrenic in-patients.
AbstractDysbindin gene (DTNBP1) has been associated with schizophrenia, but literature findings are inconsistent, and further analyses are required. This study is aimed to investigate if a set of DTNBP1 variations might influence clinic psychotic phenotype or treatment response in a sample of 240 Korean schizophrenic in-patients. Four variants have been selected (rs3213207; rs1011313; rs16876759; rs2619522) on the basis of previous findings of association with schizophrenia, bipolar disorder and antidepressant response. Single marker analysis gave marginal results. Haplotype analysis identified a significant association between A-A (rs3213207(A/G), rs1011313(A/G)) haplotype and lower PANSS total and positive scores at baseline (p=0.01; 0.02) and at discharge (p=0.008; 0.005). Covariate analysis revealed a more stable significant association between A-A haplotype and baseline scores. These results suggest a protective effect of A-A haplotype on psychotic positive symptoms at baseline.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
110Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Oct 147B: 1159-66
PMID18314870
TitleComprehensive analysis of tagging sequence variants in DTNBP1 shows no association with schizophrenia or with its composite neurocognitive endophenotypes.
AbstractIn a previous study we identified a relatively homogeneous subtype of schizophrenia characterized by pervasive cognitive deficit, which was the exclusive contributor to our findings of linkage to 6p25-p24. The 6p region contains Dysbindin (DTNBP1), considered to be one of the major schizophrenia candidate genes. While multiple studies have reported association between genetic variation in DTNBP1 and schizophrenia, the findings have been inconsistent and controversial, leading to recent calls for systematic re-examination and unambiguous evidence of association. To address this, we have undertaken a comprehensive survey of common genetic variation within DTNBP1 and its association with schizophrenia, using a HapMap-based gene-tagging approach. We genotyped 39 tSNPs in a sample of 336 cases and 172 controls of Anglo-Irish ancestry, with the phenotype defined as clinical schizophrenia, and as composite neurocognitive endophenotypes. Allele and haplotype frequencies, and LD structure in our control sample were similar to those in other European populations. Using multivariate generalized linear modeling, we observed no significant association between any tSNP and any outcome variable. Association with haplotypes was examined across the gene and in the previously associated 5' region. Neither global haplotype tests, nor specific analysis of the "risk" haplotype previously reported in an ethnically related population, the Irish high-density schizophrenia families, showed significant evidence of association with schizophrenia or with the neurocognitive endophenotypes in our sample. The framework and results of this study should facilitate further attempts at re-analysis of DTNBP1, in terms of standardized approaches to both phenotype definition and analysis of genetic variation.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
111J Psychiatr Res 2008 Mar 42: 278-88
PMID17408693
TitleAssociation of schizophrenia with DTNBP1 but not with DAO, DAOA, NRG1 and RGS4 nor their genetic interaction.
AbstractRecent 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
112Biol. Psychiatry 2008 Jan 63: 24-31
PMID17618940
TitleDysbindin (DTNBP1) and the biogenesis of lysosome-related organelles complex 1 (BLOC-1): main and epistatic gene effects are potential contributors to schizophrenia susceptibility.
AbstractThe DTNBP1 gene, encoding dysbindin, has been strongly implicated in schizophrenia (SZ) susceptibility by a series of independent genetic association and gene expression studies. Among its known functions, dysbindin is part of a protein complex, termed the biogenesis of lysosome-related organelles complex 1 (BLOC-1), the molecular components of which might be involved in the regulation of vesicular trafficking and dendrite branching.
A systematic investigation of the other seven BLOC-1 genes (MUTED, PLDN, CNO, SNAPAP, BLOC1S1, BLOC1S2, and BLOC1S3) for evidence of association with SZ was undertaken in a sample of 373 SZ cases and 812 control subjects. Possible epistasis between combinations of BLOC-1 genes, including DTNBP1, was tested with a novel method of investigating for gene-gene interaction. Quality control measures were incorporated into genotyping strategy, and all results were corrected for multiple testing to prevent false positive results.
We identified significant evidence of association between BLOC1S3 and SZ (odds ratio = 1.45, confidence interval = 1.13-1.86, p = .0028, corrected p = .0389). We also report evidence for epistatic interaction between DTNBP1 and MUTED contributing to SZ in the absence of a significant main effect at MUTED (p = .0009, corrected p = .0252). Single marker and epistasis results remained significant after correction for multiple testing.
Together these data provide evidence for the involvement of the BLOC-1 protein complex in SZ pathogenesis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
113Biol. Psychiatry 2008 Jan 63: 191-6
PMID17555717
TitleThe dysbindin gene (DTNBP1) is associated with methamphetamine psychosis.
AbstractThe dysbindin (DTNBP1 [dystrobrevin-binding protein 1]) gene has repeatedly been shown to be associated with schizophrenia across diverse populations. One study also showed that risk haplotypes were shared with a bipolar disorder subgroup with psychotic episodes, but not with all cases. DTNBP1 may confer susceptibility to psychotic symptoms in various psychiatric disorders besides schizophrenia.
Methamphetamine psychosis, the psychotic symptoms of which are close to those observed in schizophrenia, was investigated through a case (n = 197)-control (n = 243) association analyses of DTNBP1.
DTNBP1 showed significant associations with methamphetamine psychosis at polymorphisms of P1635 (rs3213207, p = .00003) and SNPA (rs2619538, p = .049) and the three-locus haplotype of P1655 (rs2619539)-P1635-SNPA (permutation p = .0005). The C-A-A haplotype, which was identical to the protective haplotype previously reported for schizophrenia and psychotic bipolar disorders, was a protective factor (p = .0013, odds ratio [OR] = .62, 95% confidence interval [CI] .51-.77) for methamphetamine psychosis. The C-G-T haplotype was a risk for methamphetamine psychosis (p = .0012, OR = 14.9, 95% CI 3.5-64.2).
Our genetic evidence suggests that DTNBP1 is involved in psychotic liability not only for schizophrenia but also for other psychotic disorders, including substance-induced psychosis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
114Biol. Psychiatry 2008 Mar 63: 449-57
PMID17825267
TitleAKT1 is associated with schizophrenia across multiple symptom dimensions in the Irish study of high density schizophrenia families.
AbstractThe phosphatidylinositol 3-kinase (PI3K)-AKT signal transduction pathway is critical to cell growth and survival. In vitro functional studies indicate that the candidate schizophrenia susceptibility gene DTNBP1 influences AKT signaling to promote neuronal viability. The AKT1 gene has also been implicated in schizophrenia by association studies and decreased protein expression in the brains of schizophrenic patients.
The association of DTNBP1 in the Irish Study of High Density schizophrenia Families (ISHDSF) prompted our investigation of AKT1 for association with disease in this sample. Eight single nucleotide polymorphisms spanning AKT1 were analyzed for association with schizophrenia across four definitions of affection and according to Operational Criteria Checklist of Psychotic Illness (OPCRIT) symptom scales. We examined expression of AKT1 messenger RNA from postmortem brain tissue of schizophrenic, bipolar, and control individuals.
No single marker showed significant association, but the risk haplotype previously found over-transmitted to Caucasian schizophrenic patients was significantly under-transmitted in the ISHDSF (.01 < p < .05), across all OPCRIT symptom dimensions. Exploratory haplotype analysis confirmed association with schizophrenia toward the 5' end of AKT1 (.008 < p < .049, uncorrected). We found significantly decreased RNA levels in prefrontal cortex of schizophrenic individuals, consistent with reduced AKT1 protein levels reported in schizophrenic brain.
The replication of association of AKT1 gene variants in a further Caucasian family sample adds support for involvement of AKT signaling in schizophrenia, perhaps encompassing a broader clinical phenotype that includes mood dysregulation. We show that AKT signaling might be compromised in schizophrenic and bipolar patients via reduced RNA expression of specific AKT isoforms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
115Schizophr. Res. 2008 Mar 100: 281-90
PMID18234478
TitleDifferential RNA expression between schizophrenic patients and controls of the dystrobrevin binding protein 1 and neuregulin 1 genes in immortalized lymphocytes.
AbstractThe dystrobrevin binding protein 1 (DTNBP1) and neuregulin 1 (NRG1) genes have been related to schizophrenia (SZ) and bipolar disorder (BP) by several whole-genome linkage and associations studies. Few expression studies in post-mortem brains have also reported a lower or a higher expression of DTNBP1 and NRG1, respectively, in SZ. Since the difficulty to access post-mortem brains, we evaluated RNA expression of DTNBP1 and NRG1 in immortalized lymphocytes of SZ patients and unrelated-family controls. An antipsychotic stimulation was also used to challenge the genetic background of the subjects and enhance differential expression. Immortalized lymphocytes of twelve SZ and twelve controls were grown individually in the presence or not of the antipsychotic olanzapine (Zyprexa; EliLilly). RNA was extracted and pooled in four groups of three SZ and four groups of three controls, and used to probe Agilent 18K microchips. Mean gene expression values were contrasted between SZ and control groups using a T-test. For DTNBP1, RNA expression was lower in SZ than in controls before (-28%; p=0.02) and after (-30%; p=0.01) olanzapine stimulation. Similarly, NRG1 GGF2 isoform showed a lower expression in SZ before (-29%; p=0.04) and after (-33%; p=0.02) olanzapine stimulation. In contrast, NRG1 GGF isoform showed no significant difference between SZ and controls (-7%; p=0.61, +3%; p=0.86, respectively), but was slightly repressed by olanzapine in controls (-8%; p=0.008) but not in SZ (+1%; p=0.91). These results are in agreement with those observed in post-mortem brain when the isoforms involved are considered.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
116Schizophr. Res. 2008 Dec 106: 218-28
PMID18774265
TitleDysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia.
Abstractschizophrenia (SCZ) is a complex trait with a high heritability. The DTNBP1 gene (encoding dysbindin) is one of the leading susceptible genes of SCZ. This risk gene has been reported to be associated with clinical symptoms such as negative symptoms and cognitive deficits. Although reduction of dysbindin expression in schizophrenic brain tissue has been reported, how this contributes to its symptomatology remains uncertain. The sandy (sdy) mouse, which harbors a spontaneously occurring deletion in the DTNBP1 gene and expresses no dysbindin protein, provides a unique tool to study the role of dysbindin in SCZ. Our recent findings reveal that the sdy mice exhibit specific defects of neurosecretion and synaptic morphology in hippocampal neurons. We here further described that sdy manifested schizophrenia-like behaviors such as social withdrawal and cognitive deficits. In sdy hippocampus, the steady-state level of snapin (a SNAP25-binding protein and a synaptic priming regulator) was reduced due to loss of dysbindin. We further characterized that a 30-residue peptide in dysbindin (90-119 amino acids) mediated the interaction with snapin. Our results suggest that the destabilization of snapin in sdy mice may lead to abnormal neurotransmission and therefore abnormal behaviors. This further defines the sdy mutant as a potential model in schizophrenia research.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
117Neurochem. Int. 2009 Jun 54: 431-8
PMID19428785
TitleDirect interaction of Dysbindin with the AP-3 complex via its mu subunit.
AbstractGenetic factors are important in the etiology of schizophrenia. Recent studies have revealed the association between genetic variation of Dysbindin (DTNBP1) and schizophrenia. Dysbindin is one of the essential components of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). BLOC-1 physically interacts with the adaptor protein (AP)-3 complex, which is essential for vesicle or protein sorting. However, it remains largely unknown how BLOC-1 interacts with the AP-3 complex. To investigate the binding mode of BLOC-1 and the AP-3 complex, we examined the relation between Dysbindin and the AP-3 complex and found that Dysbindin formed a complex with the AP-3 complex through the direct binding to its mu subunit. Dysbindin partially co-localized with the AP-3 complex in CA1 and CA3 of mouse hippocampus, and at presynaptic terminals and axonal growth cones of cultured hippocampal neurons. Suppression of Dysbindin results in the reduction of presynaptic protein expression and glutamate release. Thus, Dysbindin appears to participate in the exocytosis or sorting of the synaptic vesicle via direct interaction with the AP-3 complex.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
118Neuropsychobiology 2009 -1 59: 142-50
PMID19439994
TitleDTNBP1, NRG1, DAOA, DAO and GRM3 polymorphisms and schizophrenia: an association study.
AbstractSeveral studies of the dystrobrevin-binding protein 1 gene (DTNBP1), neuregulin 1 (NRG1), D-amino-acid oxidase (DAO), DAO activator (DAOA, G72), and metabotropic glutamate receptor 3 (GRM3) genes have suggested an association between variants of these genes and schizophrenia.
In a replication attempt, single-nucleotide polymorphisms of the DTNBP1, NRG1, DAO, DAOA, and GRM3 genes were analyzed in three independent Scandinavian schizophrenia case-control samples.
One DTNBP1 and three GRM3 single-nucleotide polymorphisms showed nominal significant associations to the disease. However, after correction for multiple testing, there were no statistically significant allele, genotype or haplotype case-control differences.
The present Scandinavian results do not verify previous associations between the analyzed DTNBP1, NRG1, DAO, DAOA, and GRM3 gene polymorphisms and schizophrenia. Additional studies and meta-analyses are warranted to shed further light on these relationships.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
119Curr. Mol. Med. 2009 May 9: 506-18
PMID19519407
TitleThe role of genes involved in neuroplasticity and neurogenesis in the observation of a gene-environment interaction (GxE) in schizophrenia.
Abstractschizophrenia is a multifactorial disease characterized by a high heritability. Several candidate genes have been suggested, with the strongest evidences for genes encoding dystrobrevin binding protein 1 (DTNBP1), neuregulin 1 (NRG1), neuregulin 1 receptor (ERBB4) and disrupted in schizophrenia 1 (DISC1), as well as several neurotrophic factors. These genes are involved in neuronal plasticity and play also a role in adult neurogenesis. Therefore, the genetic basis of schizophrenia could involve different factors more or less specifically required for neuroplasticity, including the synapse maturation, potentiation and plasticity as well as neurogenesis. Following the model of Knudson in tumors, we propose a two-hit hypothesis of schizophrenia. In this model of gene-environment interaction, a variant in a gene related to neurogenesis is transmitted to the descent (first hit), and, secondarily, an environmental factor occurs during the development of the central nervous system (second hit). Both of these vulnerability and trigger factors are probably necessary to generate a deficit in neurogenesis and therefore to cause schizophrenia. The literature supporting this gene x environment hypothesis is reviewed, with emphasis on some molecular pathways, raising the possibility to propose more specific molecular medicine.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
120Prog. Brain Res. 2009 -1 179: 87-94
PMID20302821
TitleThe sandy (sdy) mouse: a dysbindin-1 mutant relevant to schizophrenia research.
AbstractDysbindin-1 reductions appear to be common in dysfunctional brain areas of schizophrenia cases. In the absence of a dysbindin-1 knockout, sandy (sdy) mice provide our only means of studying the potential contribution of this protein to clinical features of schizophrenia in live animals. Our knowledge of sandy mice is reviewed here. These mice have a deletion mutation that arose spontaneously in DBA/2J mice in the gene encoding dysbindin-1 (DTNBP1). This null protein mutation (DTNBP1(sdy)) leads to an absence of dysbindin-1 in homozygotes, as well as reductions in several direct and indirect binding partners of dysbindin-1 that contribute to the protein assembly known as BLOC-1. Studies of sdy mice on the original DBA/2J background and on a C57BL/6J background indicate that the DTNBP1(sdy) mutation does not affect viability, basic sensory or motor functions, or measures of anxiety and motivation. Such studies do indicate, however, that the mutation affects several biological functions, including adrenal neurosecretion and pre- and postsynaptic aspects of dopaminergic, glutamatergic, and GABAergic transmission. These effects and those on prepulse inhibition, social interaction, and diverse aspects of spatial memory suggest that homozygous sdy mice may model various features of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
121Biochem. Biophys. Res. Commun. 2009 Feb 379: 191-5
PMID19094965
TitleDysbindin engages in c-Jun N-terminal kinase activity and cytoskeletal organization.
AbstractA number of reports have provided genetic evidence for an association between the DTNBP1 gene (coding dysbindin) and schizophrenia. In addition, sandy mice, which harbor a deletion in the DTNBP1 gene and lack dysbindin, display behavioral abnormalities suggestive of an association with schizophrenia. However, the mechanism by which the loss of dysbindin induces schizophrenia-like behaviors remains unclear. Here, we report that small interfering RNA-mediated knockdown of dysbindin resulted in the aberrant organization of actin cytoskeleton in SH-SY5Y cells. Furthermore, we show that morphological abnormalities of the actin cytoskeleton were similarly observed in growth cones of cultured hippocampal neurons derived from sandy mice. Moreover, we report a significant correlation between dysbindin expression level and the phosphorylation level of c-Jun N-terminal kinase (JNK), which is implicated in the regulation of cytoskeletal organization. These findings suggest that dysbindin plays a key role in coordinating JNK signaling and actin cytoskeleton required for neural development.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
122Eur Arch Psychiatry Clin Neurosci 2009 Apr 259: 137-42
PMID19252939
TitleDysbindin gene (DTNBP1) and schizophrenia in Korean population.
AbstractDysbindin gene (DTNBP1) has been consistently reported to be associated with schizophrenia. However data from East Asian population has been sparse and inconsistent till today. This study tried to replicate the genetic association of DTNBP1 with schizophrenia in a large Korean sample, as well as analyzing the association of DTNBP1 with clinical variables. Nine hundred and eight (908) patients with schizophrenia and 601 controls were investigated. The high-throughput genotyping method using pyrosequencer (Biotage AB, Sweden) was used for genotyping 4 SNPs (rs3213207, rs1011313, rs760761, and rs2619522). Haplotype analyses revealed a significant association with schizophrenia (P < 0.0001) with the haplotypes A-C-C-C and A-C-T-A having an eminent protective effect toward schizophrenia. The major contribution to the difference in the haplotype distribution between patients and the controls was the rs760761 (C/T) and rs2619522 (A/C) haplotypes (P < 0.0001). No association of DTNBP1 with other clinical variables was found. In conclusion, the present study suggests a possible protective effect of rare DTNBP1 variants in schizophrenia, although subsequent studies in different ethnic groups are warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
123Ann Gen Psychiatry 2009 -1 8: 12
PMID19445674
TitleSchizophrenia pathophysiology: are we any closer to a complete model?
Abstractschizophrenia, a severe brain disorder that involves hallucinations, disordered thinking and deficiencies in cognition, has been studied for decades in order to determine the early events that lead to this neurological disorder. In this review, we interpret the developmental and genetic models that have been proposed and treatment options associated with these models. schizophrenia was initially thought to be hereditary based on studies of high incidence in certain families. Additionally, studies on specific genes such as ZDHHC8 and DTNBP1 seem to suggest susceptibility to the onset of this disorder. However, no single gene variation has been linked to schizophrenia, and recent evidence on sporadic cases of schizophrenia refutes genetics as being a singular cause of the disease. In addition, current data suggests neurodevelopmental or environmental causes such as viral infections and prenatal/perinatal complications. Before any brain disorder can be understood, however, multiple cognitive neuroscientific models that accommodate evidence from many biomedical research fields should be considered, and unfortunately, many of these models are in the earliest stages of development. Consequently, it makes us question whether we are any closer to an adequate understanding of the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
124Psychiatry Clin. Neurosci. 2009 Aug 63: 550-6
PMID19496996
TitleAssociation between the dysbindin gene (DTNBP1) and cognitive functions in Japanese subjects.
AbstractThe dysbindin gene (dystrobrevin binding protein 1: DTNBP1) is a susceptibility gene for schizophrenia. Susceptibility genes for schizophrenia have been hypothesized to mediate liability for the disorder at least partly by influencing cognitive performance. This report investigated the relationship between cognitive function and the dysbindin gene.
The possible association between a single nucleotide polymorphism (SNP) of DTNBP1 (rs2619539: P1655), which is a risk-independent SNP for schizophrenia in Japanese populations, and memory and IQ was investigated in 70 schizophrenia patients and 165 healthy volunteers in a Japanese population.
This SNP was associated with two memory scales, verbal memory and general memory, on the Wechsler Memory Scale-Revised (WMS-R), and three subcategories of the Wechsler Adult Intelligence Scale-Revised (WAIS-R), vocabulary, similarities and picture completion in healthy subjects. The SNP, however, did not influence either the indices of WMS-R, IQ or subcategories of WAIS-R in schizophrenia patients.
A risk-independent SNP in DTNBP1 may have an impact on cognitive functions such as memory and IQ in healthy subjects.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
125Sci Signal 2009 -1 2: pe66
PMID19843956
TitleSchizophrenia: the "BLOC" may be in the endosomes.
AbstractGenome-wide association studies have identified multiple genetic polymorphisms associated with schizophrenia. These polymorphisms conform to a polygenic disease model in which multiple alleles cumulatively increase the risk of developing disease. Two genes linked to schizophrenia, DTNBP1 and MUTED, encode proteins that belong to the endosome-localized Biogenesis of Lysosome-related Organelles Complex-1 (BLOC-1). BLOC-1 plays a key role in endosomal trafficking and as such has been found to regulate cell-surface abundance of the D2 dopamine receptor, the biogenesis and fusion of synaptic vesicles, and neurite outgrowth. These functions are pertinent to both neurodevelopment and synaptic transmission, processes tightly regulated by selective cell-surface delivery of membrane proteins to and from endosomes. We propose that cellular processes, such as endosomal trafficking, act as convergence points in which multiple small effects from polygenic genetic polymorphisms accumulate to promote the development of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
126Schizophr Bull 2009 Nov 35: 1163-82
PMID18552348
TitleSchizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii.
AbstractMany genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind to influenza, rubella, or poliovirus genes. Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
127Acta Neuropsychiatr 2009 Jun 21: 109-20
PMID26953749
TitleSchizophrenia: genetics, prevention and rehabilitation.
AbstractGenetic factors are largely implicated in predisposing to schizophrenia. Environmental factors contribute to the onset of the disorder in individuals at increased genetic risk. Cognitive deficits have emerged as endophenotypes and potential therapeutic targets for schizophrenia because of their association with functional outcome. The aims of this review were to analyse the joint effect of genetic and environmental (GE) factors on liability to schizophrenia and to investigate relationships between genes and cognitive endophenotypes focusing on practical applications for prevention and rehabilitation.
Medline search of relevant studies published between 1990 and 2008.
In schizophrenia, examples of GE interaction include the catechol-O-methyl transferase (COMT) (Val158Met) polymorphism, which was found to moderate the onset of psychotic manifestations in response to stress and to increase the risk for psychosis related to cannabis use, and neurodevelopmental genes such as AKT1 (serine-threonine kinase), brain-derived neurotrophic factor (BDNF), DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate receptor 3), which were associated with development of schizophrenia in adulthood after exposure to perinatal obstetric complications. Neurocognitive deficits are recognised as core features of schizophrenia that facilitate the onset of the disorder and have a great impact on functional outcome. Neurocognitive deficits are also endophenotypes that have been linked to a variety of genes [COMT, neuregulin (NRG1), BDNF, Disrupted-In-schizophrenia 1 (DISC1) and dysbindin] conferring susceptibility to schizophrenia. Recently, it has emerged that cognitive improvement during rehabilitation therapy was under control of COMT (Val158Met) polymorphism.
This review could indicate a pivotal role of psychiatric genetics in prevention and rehabilitation of schizophrenic psychoses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
128Psychol Med 2009 Nov 39: 1783-97
PMID19573260
TitleThe effect of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on hippocampal and lateral ventricular volume in psychosis.
AbstractMorphometric endophenotypes which have been proposed for psychotic disorders include lateral ventricular enlargement and hippocampal volume reductions. Genetic epidemiological studies support an overlap between schizophrenia and bipolar disorder, and COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes have been implicated in the aetiology of both these disorders. This study examined associations between these candidate genes and morphometric endophenotypes for psychosis.
A total of 383 subjects (128 patients with psychosis, 194 of their unaffected relatives and 61 healthy controls) from the Maudsley Family Psychosis Study underwent structural magnetic resonance imaging and genotyping. The effect of candidate genes on brain morphometry was examined using linear regression models adjusting for clinical group, age, sex and correlations between members of the same family.
The results showed no evidence of association between variation in COMT genotype and lateral ventricular, and left or right hippocampal volumes. Neither was there any effect of the BDNF, 5-HTTLPR, NRG1 and DTNBP1 genotypes on these regional brain volumes.
Abnormal hippocampal and lateral ventricular volumes are among the most replicated endophenotypes for psychosis; however, the influences of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on these key brain regions must be very subtle if at all present.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
129J. Neurogenet. 2009 -1 23: 341-52
PMID19225952
TitleSurvey of schizophrenia and bipolar disorder candidate genes using chromatin immunoprecipitation and tiled microarrays (ChIP-chip).
AbstractIt has been difficult to identify disease-causing alleles in schizophrenia (SZ) and bipolar disorder (BD) candidate genes. One reason is that responsible functional variants may exist in unidentified regulatory domains. With the advent of microarray technology and high throughput sequencing, however, it is now feasible to screen genes for such regulatory domains relatively easily by using chromatin immunoprecipitation-based methodologies, such as ChIP-chip and ChIP-seq. In ChIP-chip, regulatory sequences can be captured from chromatin immunoprecipitates prepared with antibodies against covalently modified histones that mark certain regulatory domains; DNA extracted from such immunoprecipitates can then be used as microarray probes. As a first step toward demonstrating the feasibility of this approach in psychiatric genetics, we used ChIP-chip to identify regulatory domains in several candidate genes: NRG1, DTNBP1, DISC1, DAO, DAOA, PDE4B, and COMT. Immunoprecipitates were generated with antibodies to histone H3 acetylated at lysine 9 (H3K9Ac) and histone H3 monomethylated at lysine 4 (H3K4me1), which mark promoters and some enhancers, using fetal brain chromatin as a substrate. Several novel putative regulatory elements, as well as the core and proximal promoters for each gene, were enriched in the immunoprecipitates. Genetic variants within these regions would be of interest to study as potential disease-associated alleles.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
130Neuropsychobiology 2009 -1 60: 31-6
PMID19729970
TitleDysbindin and d-amino-acid-oxidase gene polymorphisms associated with positive and negative symptoms in schizophrenia.
Abstractschizophrenia is a genetically complex disorder with an unknown pathophysiology. Several genes implicated in glutamate metabolism have been associated with the disorder. Recent studies of polymorphisms in the dystrobrevin-binding protein 1 gene (DTNBP1; dysbindin) and D-amino-acid-oxidase (DAO) gene, both involved in glutamate receptor function, reported associations with negative symptoms and with anxiety and depression, respectively, when measured with the Positive and Negative Syndrome Scale (PANSS).
In the present study, the suggested association between dysbindin and DAO single nucleotide polymorphisms (SNPs) and PANSS scores was analyzed in 155 Norwegian schizophrenia patients.
There was a significant association between the dysbindin SNP rs3213207 and severity of both negative symptoms and total symptom load, as well as between the DAO SNP rs2070587 and total symptom score and severity of anxiety and depression.
The present association of dysbindin SNPs with negative symptoms and DAO SNPs with anxiety and depression is a replication of earlier findings and strengthens the hypothesis of a genetic association. It further indicates involvement of glutamate abnormalities in schizophrenia pathophysiology, as suggested by previous studies, and suggests that polymorphisms may be associated with subgroups of clinical characteristics in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
131Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Aug 33: 1046-9
PMID19482054
TitleG72 gene is associated with susceptibility to methamphetamine psychosis.
AbstractMethamphetamine psychosis is considered as one of the pharmacological models of schizophrenia, and a hyperdopaminergic one. However, many lines of experimental evidence indicate that glutamatergic signaling is also involved in development of methamphetamine psychosis. Several genes related to glutamate function, e.g. the DTNBP1, G72, and GRM3 genes, were shown to be associated with schizophrenia susceptibility. Recently, we found significant association of the DTNBP1 gene with methamphetamine psychosis. This finding prompted us to examine the G72 gene encoding the d-amino acid oxidase activator (DAOA), which metabolizes d-serine, an NMDA co-agonist, in methamphetamine psychosis. Six SNPs of the G72 gene, which previously showed significant association with schizophrenia, were analyzed in 209 patients with methamphetamine psychosis and 291 age- and sex-matched normal controls. One SNP of M22 (rs778293) showed a significant association with methamphetamine psychosis (genotype: p=0.00016, allele: p=0.0015). Two haplotypes G-A of M12 (rs3916965)-M15 (rs2391191) (p=0.00024) and T-T of M23 (rs947267)-M24 (rs1421292) (p=0.00085) also showed associations with methamphetamine psychosis. The present findings suggest that the G72 gene may contribute to a predisposition to not only schizophrenia but also to methamphetamine psychosis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
132Biol. Psychiatry 2009 Dec 66: 990-6
PMID19782967
TitleMixture model clustering of phenotype features reveals evidence for association of DTNBP1 to a specific subtype of schizophrenia.
AbstractWhile DTNBP1, DISC1, and NRG1 have been extensively studied as candidate genes of schizophrenia, results remain inconclusive. Possible explanations for this are that the genes might be relevant only to certain subtypes of the disease and/or only in certain populations.
We performed unsupervised clustering of individuals from Finnish schizophrenia families, based on extensive clinical and neuropsychological data, including Structured Clinical Interview for DSM-IV (SCID) information. Families with at least one affected member with DSM-IV diagnosis of a schizophrenia spectrum psychosis were included in a register-based ascertainment. Final sample consisted of 904 individuals from 288 families. We then used the cluster phenotypes in a genetic association study of candidate genes.
A robust three-class clustering of individuals emerged: 1) psychotic disorder with mood symptoms (n = 172), 2) core schizophrenia (n = 223), and 3) absence of psychotic disorder (n = 509). One third of the individuals diagnosed with schizophrenia were assigned to cluster 1. These individuals had fewer negative and positive psychotic symptoms and cognitive deficits but more depressive symptoms than individuals in cluster 2. There was a significant association of cluster 2 cases with the DTNBP1 gene, while the DISC1 gene indicated a significant association with schizophrenia spectrum disorders based on the DSM-IV criteria.
In the Finnish population, DTNBP1 gene is associated with a schizophrenia phenotype characterized by prominent negative symptoms, generalized cognitive impairment, and few mood symptoms. Identification of genes and pathways related to schizophrenia necessitates novel definitions of disease phenotypes associated more directly with underlying biology.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
133Zh Nevrol Psikhiatr Im S S Korsakova 2009 -1 109: 70-5
PMID19672240
Title[Serotonin receptor (5-HTR2A) and dysbindin (DTNBP1) genes and component process variables of short-term verbal memory in schizophrenia].
AbstractAn association study of variations in the DTNBP1 (P1763 and P1578) and 5-HTR2A (T102C and A-1438G) genes with short-term verbal memory efficiency and its component process variables was carried out in 405 patients with schizophrenia and 290 healthy controls. All subjects were asked to recall immediately two sets of 10 words. Total recall, List 1 recall, immediate recall or attention span, proactive interference and a number of intrusions were measured. Patients significantly differed from controls by all memory variables. The efficiency of test performance, efficiency of immediate memory, effect of proactive interference as well as number of intrusions were decreased in the group of patients. Both 5-HTR2A polymorphisms were associated with short-term verbal memory efficiency in the combined sample, with the worst performance observed in carriers of homozygous CC (T102C) and GG (A-1438G) genotypes. The significant effect of the P1763 (DTNBP1) marker on the component process variables (proactive interference and intrusions) was found while its effect on the total recall was non-significant. The homozygotes for GG (P1763) had the worst scores. Overall, the data obtained are in line with the conception of DTNBP1 and 5-HTR2A involvement in different component process variables of memory in healthy subjects and patients with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
134Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Oct 150B: 893-9
PMID19132710
TitleEvidence that putative ADHD low risk alleles at SNAP25 may increase the risk of schizophrenia.
AbstractSynaptosomal Associated Protein 25 kDa (SNAP25) has been implicated in the pathogenesis of schizophrenia by numerous neuropathological studies and genetic variation at SNAP25 has been reported to be associated with ADHD. Expression levels of the putative schizophrenia susceptibility gene DTNBP1 has been shown to influence the levels of SNAP25 in vitro. We undertook directed mutation screening of SNAP25 in UK schizophrenic cases followed by direct association analysis of all variants identified and identified known exonic SNPs that showed evidence for association (rs3746544 P = 0.004 OR = 1.26, rs8636 P = 0.003 OR = 1.27), although these SNPs are highly correlated (r(2) > 0.99). We additionally genotyped a further 31 tag SNPs spanning the SNAP25 locus and identified several independent SNPs that were nominally associated with schizophrenia (strongest association at rs3787283, P = 0.006, OR = 1.25) however, due to the number of tests performed no SNP met experiment-wise significance (minimum permuted P-value = 0.1). Post hoc analysis revealed that the SNPs nominally associated with schizophrenia (rs3787283, rs3746544) were the same as those previously demonstrated to be associated with ADHD but with the opposite alleles, allowing the intriguing hypothesis that genetic variation at SNAP25 may be differentially associated with both schizophrenia and ADHD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
135Neuropsychopharmacology 2009 Nov 34: 2601-8
PMID19641486
TitleDysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice.
AbstractBehavioral genetic studies of humans have associated variation in the DTNBP1 gene with schizophrenia and its cognitive deficit phenotypes. The protein coded for by DTNBP1, dysbindin, is expressed within forebrain glutamatergic neurons, in which it interacts with proteins involved in vesicular trafficking and exocytosis. In order to further delineate the cellular, physiological, and behavioral phenotypes associated with reduced dysbindin expression, we conducted studies in mice carrying a null mutation within the DTNBP1 gene. Dysbindin mutants showed impairments of spatial working memory compared with wild-type controls; heterozygous mice showed intermediate levels of cognitive dysfunction. Deep-layer pyramidal neurons recorded in the prefrontal cortex of mutant mice showed reductions in paired-pulse facilitation, and evoked and miniature excitatory post-synaptic currents, indicating a difference in the function of pre-synaptic glutamatergic terminals as well as elevated spike thresholds. Taken together, these data indicate that dysbindin potently regulates excitatory transmission in the prefrontal cortex, potentially through a pre-synaptic mechanism, and consequently modulates cognitive functions depending on this brain region, providing new insights into the molecular mechanisms underlying cortical dysfunction in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
136PLoS ONE 2009 -1 4: e5246
PMID19370154
TitleIn silico whole genome association scan for murine prepulse inhibition.
AbstractThe complex trait of prepulse inhibition (PPI) is a sensory gating measure related to schizophrenia and can be measured in mice. Large-scale public repositories of inbred mouse strain genotypes and phenotypes such as PPI can be used to detect Quantitative Trait Loci (QTLs) in silico. However, the method has been criticized for issues including insufficient number of strains, not controlling for false discoveries, the complex haplotype structure of inbred mice, and failing to account for genotypic and phenotypic subgroups.
We have implemented a method that addresses these issues by incorporating phylogenetic analyses, multilevel regression with mixed effects, and false discovery rate (FDR) control. A genome-wide scan for PPI was conducted using over 17,000 single nucleotide polymorphisms (SNPs) in 37 strains phenotyped. Eighty-nine SNPs were significant at a false discovery rate (FDR) of 5%. After accounting for long-range linkage disequilibrium, we found 3 independent QTLs located on murine chromosomes 1 and 13. One of the PPI positives corresponds to a region of human chromosome 6p which includes DTNBP1, a gene implicated in schizophrenia. Another region includes the gene Tsn which alters PPI when knocked out. These genes also appear to have correlated expression with PPI.
These results support the usefulness of using an improved in silico mapping method to identify QTLs for complex traits such as PPI which can be then be used for to help identify loci influencing schizophrenia in humans.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
137Genes Brain Behav. 2009 Jun 8: 390-7
PMID19220483
TitleNeurobehavioral abnormalities in the dysbindin-1 mutant, sandy, on a C57BL/6J genetic background.
AbstractSandy mice have a deletion mutation in the gene encoding dysbindin-1, DTNBP1, with consequent reduction of the protein in heterozygotes and its loss in homozygotes. The sandy mouse thus serves as an animal model of dysbindin-1 function. As this protein is concentrated in synaptic tissue and affects transmitter release, it may affect neuronal processes that mediate behavior. To investigate the neurobehavioral effects of the DTNBP1 mutation, we studied littermate sandy and wild-type controls on a C57BL/6J genetic background. The three animal groups were indistinguishable in their external physical characteristics, sensorimotor skills and indices of anxiety-like behaviors. In the open field, however, homozygous animals were hyperactive and appeared to show less habituation to the initially novel environment. In the Morris water maze, homozygous animals displayed clear deficits in spatial learning and memory with marginal deficits in visual association learning. Apart from the last mentioned deficits, these abnormalities are consistent with hippocampal dysfunction and in some cases with elevated dopaminergic transmission via D2 dopamine receptors. As similar deficits in spatial learning and memory have been found in schizophrenia, where decreased dysbindin-1 has been found in the hippocampus, the sandy mouse may also model certain aspects of cognition and behavior relevant to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
138Neuroimage 2009 Oct 47: 2016-22
PMID19497374
TitleGenetic variation in schizophrenia-risk-gene dysbindin 1 modulates brain activation in anterior cingulate cortex and right temporal gyrus during language production in healthy individuals.
AbstractGenetic variation in dysbindin 1 (DTNBP1) gene region tagged by SNP rs1018381 exhibits a linkage with cognitive deficits in patients with schizophrenia and healthy subjects. Language production deficits are core features of schizophrenia with more impairment in semantic than lexical verbal fluency tasks. We investigated the link between brain activation and DTNBP1 SNP rs1018381 during semantic verbal fluency task in a German healthy population. 46 healthy subjects genotyped for SNP rs1018381 status were divided in heterozygous risk-allele carriers (T/C) and homozygous non-carriers (C/C). Neural correlates of semantic verbal fluency were investigated with functional magnetic resonance imaging (fMRI). Stronger right hemispherical brain activation in anterior cingulate gyrus (BA 24), superior (BA 22, 38) and middle (BA 21) temporal gyrus was observed in the carriers compared to non-carriers. Brain activations occurred in the absence of task performance differences. No significant correlations were found between personality traits and brain activation differences. The results point to an influence of genetic variation in DTNBP1 gene region tagged by SNP rs1018381 on neural correlates of language production. Carriers may exhibit higher processing efforts to reach the same behavioural performance as non-carriers as reflected in activation of schizophrenia-related regions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
139Pharmacogenet. Genomics 2009 Jun 19: 437-46
PMID19369910
TitleThe efficacies of clozapine and haloperidol in refractory schizophrenia are related to DTNBP1 variation.
AbstractThe prototypical atypical antipsychotic agent, clozapine, is more efficacious for refractory schizophrenia than the 'typical' antipsychotics, but the mechanism underlying this enhanced efficacy is still under investigation. Since 2002, at least 22 association studies have shown that the DTNBP1 can be associated with the risk for schizophrenia. We hypothesized that DTNBP1 might also influence the response to antipsychotic treatments. This study aimed to investigate the relationship between the DTNBP1 and the effects of clozapine and haloperidol on refractory schizophrenia.
Patients with refractory schizophrenia were assigned to clozapine (n=85) or haloperidol (n=96) and followed for 3 months. Symptom improvement was evaluated by Positive and Negative Syndrome Scale score. Six markers at DTNBP1 and 38 ancestry-informative markers were genotyped in all participants. The relationships between the effects of antipsychotics and the diplotypes, haplotypes, genotypes, and alleles of DTNBP1 were tested by analysis of covariance, analysis of variance, and t-test.
Patients with diplotype ACCCTC/GTTGCC, genotypes T/T+T/C, or allele T of marker rs742105 (P1333) have better response to clozapine (0.005< or =P< or =0.049), and patients with diplotype ACCCTC/GCCGCC, genotype A/G, or allele A of marker rs909706 (P1583) have better response to haloperidol (0.007< or =P< or =0.080) in European-Americans, African-Americans, and/or the combined sample; European-American patients with diplotype ACCCTC/GCCGCC have worse response to clozapine on positive symptoms (P=0.011).
This study shows that the DTNBP1 gene modulates the effects of both the atypical antipsychotic clozapine and the typical antipsychotic haloperidol. Participants with different DTNBP1 diplotypes, haplotypes, genotypes, or alleles might have different responses to these antipsychotics.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
140Schizophr. Res. 2009 Dec 115: 245-53
PMID19800201
TitleThe dystrobrevin binding protein 1 (DTNBP1) gene is associated with schizophrenia in the Irish Case Control Study of Schizophrenia (ICCSS) sample.
AbstractDTNBP1 is associated with schizophrenia in many studies, but the associated alleles and haplotypes vary between samples.
We assessed nine single nucleotide polymorphisms (SNPs) in this gene for association with schizophrenia in a new sample of 1021 cases and 626 controls from Ireland.
Four SNPs give evidence of association (0.000018DTNBP1 gene also gives evidence for association (p=0.0002). Secondary analyses showed no difference in the association signal based on sex or family history. These results are in agreement with the most consistently observed association with common alleles and common-allele haplotypes, reported in a previous study of Irish cases and controls but not in an Irish high-density family sample. Our results do not support the prior report from a Swedish sample of increased association in cases with a family history of psychotic illness. Comparison of human, chimpanzee and rhesus sequence suggest that rs760761 is a particularly variable position in the primate lineage.
This study provides further evidence from a large case/control sample for association of common DTNBP1 alleles and haplotypes with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
141Psychiatr. Genet. 2009 Dec 19: 292-304
PMID19862852
TitleAssociation study of DTNBP1 with schizophrenia in a US sample.
AbstractStraub et al. (2002b) located a susceptibility region for schizophrenia at the DTNBP1 locus. At least 40 studies (including one study in US populations) attempted to replicate this original finding, but the reported findings are highly diverse and at least five pathways by which dysbindin protein might be involved in schizophrenia have been proposed. This study aimed to test the association in two common US populations by using powerful analytic methods.
Six markers at DTNBP1 were genotyped by mass spectroscopy ('MassARRAY' technique) in a sample of 663 individuals, including 346 healthy individuals European-Americans (EAs) and 48 African-Americans (AAs), and 317 individuals with schizophrenia (235 EAs and 82 AAs). Thirty-eight ancestry-informative markers were genotyped in this sample to infer the ancestry proportions. Diplotype, haplotype, genotype, and allele frequency distributions were compared between the cases and controls, controlling for possible population stratification, admixture, and sex-specific effects, and taking interaction effects into account, using a logistic regression analysis (an extended structured association method).
Conventional case-control comparisons showed that genotypes of the markers P1578 (rs1018381) and P1583 (rs909706) were nominally associated with schizophrenia in EAs and in AAs, respectively. These associations became less or nonsignificant after controlling for population stratification and admixture effects (using structured association or regression analysis), and became nonsignificant after correction for multiple testing. However, regression analysis showed that the common diplotypes (ACCCTT/GCCGCC or GCCGCC/GCCGCC) and the interaction effects of haplotypes GCCGCC/GCCGCC significantly affected risk for schizophrenia in EAs, effects that were modified by sex. Fine-mapping using d or J statistics located the specific markers (d: P1328; J: P1333) closest to the putative risk sites in EAs.
This study shows that DTNBP1 is a risk gene for schizophrenia in EAs. Variation at DTNBP1 may modify risk for schizophrenia in this population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
142Hum. Mol. Genet. 2009 Oct 18: 3851-63
PMID19617633
TitleDysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to dysbindin-1 mRNA expression.
AbstractDTNBP1 (dystrobrevin binding protein 1) remains a top candidate gene in schizophrenia. Reduced expression of this gene and of its encoded protein, dysbindin-1, have been reported in the brains of schizophrenia cases. It has not been established, however, if the protein reductions encompass all dysbindin-1 isoforms or if they are associated with decreased DTNBP1 gene expression. Using a matched pairs design in which each of 28 Caucasian schizophrenia cases was matched in age and sex to a normal Caucasian control, Western blotting of whole-tissue lysates of dorsolateral prefrontal cortex (DLPFC) revealed significant reductions in dysbindin-1C (but not in dysbindin-1A or -1B) in schizophrenia (P = 0.022). These reductions occurred without any significant change in levels of the encoding transcript in the same tissue samples and in the absence of the only DTNBP1 risk haplotype for schizophrenia reported in the USA. Indeed, no significant correlations were found between case-control differences in any dysbindin-1 isoform and the case-control differences in its encoding mRNA. Consequently, the mean 60% decrease in dysbindin-1C observed in 71% of our case-control pairs appears to reflect abnormalities in mRNA translation and/or processes promoting dysbindin-1C degradation (e.g. oxidative stress, phosphorylation and/or ubiquitination). Given the predominantly post-synaptic localization of dysbindin-1C and known post-synaptic effects of dysbindin-1 reductions in the rodent equivalent of the DLPFC, the present findings suggest that decreased dysbindin-1C in the DLPFC may contribute to the cognitive deficits of schizophrenia by promoting NMDA receptor hypofunction in fast-spiking interneurons.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
143Hum Brain Mapp 2009 Nov 30: 3783-94
PMID19449336
TitleDTNBP1 is associated with imaging phenotypes in schizophrenia.
AbstractDystrobrevin binding protein 1 (DTNBP1) has been identified as putative schizophrenia susceptibility gene, but it remains unknown whether polymorphisms relate to altered cerebral structure. We examined relationships between a previously implicated DTNBP1 risk variant [P1578] and global and segmented brain tissue volumes and regional cortical thickness in schizophrenia (n = 62; 24 risk carriers) and healthy subjects (n = 42; 11 risk carriers), across ethnic groups and within Caucasians. schizophrenia patients showed similar brain volumes, but significantly reduced brain-size adjusted gray matter and CSF volumes and cortical thinning in a widespread neocortical distribution compared to controls. DTNBP1 risk was found associated with reduced brain volume, but not with tissue sub-compartments. Cortical thickness, which was weakly associated with brain size, showed regional variations in association with genetic risk, although effects were dominated by highly significant genotype by diagnosis interactions over broad areas of cortex. Risk status was found associated with regional cortical thinning in patients, particularly in temporal networks, but with thickness increases in controls. DTNBP1 effects for brain volume and cortical thickness appear driven by different neurobiological processes. Smaller brain volumes observed in risk carriers may relate to previously reported DTNBP1/cognitive function relationships irrespective of diagnosis. Regional cortical thinning in patient, but not in control risk carriers, may suggest that DTNBP1 interacts with other schizophrenia-related risk factors to affect laminar thickness. Alternatively, DTNBP1 may influence neural processes for which individuals with thicker cortex are less vulnerable. Although DTNBP1 relates to cortical thinning in schizophrenia, morphological changes in the disorder are influenced by additional genetic and/or environmental factors.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
144Psychol Med 2009 Oct 39: 1657-65
PMID19335929
TitleAssociation of the DTNBP1 genotype with cognition and personality traits in healthy subjects.
Abstractschizophrenia is a complex disorder with a high heritability. Family members have an increased risk not only for schizophrenia per se but also for schizophrenia spectrum disorders. Impairment of neuropsychological functions found in schizophrenia patients are also frequently observed in their relatives. The dystrobrevin-binding protein 1 (DTNBP1) gene located at chromosome 6p22.3 is one of the most often replicated vulnerability genes for schizophrenia. In addition, this gene has been shown to modulate general cognitive abilities both in healthy subjects and in patients with schizophrenia.
In a sample of 521 healthy subjects we investigated an association between the DTNBP1 genotype [single nucleotide polymorphism (SNP) rs1018381], personality traits [using the NEO Five-Factor Inventory (NEO-FFI) and the schizotypal Personality Questionnaire - Brief Version (SPQ-B)] and cognitive function (estimated IQ, verbal fluency, attention, working memory and executive function).
Significantly lower scores on the SPQ-B (p=0.0005) and the Interpersonal Deficit subscale (p=0.0005) in carriers of the A-risk allele were detected. There were no differences in any of the cognitive variables between groups.
The results indicate that genetic variation of the DTNBP1 genotype might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
145PLoS ONE 2009 -1 4: e4199
PMID19142223
TitleDysbindin-1, a schizophrenia-related protein, functionally interacts with the DNA- dependent protein kinase complex in an isoform-dependent manner.
AbstractDTNBP1 has been recognized as a schizophrenia susceptible gene, and its protein product, dysbindin-1, is down-regulated in the brains of schizophrenic patients. However, little is known about the physiological role of dysbindin-1 in the central nervous system. We hypothesized that disruption of dysbindin-1 with unidentified proteins could contribute to pathogenesis and the symptoms of schizophrenia. GST pull-down from human neuroblastoma lysates showed an association of dysbindin-1 with the DNA-dependent protein kinase (DNA-PK) complex. The DNA-PK complex interacts only with splice isoforms A and B, but not with C. We found that isoforms A and B localized in nucleus, where the kinase complex exist, whereas the isoform C was found exclusively in cytosol. Furthermore, results of phosphorylation assay suggest that the DNA-PK complex phosphorylated dysbindin-1 isoforms A and B in cells. These observations suggest that DNA-PK regulates the dysbindin-1 isoforms A and B by phosphorylation in nucleus. Isoform C does not contain exons from 1 to 6. Since schizophrenia-related single nucleotide polymorphisms (SNPs) occur in these introns between exon 1 and exon 6, we suggest that these SNPs might affect splicing of DTNBP1, which leads to impairment of the functional interaction between dysbindin-1 and DNA-PK in schizophrenic patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
146Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Sep 150B: 836-44
PMID19089808
TitleAssociation of the dystrobrevin binding protein 1 gene (DTNBP1) in a bipolar case-control study (BACCS).
AbstractRecent studies suggest a degree of overlap in genetic susceptibility across the traditional categories of schizophrenia and bipolar disorder. There is some evidence for an association of the dystrobrevin binding protein 1 gene (DTNBP1) with schizophrenia, and, thus, this gene has also become a focus of further investigation in bipolar disorder (BD). The aim of our study is to explore the association of DTNBP1 with BD and with a sub phenotype, presence/absence of psychotic symptoms, in a sample of 515 patients with BD (ICD10/DSMIV) and 1,316 ethnically matched control subjects recruited from the UK. Seven DTNBP1 SNPs: rs2743852 (SNP C), rs760761 (P1320), rs1011313 (P1325), rs3213207 (P1635), rs2619539 (P1655), rs16876571 and rs17470454 were investigated using the SNPlex genotyping system and 1 SNP (rs2619522) genotypes were imputed. Association analyses were conducted in a sample of 452 cases and 956 controls. We found significant differences in genotypic and allelic frequencies of rs3213207 and rs760761 of DTNBP1 between bipolar patients and controls. We also showed a global haplotypic association and an association of a particular haplotype with BD. Our results are consistent with previous studies in term of a general association between DTNBP1 and bipolar disorder and provide additional evidence that a portion of the genotypic overlap between schizophrenia and bipolar affective disorder is attributable to this gene.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
147Mol. Psychiatry 2009 Jan 14: 18-29
PMID18663367
TitleThe dystrobrevin-binding protein 1 gene: features and networks.
AbstractThe dystrobrevin-binding protein 1 (DTNBP1) gene has been one of the most studied and promising schizophrenia susceptibility genes since it was first reported to be associated with schizophrenia in the Irish Study of High Density schizophrenia Families (ISHDSF). Although many studies have been performed both at the functional level and in association with psychiatric disorders, there has been no systematic review of the features of the DTNBP1 gene, protein or the relationship between function and phenotype. Using a bioinformatics approach, we identified the DTNBP1 gene in 13 vertebrate species. The comparison of these genes revealed a conserved gene structure, protein-coding sequence and dysbindin domain, but a diverse noncoding sequence. The molecular evolutionary analysis suggests the DTNBP1 gene probably originated in chordates and matured in vertebrates. No signature of recent positive selection was seen in any primate lineage. The DTNBP1 gene likely has many more alternative transcripts than the current three major isoforms annotated in the NCBI database. Our examination of risk haplotypes revealed that, although the frequency of a single nucleotide polymorphism (SNP) or haplotype might be significantly different in cases from controls, difference between major geographic populations was even larger. Finally, we constructed the first DTNBP1 interactome and explored its network features. Besides the biogenesis of lysosome-related organelles complex 1 and dystrophin-associated protein complex, several molecules in the DTNBP1 network likely provide insight into the role of DTNBP1 in biological systems: retinoic acid, beta-estradiol, calmodulin and tumour necrosis factor. Studies of these subnetworks and pathways may provide opportunities to deepen our understanding of the mechanisms of action of DTNBP1 variants.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
148Acta Neuropsychiatr 2009 Jun 21: 109-20
PMID26953749
TitleSchizophrenia: genetics, prevention and rehabilitation.
AbstractGenetic factors are largely implicated in predisposing to schizophrenia. Environmental factors contribute to the onset of the disorder in individuals at increased genetic risk. Cognitive deficits have emerged as endophenotypes and potential therapeutic targets for schizophrenia because of their association with functional outcome. The aims of this review were to analyse the joint effect of genetic and environmental (GE) factors on liability to schizophrenia and to investigate relationships between genes and cognitive endophenotypes focusing on practical applications for prevention and rehabilitation.
Medline search of relevant studies published between 1990 and 2008.
In schizophrenia, examples of GE interaction include the catechol-O-methyl transferase (COMT) (Val158Met) polymorphism, which was found to moderate the onset of psychotic manifestations in response to stress and to increase the risk for psychosis related to cannabis use, and neurodevelopmental genes such as AKT1 (serine-threonine kinase), brain-derived neurotrophic factor (BDNF), DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate receptor 3), which were associated with development of schizophrenia in adulthood after exposure to perinatal obstetric complications. Neurocognitive deficits are recognised as core features of schizophrenia that facilitate the onset of the disorder and have a great impact on functional outcome. Neurocognitive deficits are also endophenotypes that have been linked to a variety of genes [COMT, neuregulin (NRG1), BDNF, Disrupted-In-schizophrenia 1 (DISC1) and dysbindin] conferring susceptibility to schizophrenia. Recently, it has emerged that cognitive improvement during rehabilitation therapy was under control of COMT (Val158Met) polymorphism.
This review could indicate a pivotal role of psychiatric genetics in prevention and rehabilitation of schizophrenic psychoses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
149Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Oct 150B: 893-9
PMID19132710
TitleEvidence that putative ADHD low risk alleles at SNAP25 may increase the risk of schizophrenia.
AbstractSynaptosomal Associated Protein 25 kDa (SNAP25) has been implicated in the pathogenesis of schizophrenia by numerous neuropathological studies and genetic variation at SNAP25 has been reported to be associated with ADHD. Expression levels of the putative schizophrenia susceptibility gene DTNBP1 has been shown to influence the levels of SNAP25 in vitro. We undertook directed mutation screening of SNAP25 in UK schizophrenic cases followed by direct association analysis of all variants identified and identified known exonic SNPs that showed evidence for association (rs3746544 P = 0.004 OR = 1.26, rs8636 P = 0.003 OR = 1.27), although these SNPs are highly correlated (r(2) > 0.99). We additionally genotyped a further 31 tag SNPs spanning the SNAP25 locus and identified several independent SNPs that were nominally associated with schizophrenia (strongest association at rs3787283, P = 0.006, OR = 1.25) however, due to the number of tests performed no SNP met experiment-wise significance (minimum permuted P-value = 0.1). Post hoc analysis revealed that the SNPs nominally associated with schizophrenia (rs3787283, rs3746544) were the same as those previously demonstrated to be associated with ADHD but with the opposite alleles, allowing the intriguing hypothesis that genetic variation at SNAP25 may be differentially associated with both schizophrenia and ADHD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
150PLoS ONE 2009 -1 4: e4199
PMID19142223
TitleDysbindin-1, a schizophrenia-related protein, functionally interacts with the DNA- dependent protein kinase complex in an isoform-dependent manner.
AbstractDTNBP1 has been recognized as a schizophrenia susceptible gene, and its protein product, dysbindin-1, is down-regulated in the brains of schizophrenic patients. However, little is known about the physiological role of dysbindin-1 in the central nervous system. We hypothesized that disruption of dysbindin-1 with unidentified proteins could contribute to pathogenesis and the symptoms of schizophrenia. GST pull-down from human neuroblastoma lysates showed an association of dysbindin-1 with the DNA-dependent protein kinase (DNA-PK) complex. The DNA-PK complex interacts only with splice isoforms A and B, but not with C. We found that isoforms A and B localized in nucleus, where the kinase complex exist, whereas the isoform C was found exclusively in cytosol. Furthermore, results of phosphorylation assay suggest that the DNA-PK complex phosphorylated dysbindin-1 isoforms A and B in cells. These observations suggest that DNA-PK regulates the dysbindin-1 isoforms A and B by phosphorylation in nucleus. Isoform C does not contain exons from 1 to 6. Since schizophrenia-related single nucleotide polymorphisms (SNPs) occur in these introns between exon 1 and exon 6, we suggest that these SNPs might affect splicing of DTNBP1, which leads to impairment of the functional interaction between dysbindin-1 and DNA-PK in schizophrenic patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
151Psychol Med 2009 Oct 39: 1657-65
PMID19335929
TitleAssociation of the DTNBP1 genotype with cognition and personality traits in healthy subjects.
Abstractschizophrenia is a complex disorder with a high heritability. Family members have an increased risk not only for schizophrenia per se but also for schizophrenia spectrum disorders. Impairment of neuropsychological functions found in schizophrenia patients are also frequently observed in their relatives. The dystrobrevin-binding protein 1 (DTNBP1) gene located at chromosome 6p22.3 is one of the most often replicated vulnerability genes for schizophrenia. In addition, this gene has been shown to modulate general cognitive abilities both in healthy subjects and in patients with schizophrenia.
In a sample of 521 healthy subjects we investigated an association between the DTNBP1 genotype [single nucleotide polymorphism (SNP) rs1018381], personality traits [using the NEO Five-Factor Inventory (NEO-FFI) and the schizotypal Personality Questionnaire - Brief Version (SPQ-B)] and cognitive function (estimated IQ, verbal fluency, attention, working memory and executive function).
Significantly lower scores on the SPQ-B (p=0.0005) and the Interpersonal Deficit subscale (p=0.0005) in carriers of the A-risk allele were detected. There were no differences in any of the cognitive variables between groups.
The results indicate that genetic variation of the DTNBP1 genotype might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
152Psychiatr. Genet. 2010 Oct 20: 191-8
PMID20421849
TitleHabituation in prepulse inhibition is affected by a polymorphism on the NMDA receptor 2B subunit gene (GRIN2B).
AbstractTo identify the reliable connectivity between causal genes or variants with an abnormality expressed in a certain endophenotype has been viewed as a crucial step in unraveling the etiology of schizophrenia because of the considerable heterogeneity in this disorder.
According to this practical and scientific demand, we aimed to investigate the relationship between seven top-ranked variants in the SZgene database [120-bpTR in DRD4, rs1801028 and rs6277 in DRD2, rs1019385 (T200G) in GRIN2B, rs1800532 in TPH1, rs1801133 (C677T) in MTHFR, rs2619528 (P1765) in DTNBP1] and prepulse inhibition (PPI) and habituation after acoustic stimulus (HAB).
Both PPI and HAB were decreased significantly in patients with schizophrenia. In addition, we observed a significant effect of GRIN2B (human NMDA receptor 2B subunit gene, NR2B) genotype on HAB (P<0.05, not corrected).
Although these findings need to be replicated in other samples, an underlying mechanism of impaired biological reaction may be influenced by NMDA hypofunctioning in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
153Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Oct 34: 1259-65
PMID20638435
TitleAn exploratory model for G x E interaction on hippocampal volume in schizophrenia; obstetric complications and hypoxia-related genes.
AbstractSmaller hippocampal volume has repeatedly been reported in schizophrenia patients. Obstetric complications (OCs) and single nucleotide polymorphism (SNP) variation in schizophrenia susceptibility genes have independently been related to hippocampal volume. We investigated putative independent and interaction effects of severe hypoxia-related OCs and variation in four hypoxia-regulated schizophrenia susceptibility genes (BDNF, DTNBP1, GRM3 and NRG1) on hippocampal volume in schizophrenia patients and healthy controls.
Clinical assessment, structural MRI scans, and blood samples for genotyping of 32 SNPs were obtained from 54 schizophrenia patients and 53 control subjects. Information on obstetric complications was collected from original birth records.
Severe OCs were related to hippocampal volume in both patients with schizophrenia and healthy control subjects. Of the 32 SNPs studied, effects of severe OCs on hippocampal volume were associated with allele variation in GRM3 rs13242038, but the interaction effect was not specific for schizophrenia. SNP variation in any of the four investigated genes alone did not significantly affect hippocampal volume.
The findings suggest a gene-environment (G x E) interaction between GRM3 gene variants and severe obstetric complications on hippocampus volume, independent of a diagnosis of schizophrenia. Due to the modest sample size, the results must be considered preliminary and require replication in independent samples.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
154Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Dec 34: 1375-80
PMID20600464
TitleGenetic findings in schizophrenia patients related to alterations in the intracellular Ca-homeostasis.
AbstractThere is a relatively high genetic heritability of schizophrenia as shown by family, twin and adoption studies. A large number of hypotheses on the causes of schizophrenia occurred over time. In this review we focus on genetic findings related to potential alterations of intracellular Ca-homeostasis in association with schizophrenia. First, we provide evidence for the NMDA/glutamatergic theory of schizophrenia including calcium processes. We mainly focus on genes including: DAO (D-amino acid oxidase), DAOA (D-amino acid oxidase activator), DTNBP1 (Dysbindin 1, dystrobrevin-binding protein 1), NRG1 (Neuregulin 1), ERBB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4, avian), NOS1 (nitric oxide synthase 1, neuronal) and NRGN (Neurogranin). Furthermore, a gene coding for a calcium channel subunit (CACNA1C: calcium channel, voltage-dependent, L type, alpha 1C subunit) is discussed in the light of schizophrenia whereas genetic findings related to alterations in the intracellular Ca-homeostasis associated specifically with dopaminergic and serotonergic neurotransmission in schizophrenia are not herein closer reviewed. Taken together there is converging evidence for the contribution of genes potentially related to alterations in intracellular Ca-homeostasis to the risk of schizophrenia. Replications and functional studies will hopefully provide further insight into these genetic variants and the underlying processes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
155J. Biol. Chem. 2010 Dec 285: 38630-40
PMID20921223
TitleNucleocytoplasmic shuttling of dysbindin-1, a schizophrenia-related protein, regulates synapsin I expression.
AbstractDysbindin-1 is a 50-kDa coiled-coil-containing protein encoded by the gene DTNBP1 (dystrobrevin-binding protein 1), a candidate genetic factor for schizophrenia. Genetic variations in this gene confer a susceptibility to schizophrenia through a decreased expression of dysbindin-1. It was reported that dysbindin-1 regulates the expression of presynaptic proteins and the release of neurotransmitters. However, the precise functions of dysbindin-1 are largely unknown. Here, we show that dysbindin-1 is a novel nucleocytoplasmic shuttling protein and translocated to the nucleus upon treatment with leptomycin B, an inhibitor of exportin-1/CRM1-mediated nuclear export. Dysbindin-1 harbors a functional nuclear export signal necessary for its nuclear export, and the nucleocytoplasmic shuttling of dysbindin-1 affects its regulation of synapsin I expression. In brains of sandy mice, a dysbindin-1-null strain that displays abnormal behaviors related to schizophrenia, the protein and mRNA levels of synapsin I are decreased. These findings demonstrate that the nucleocytoplasmic shuttling of dysbindin-1 regulates synapsin I expression and thus may be involved in the pathogenesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
156Behav Brain Funct 2010 -1 6: 54
PMID20846375
TitleThe effects of a DTNBP1 gene variant on attention networks: an fMRI study.
AbstractAttention deficits belong to the main cognitive symptoms of schizophrenia and come along with altered neural activity in previously described cerebral networks. Given the high heritability of schizophrenia the question arises if impaired function of these networks is modulated by susceptibility genes and detectable in healthy risk allele carriers.
The present event-related fMRI study investigated the effect of the single nucleotide polymorphism (SNP) rs1018381 of the DTNBP1 (dystrobrevin-binding protein 1) gene on brain activity in 80 subjects while performing the attention network test (ANT). In this reaction time task three domains of attention are probed simultaneously: alerting, orienting and executive control of attention.
Risk allele carriers showed impaired performance in the executive control condition associated with reduced neural activity in the left superior frontal gyrus [Brodmann area (BA) 9]. Risk allele carriers did not show alterations in the alerting and orienting networks.
BA 9 is a key region of schizophrenia pathology and belongs to a network that has been shown previously to be involved in impaired executive control mechanisms in schizophrenia. Our results identified the impact of DTNBP1 on the development of a specific attention deficit via modulation of a left prefrontal network.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
157Neurosci. Behav. Physiol. 2010 Oct 40: 934-40
PMID20683774
TitlePolymorphism of serotonin receptor genes (5-HTR2A) and Dysbindin (DTNBP1) and individual components of short-term verbal memory processes in Schizophrenia.
AbstractAssociations between polymorphisms in the T102C and A-1438G loci of the 5-HTR2A and the P1763 and P1578 markers of the DTNBP1 gene with the overall productivity and individual subprocesses of shortterm verbal memory were studied in 4-5 patients with schizophrenia and 290 healthy subjects. Subjects were asked to reproduce immediately two lists of 10 words. The overall productivity of reproduction was assessed, along with the reproduction productivity of the first list (immediate memory or general attention), the effect of proactive interference, and the number of intrusions. Patients were significantly different from controls on all measures. Patients showed decreases in overall task performance productivity, in immediate memory productivity, and in the effect of proactive interference; fewer intrusions were seen. Both markers of the 5-HTR2A gene were associated with short-term memory productivity in the combined cohort: assessments were worse in T102C CC and A-1438G GG homozygotes. The P1763 marker of the DTNBP1 gene, conversely, had significant influences on the memory subprocesses reflected in the levels of interference and intrusions but had insignificant influence on overall productivity. Homozygotes for P1763G GG had the worst parameters. Overall, these data are consistent with the concept that these polymorphic genes are involved in different subprocesses of short-term memory both in normal subjects and in patients with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
158Chin. Med. Sci. J. 2010 Jun 25: 85-9
PMID20598229
TitleDTNBP1 gene is associated with some symptom factors of schizophrenia in Chinese Han nationality.
AbstractTo study the association of DTNBP1 gene with some symptom factors of schizophrenia.
A total of 285 unrelated schizophrenic individuals were recruited from December 2004 to January 2009 for genetic analysis, and their symptom factors were assessed based on the Positive and Negative Syndrome Scale (PANSS). The quantitative trait test was performed by the UNPHASED program (version 3.0.12) to investigate the association between scored positive and negative symptoms and the single nucleotide polymorphisms (SNPs) in DTNBP1 gene.
The quantitative trait test showed allelic association of rs909706 with the excitement symptom of schizophrenia (P<0.05, adjusted by 10,000 permutations), while the genotype C/G of rs2619539 with a negative symptom, lack of spontaneity and flow of conversation (P<0.05, adjusted by 10,000 permutations).
DTNBP1 variations are possibly associated with some symptoms of schizophrenia, which could partly explain the relationship between the susceptibility gene DTNBP1 and that disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
159Nihon Shinkei Seishin Yakurigaku Zasshi 2010 Jun 30: 103-7
PMID20666140
Title[Risk genes for schizophrenia and neuronal plasticity: molecular target for antipsychotic discovery].
AbstractThe dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) has been identified as a susceptibility gene for schizophrenia. Genetic variations of DTNBP1 were reported to be associated with several intermediate phenotypes such as general cognitive ability, memory, and regional brain activation and cortical volume. In studies on postmortem brain tissue, decreased expression levels of dysbindin-1 were shown in patients with schizophrenia. Risk genetic variation of dysbindin for schizophrenia was associated with reduced expression of dysbindin in human brains. These data indicate that the dysbindin-1 gene may confer susceptibility to schizophrenia through reduced expression and that sandy mice lacking dysbindin-1 protein could be a unique animal model of schizophrenia. Sandy mice were less active, had heightened anxiety-like response, demonstrated deficits in social interaction and showed impaired long-term memory retention and working memory. Sandy mice demonstrated lower levels of dopamine, but not glutamate, in restricted brain regions. Several neuronal functions of dysbindin were reported, such as neurotransmitter release, direct interaction with presynaptic molecules, neuroprotection, cytosckeletal organization, and gene expression. To investigate dysbindin function in the brain could shed light on the etiology of schizophrenia and lead us to new hypotheses, novel diagnostic tools, and more effective therapies for the disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
160Hum. Hered. 2010 -1 69: 71-9
PMID19996605
TitleAllelic heterogeneity in genetic association meta-analysis: an application to DTNBP1 and schizophrenia.
AbstractMeta-analysis of genetic association studies is a useful approach when individual investigations do not yield studywise significant results but the evidence across studies is modest and homogeneous. Current meta-analysis methods account for heterogeneity by down-weighting studies as a function of between-study variance. We contend that current approaches may obscure interesting phenomena in genetic association data. However, an appropriate approach to examining heterogeneity across studies is lacking.
We develop a novel approach, based on the EM algorithm, to detect allelic heterogeneity, identify subpopulations and assign studies to those subpopulations. We then apply these methods to the association between DTNBP1 and schizophrenia (Scz), one of the most studied relationships in complex disease genetics. We examined 32 published and unpublished population and family-based association studies containing up to 14 SNPs spanning the DTNBP1 locus.
We explored heterogeneity in several ways including meta-regression and approaches aimed at exploring the mixture of heterogeneous studies at a particular SNP. We found significant evidence for a mixture of association distributions at multiple loci.
We propose a novel approach that is broadly applicable and may be useful in large scale genetic association meta-analyses to detect significant allelic heterogeneity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
161Biol. Psychiatry 2010 Dec 68: 1126-33
PMID21130223
TitleMeta-analysis of genetic variation in DTNBP1 and general cognitive ability.
AbstractThe human dystrobrevin binding protein 1 (DTNBP1) gene has been linked to risk for schizophrenia. Recent studies indicate that several single nucleotide polymorphisms (SNPs) in the DTNBP1 gene may also influence general cognitive ability in both schizophrenic patients and healthy control subjects. We examined the relationship between DTNBP1 SNPs and general cognitive ability in nonpsychiatric healthy samples via meta-analysis.
MEDLINE search (12/31/09) yielded 11 articles examining DTNBP1 variation and general cognitive ability, of which 8 studies had data available encompassing 10 independent cohorts (total n = 7592). The phenotype was defined as either the first principal component score from multiple neuropsychological tests (Spearman's g) or full-scale IQ. Meta-analyses were conducted for nine SNPs for which cognitive data were available from at least three cohorts. For each SNP in each cohort, effect size was computed between major allele homozygotes and minor allele carriers; effect size was then pooled across studies using a random effect model.
Pooled effect sizes from two of the nine SNPs (rs1018381 and rs2619522) were -.123 and -.083, ps < .01, respectively, suggesting that the minor allele carriers of these SNPs had lower cognitive ability scores than the major allele homozygotes. Results remained significant after examining heterogeneity among samples and potential publication biases. Other SNPs did not show significant effects on general cognitive ability.
Genetic variation in DTNBP1 modestly influences general cognitive ability. Further studies are needed to elucidate the biological mechanisms that may account for this relationship.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
162Eur. Psychiatry 2010 Oct 25: 314-9
PMID20615671
TitleAnalysis of HapMap tag-SNPs in dysbindin (DTNBP1) reveals evidence of consistent association with schizophrenia.
AbstractDystrobrevin binding protein 1 (DTNBP1), or dysbindin, is thought to be critical in regulating the glutamatergic system. While the dopamine pathway is known to be important in the aetiology of schizophrenia, it seems likely that glutamatergic dysfunction can lead to the development of schizophrenia. DTNBP1 is widely expressed in brain, levels are reduced in brains of schizophrenia patients and a DTNBP1 polymorphism has been associated with reduced brain expression. Despite numerous genetic studies no DTNBP1 polymorphism has been strongly implicated in schizophrenia aetiology. Using a haplotype block-based gene-tagging approach we genotyped 13 SNPs in DTNBP1 to investigate possible associations with DTNBP1 and schizophrenia. Four polymorphisms were found to be significantly associated with schizophrenia. The strongest association was found with an A/C SNP in intron 7 (rs9370822). Homozygotes for the C allele of rs9370822 were more than two and a half times as likely to have schizophrenia compared to controls. The other polymorphisms showed much weaker association and are less likely to be biologically significant. These results suggest that DTNBP1 is a good candidate for schizophrenia risk and rs9370822 is either functionally important or in disequilibrium with a functional SNP, although our observations should be viewed with caution until they are independently replicated.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
163Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Mar 153B: 700-5
PMID19760674
TitleNo association of dysbindin with symptom factors of schizophrenia in an Irish case-control sample.
AbstractRobust associations between the dysbindin gene (DTNBP1) and schizophrenia have been demonstrated in many but not all samples, and evidence that this gene particularly predisposes to negative symptoms in this illness has been presented. The current study sought to replicate the previously reported negative symptom associations in an Irish case-control sample. Association between dysbindin and schizophrenia has been established in this cohort, and a factor analysis of the assessed symptoms yielded three factors, Positive, Negative, and Schneiderian. The sequential addition method was applied using UNPHASED to assess the relationship between these symptom factors and the high-risk haplotype. No associations were detected for any of the symptom factors indicating that the dysbindin risk haplotype does not predispose to a particular group of symptoms in this sample. Several possibilities, such as differing risk haplotypes, may explain this finding.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
164Behav Brain Funct 2010 -1 6: 41
PMID20615259
TitleA polymorphism in the dysbindin gene (DTNBP1) associated with multiple psychiatric disorders including schizophrenia.
AbstractA number of studies have found associations between dysbindin (DTNBP1) polymorphisms and schizophrenia. Recently we identified a DTNBP1 SNP (rs9370822) that is strongly associated with schizophrenia. Individuals diagnosed with schizophrenia were nearly three times as likely to carry the CC genotype compared to the AA genotype.
To investigate the importance of this SNP in the function of DTNBP1, a number of psychiatric conditions including addictive behaviours and anxiety disorders were analysed for association with rs9370822.
The DTNBP1 polymorphism was significantly associated with post-traumatic stress disorder (PTSD) as well as nicotine and opiate dependence but not alcohol dependence. Individuals suffering PTSD were more than three times as likely to carry the CC genotype compared to the AA genotype. Individuals with nicotine or opiate dependence were more than twice as likely to carry the CC genotype compared to the AA genotype.
This study provides further support for the importance of DTNBP1 in psychiatric conditions and suggests that there is a common underlying molecular defect involving DTNBP1 that contributes to the development of several anxiety and addictive disorders that are generally recognised as separate clinical conditions. These disorders may actually be different expressions of a single metabolic pathway perturbation. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
165Schizophr. Res. 2010 May 118: 98-105
PMID20083391
TitleA reappraisal of the association between Dysbindin (DTNBP1) and schizophrenia in a large combined case-control and family-based sample of German ancestry.
AbstractDysbindin (DTNBP1) is a widely studied candidate gene for schizophrenia (SCZ); however, inconsistent results across studies triggered skepticism towards the validity of the findings. In this HapMap-based study, we reappraised the association between Dysbindin and SCZ in a large sample of German ethnicity.
Six hundred thirty-four cases with DSM-IV SCZ, 776 controls, and 180 parent-offspring trios were genotyped for 38 Dysbindin SNPs. We also studied two phenotypically-defined subsamples: 147 patients with a positive family history of SCZ (FH-SCZ+) and SCZ patients characterized for cognitive performance with Trail-Making Tests A and B (TMT-A: n=219; TMT-B: n=247). Given previous evidence of gene-gene interactions in SCZ involving the COMT gene, we also assessed epistatic interactions between Dysbindin markers and 14 SNPs in COMT.
No association was detected between Dysbindin markers and SCZ, or in the FH-SCZ+ subgroup. Only one marker (rs1047631, previously reported to be part of a risk haplotype), showed a nominally significant association with performance on TMT-A and TMT-B; these findings did not remain significant after correction for multiple comparisons. Similarly, no pair-wise epistatic interactions between Dysbindin and COMT markers remained significant after correction for 504 pair-wise comparisons.
Our results, based on one of the largest samples of European Caucasians and using narrowly-defined criteria for SCZ, do not support the etiological involvement of Dysbindin markers in SCZ. Larger samples may be needed in order to unravel Dysbindin's possible role in the genetic basis of proposed intermediate phenotypes of SCZ or to detect epistatic interactions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
166Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Apr 153B: 792-801
PMID19937977
TitleAssociation study of NRG1, DTNBP1, RGS4, G72/G30, and PIP5K2A with schizophrenia and symptom severity in a Hungarian sample.
AbstractGenetic 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
167Chin. Med. Sci. J. 2010 Jun 25: 85-9
PMID20598229
TitleDTNBP1 gene is associated with some symptom factors of schizophrenia in Chinese Han nationality.
AbstractTo study the association of DTNBP1 gene with some symptom factors of schizophrenia.
A total of 285 unrelated schizophrenic individuals were recruited from December 2004 to January 2009 for genetic analysis, and their symptom factors were assessed based on the Positive and Negative Syndrome Scale (PANSS). The quantitative trait test was performed by the UNPHASED program (version 3.0.12) to investigate the association between scored positive and negative symptoms and the single nucleotide polymorphisms (SNPs) in DTNBP1 gene.
The quantitative trait test showed allelic association of rs909706 with the excitement symptom of schizophrenia (P<0.05, adjusted by 10,000 permutations), while the genotype C/G of rs2619539 with a negative symptom, lack of spontaneity and flow of conversation (P<0.05, adjusted by 10,000 permutations).
DTNBP1 variations are possibly associated with some symptoms of schizophrenia, which could partly explain the relationship between the susceptibility gene DTNBP1 and that disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
168PLoS ONE 2010 -1 5: e8773
PMID20098743
TitleDysbindin regulates the transcriptional level of myristoylated alanine-rich protein kinase C substrate via the interaction with NF-YB in mice brain.
AbstractAn accumulating body of evidence suggests that DTNBP1 (Dysbindin) is a key susceptibility gene for schizophrenia. Using the yeast-two-hybrid screening system, we examined the candidate proteins interacting with Dysbindin and revealed one of these candidates to be the transcription factor NF-YB.
We employed an immunoprecipitation (IP) assay to demonstrate the Dysbindin-NF-YB interaction. DNA chips were used to screen for altered expression of genes in cells in which Dysbindin or NF-YB was down regulated, while Chromatin IP and Reporter assays were used to confirm the involvement of these genes in transcription of Myristoylated alanine-rich protein kinase C substrate (MARCKS). The sdy mutant mice with a deletion in Dysbindin, which exhibit behavioral abnormalities, and wild-type DBA2J mice were used to investigate MARCKS expression.
We revealed an interaction between Dysbindin and NF-YB. DNA chips showed that MARCKS expression was increased in both Dysbindin knockdown cells and NF-YB knockdown cells, and Chromatin IP revealed interaction of these proteins at the MARCKS promoter region. Reporter assay results suggested functional involvement of the interaction between Dysbindin and NF-YB in MARCKS transcription levels, via the CCAAT motif which is a NF-YB binding sequence. MARCKS expression was increased in sdy mutant mice when compared to wild-type mice.
These findings suggest that abnormal expression of MARCKS via dysfunction of Dysbindin might cause impairment of neural transmission and abnormal synaptogenesis. Our results should provide new insights into the mechanisms of neuronal development and the pathogenesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
169Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Apr 153B: 766-74
PMID19859905
TitleMutation screening of the DTNBP1 exonic sequence in 669 schizophrenics and 710 controls using high-resolution melting analysis.
AbstractA large number of independent studies have reported evidence for association between the dysbindin gene (DTNBP1) and schizophrenia; however, specific risk alleles have been not been implicated as causal. In this study we set out to perform a comprehensive assessment of DNA variation within the exonic sequence of DTNBP1. To achieve this we optimized a high-resolution melting analysis (HRMA) protocol and applied it to screen all 11 DTNBP1 exons for DNA variants in a sample of 669 cases and 710 controls from the UK. Despite identifying seven exonic variants with a minor allele frequency (MAF) >0.01, none was significantly associated with schizophrenia (minimum P = 0.054), showing that the strong association we previously reported in this sample is not the result of association to a common functional variant located within the exonic sequence of any of the three major DTNBP1 transcripts. We also sought additional support for DTNBP1 as a susceptibility gene for schizophrenia by testing the hypothesis that rare exonic highly penetrant variants exist at the DTNBP1 locus. Our analysis failed to identify an enrichment of rare functional variants in the patients compared to the controls. Taken as a whole, this data demonstrate that if DTNBP1 is a risk gene for schizophrenia then risk is not conferred by mutations that affect the structure of the dysbindin protein.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
170Neurosci. Lett. 2010 Feb 470: 134-8
PMID20045719
TitleDysfunction of dopamine release in the prefrontal cortex of dysbindin deficient sandy mice: an in vivo microdialysis study.
AbstractDystrobrevin binding protein-1 gene (DTNBP1), which encodes dysbindin protein, has been identified as a schizophrenia susceptibility gene. Dysbindin has been shown to contribute to the regulation of exocytosis and formation of synaptic vesicles. Although hypofrontality in schizophrenia underlies its pathophysiology, the molecular function of dysbindin in synaptic neurotransmission remains unclear. In the present study, we investigated depolarization-evoked dopamine (DA) and serotonin (5-HT) release in the prefrontal cortex (PFC) of sandy (sdy) mice, which have a deletion mutation in the gene encoding DTNBP1. In vivo microdialysis analysis revealed that extracellular DA levels in the PFC of wild-type mice were increased by 60mM KCl stimulation, and the KCl-evoked DA release was significantly decreased in sdy mice compared with wild-type mice. Extracellular 5-HT levels in the PFC of wild-type mice were also increased by 60mM KCl stimulation. The KCl-evoked 5-HT release did not differ between wild-type and sdy mice. There was no difference in basal levels of DA and 5-HT before the stimulation between two groups. Behavioral sensitization after repeated methamphetamine (METH) treatment was significantly reduced in sdy mice compared with wild-type mice whereas no difference was observed in METH-induced hyperlocomotion between two groups. These results suggest that dysbindin may have a role in the regulation of depolarization-evoked DA release in the PFC and in the development of behavioral sensitization induced by repeated METH treatment.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
171Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Jan 153B: 323-31
PMID19475563
TitleAssociation analysis of the PIP4K2A gene on chromosome 10p12 and schizophrenia in the Irish study of high density schizophrenia families (ISHDSF) and the Irish case-control study of schizophrenia (ICCSS).
AbstractMolecular studies support pharmacological evidence that phosphoinositide signaling is perturbed in schizophrenia and bipolar disorder. The phosphatidylinositol-4-phosphate-5-kinase type-II alpha (PIP4K2A) gene is located on chromosome 10p12. This region has been implicated in both diseases by linkage, and PIP4K2A directly by association. Given linkage evidence in the Irish Study of High Density schizophrenia Families (ISHDSF) to a region including 10p12, we performed an association study between genetic variants at PIP4K2A and disease. No association was detected through single-marker or haplotype analysis of the whole sample. However, stratification into families positive and negative for the ISHDSF schizophrenia high-risk haplotype (HRH) in the DTNBP1 gene and re-analysis for linkage showed reduced amplitude of the 10p12 linkage peak in the DTNBP1 HRH positive families. Association analysis of the stratified sample showed a trend toward association of PIP4K2A SNPs rs1417374 and rs1409395 with schizophrenia in the DTNBP1 HRH positive families. Despite this apparent paradox, our data may therefore suggest involvement of PIP4K2A in schizophrenia in those families for whom genetic variation in DTNBP1 appears also to be a risk factor. This trend appears to arise from under-transmission of common alleles to female cases. Follow-up association analysis in a large Irish schizophrenia case-control sample (ICCSS) showed significant association with disease of a haplotype comprising these same SNPs rs1417374-rs1409395, again more so in affected females, and in cases with negative family history of the disease. This study supports a minor role for PIP4K2A in schizophrenia etiology in the Irish population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
172Hum Brain Mapp 2010 Feb 31: 266-75
PMID19650139
TitleImpact of schizophrenia-risk gene dysbindin 1 on brain activation in bilateral middle frontal gyrus during a working memory task in healthy individuals.
AbstractWorking memory (WM) dysfunction is a hallmark feature of schizophrenia. Functional imaging studies using WM tasks have documented both prefrontal hypo- and hyperactivation in schizophrenia. schizophrenia is highly heritable, and it is unclear which susceptibility genes modulate WM and its neural correlates. A strong linkage between genetic variants in the dysbindin 1 gene and schizophrenia has been demonstrated. The aim of this study was to investigate the influence of the DTNBP1 schizophrenia susceptibility gene on WM and its neural correlates in healthy individuals. Fifty-seven right-handed, healthy male volunteers genotyped for DTNBP1 SNP rs1018381 status were divided in heterozygous risk-allele carriers (T/C) and homozygous noncarriers (C/C). WM was assessed by a 2-back vs. 0-back version of the Continuous Performance Test (CPT), while brain activation was measured with fMRI. DTNBP1 SNP rs1018381 carrier status was determined and correlated with WM performance and brain activation. Despite any differences in behavioral performance, risk-allele carriers exhibited significantly increased activation of the bilateral middle frontal gyrus (BA 9), a part of the dorsolateral prefrontal cortex (DLPFC), compared to noncarriers. This difference did not correlate with WM performance. The fMRI data provide evidence for an influence of genetic variation in DTNBP1 gene region tagged by SNP rs1018381 on bilateral middle frontal gyrus activation during a WM task. The increased activation in these brain areas may be a consequence of "inefficient" or compensatory DLPFC cognitive control functions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
173Neuropsychobiology 2010 -1 62: 245-9
PMID20829635
TitleNo influence of DTNBP1 polymorphisms on the response to aripiprazole.
AbstractThe aim of the present study was to investigate possible influences of a panel of markers in the dysbindin gene DTNBP1 (rs3213207, rs1011313, rs2005976, rs760761 and rs2619522) on the clinical outcome and side effects associated to the treatment with aripiprazole in schizophrenic patients.
Efficacy was assessed at baseline and weeks 1, 2, 4, 6 and 8 using the Clinical Global Impression Severity and Improvement Scales, the Brief Psychiatric Rating Scale and the Schedule for the Assessment of Negative Symptoms. Side effects were evaluated by the Simpson-Angus, Barnes Akathisia and Abnormal Involuntary Movement Scales. Multivariate analysis of covariance was used to test possible influences of single nucleotide polymorphisms on clinical and safety scores. Analysis of haplotypes was also performed.
No relevant association between DTNBP1 variants and clinical or safety scores was observed. Additionally, haplotype analysis did not reveal any significant association with clinical and safety scores at any time as well.
Our data suggest no association between the investigated alleles and genotypes in DTNBP1 and the response to aripiprazole. However, because several limitations characterize the present study, further investigations are required.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
174Genes Brain Behav. 2010 Jul 9: 489-97
PMID20180862
TitleDTNBP1 (dysbindin) gene variants modulate prefrontal brain function in schizophrenic patients--support for the glutamate hypothesis of schizophrenias.
AbstractDysbindin (DTNBP1) is a recently characterized protein that seems to be involved in the modulation of glutamatergic neurotransmission in the human brain, thereby influencing prefrontal cortex function and associated cognitive processes. While association, neuroanatomical and cellular studies indicate that DTNBP1 might be one of several susceptibility genes for schizophrenia, the effect of dysbindin on prefrontal brain function at an underlying neurophysiological level has not yet been explored for these patients. The NoGo-anteriorization (NGA) is a topographical event-related potential measure, which has been established as a valid neurophysiological marker of prefrontal brain function. In the present study, we investigated the influence of seven dysbindin gene variants on the NGA in a group of 44 schizophrenic patients. In line with our a priori hypothesis, one DTNBP1 polymorphism previously linked to schizophrenia (rs2619528) was found to be associated with changes in the NGA; however, the direction of this association directly contrasts with our previous findings in a healthy control sample. This differential impact of DTNBP1 gene variation on prefrontal functioning in schizophrenic patients vs. healthy controls is discussed in terms of abnormal glutamatergic baseline levels in patients suffering from schizophrenic illnesses. This is the first report on a role of DTNBP1 gene variation for prefrontal functioning at a basic neurophysiological level in schizophrenic patients. An impact on fundamental processes of cognitive response control may be one mechanism by which DTNBP1 gene variants via glutamatergic transmission contribute to the pathophysiology underlying schizophrenic illnesses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
175Neuroimage 2010 Jan 49: 817-22
PMID19631276
TitleDysbindin modulates brain function during visual processing in children.
Abstractschizophrenia is a neurodevelopmental disorder, and risk genes are thought to act through disruption of brain development. Several genetic studies have identified dystrobrevin binding protein 1 (DTNBP1, also known as dysbindin) as a potential susceptibility gene for schizophrenia, but its impact on brain function is poorly understood. It has been proposed that DTNBP1 may be associated with differences in visual processing. To test this, we examined the impact on visual processing in 61 healthy children aged 10-12 years of a genetic variant in DTNBP1 (rs2619538) that was common to all schizophrenia associated haplotypes in an earlier UK-Irish study. We tested the hypothesis that carriers of the risk allele would show altered occipital cortical function relative to noncarriers. Functional Magnetic Resonance Imaging (fMRI) was used to measure brain responses during a visual matching task. The data were analysed using statistical parametric mapping and statistical inferences were made at p<0.05 (corrected for multiple comparisons). Relative to noncarriers, carriers of the risk allele had greater activation in the lingual, fusiform gyrus and inferior occipital gyri. In these regions DTNBP1 genotype accounted for 19%, 20% and 14% of the inter-individual variance, respectively. Our results suggest that that genetic variation in DTNBP1 is associated with differences in the function of brain areas that mediate visual processing, and that these effects are evident in young children. These findings are consistent with the notion that the DTNBP1 gene influences brain development and can thereby modulate vulnerability to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
176Hum Brain Mapp 2010 Feb 31: 203-9
PMID19621369
TitleThe impact of dystrobrevin-binding protein 1 (DTNBP1) on neural correlates of episodic memory encoding and retrieval.
AbstractEpisodic memory impairment is a frequently reported symptom in schizophrenia. It has been shown to be associated with reduced neural activity of the hippocampus and prefrontal cortex. Given the high heritability of schizophrenia the question arises if alterations in brain activity are modulated by susceptibility genes and might be detectable in healthy risk allele carriers. The present study investigated the effect of the single nucleotide polymorphism (SNP) rs1018381 (P1578) of the dystrobrevin-binding protein 1 (DTNBP1) on brain activity in 84 healthy subjects assessed by functional magnetic resonance imaging (fMRI) while they performed an episodic memory task comprising encoding and retrieval of faces. During encoding, the group of risk allele carriers (n = 29) showed enhanced neural activity in the left middle frontal gyrus (BA 11) and bilaterally in the cuneus (BA 17, 7) when compared with the nonrisk carrier group (n = 55). During retrieval, the risk group (compared to the non risk group) showed increased right hemispheric neural activity comprising the medial frontal gyrus (BA 9), inferior frontal gyrus (BA 9), and inferior parietal lobule (BA 40). Since there were no behavioral performance differences, increased neural activity of the risk group might be interpreted as a correlate of higher effort or differing cognitive strategies in order to compensate for a genetically determined slight cognitive deficit. Interestingly, the laterality of increased prefrontal activity is in accordance with the well known hemispheric encoding/retrieval asymmetry (HERA) model of episodic memory.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
177World J. Biol. Psychiatry 2010 Mar 11: 431-8
PMID19353385
TitleA genetic variation in the dysbindin gene (DTNBP1) is associated with memory performance in healthy controls.
Abstractschizophrenia is a common psychiatric disorder characterized by disturbances of cognition, emotion and social functioning. There are few studies investigating a possible genetic basis for the underlying mechanism of cognitive dysfunctions. A genetic variation in the dysbindin gene (DTNBP1: dystrobrevin binding protein 1), a susceptibility gene for schizophrenia, has been reported to be associated with general cognitive ability and cognitive decline in patients with schizophrenia. Although profound disturbances of memory performance are observed in schizophrenia, only one study has reported a relationship between this gene and spatial working memory in a Caucasian population. We examined a possible association between a protective haplotype of DTNBP1 for developing schizophrenia and memory performance measured by the Wechsler Memory Scale-Revised (WMS-R) and the Wechsler Adult Intelligence Scale-Revised (WAIS-R) in 165 healthy volunteers and 70 patients with schizophrenia in a Japanese population. Healthy controls that carry the protective haplotype showed higher performance in several memory domains measured by the WMS-R than those who did not. Genotype effect on memory performance was not observed in patients with schizophrenia. This haplotype did not affect IQ and its sub-scores as measured by the Wechsler Adult Intelligence Scale-Revised in both groups. These data suggest that DTNBP1 may have impact on parts of memory functions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
178Hum. Mol. Genet. 2010 Mar 19: 861-78
PMID20015953
TitleGenetic modifiers of abnormal organelle biogenesis in a Drosophila model of BLOC-1 deficiency.
AbstractBiogenesis of lysosome-related organelles complex 1 (BLOC-1) is a protein complex formed by the products of eight distinct genes. Loss-of-function mutations in two of these genes, DTNBP1 and BLOC1S3, cause Hermansky-Pudlak syndrome, a human disorder characterized by defective biogenesis of lysosome-related organelles. In addition, haplotype variants within the same two genes have been postulated to increase the risk of developing schizophrenia. However, the molecular function of BLOC-1 remains unknown. Here, we have generated a fly model of BLOC-1 deficiency. Mutant flies lacking the conserved Blos1 subunit displayed eye pigmentation defects due to abnormal pigment granules, which are lysosome-related organelles, as well as abnormal glutamatergic transmission and behavior. Epistatic analyses revealed that BLOC-1 function in pigment granule biogenesis requires the activities of BLOC-2 and a putative Rab guanine-nucleotide-exchange factor named Claret. The eye pigmentation phenotype was modified by misexpression of proteins involved in intracellular protein trafficking; in particular, the phenotype was partially ameliorated by Rab11 and strongly enhanced by the clathrin-disassembly factor, Auxilin. These observations validate Drosophila melanogaster as a powerful model for the study of BLOC-1 function and its interactions with modifier genes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
179Mol. Psychiatry 2010 Feb 15: 115, 204-15
PMID19546860
TitleThe dysbindin-containing complex (BLOC-1) in brain: developmental regulation, interaction with SNARE proteins and role in neurite outgrowth.
AbstractPrevious studies have implicated DTNBP1 as a schizophrenia susceptibility gene and its encoded protein, dysbindin, as a potential regulator of synaptic vesicle physiology. In this study, we found that endogenous levels of the dysbindin protein in the mouse brain are developmentally regulated, with higher levels observed during embryonic and early postnatal ages than in young adulthood. We obtained biochemical evidence indicating that the bulk of dysbindin from brain exists as a stable component of biogenesis of lysosome-related organelles complex-1 (BLOC-1), a multi-subunit protein complex involved in intracellular membrane trafficking and organelle biogenesis. Selective biochemical interaction between brain BLOC-1 and a few members of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) superfamily of proteins that control membrane fusion, including SNAP-25 and syntaxin 13, was demonstrated. Furthermore, primary hippocampal neurons deficient in BLOC-1 displayed neurite outgrowth defects. Taken together, these observations suggest a novel role for the dysbindin-containing complex, BLOC-1, in neurodevelopment, and provide a framework for considering potential effects of allelic variants in DTNBP1--or in other genes encoding BLOC-1 subunits--in the context of the developmental model of schizophrenia pathogenesis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
180Genes Brain Behav. 2010 Jul 9: 489-97
PMID20180862
TitleDTNBP1 (dysbindin) gene variants modulate prefrontal brain function in schizophrenic patients--support for the glutamate hypothesis of schizophrenias.
AbstractDysbindin (DTNBP1) is a recently characterized protein that seems to be involved in the modulation of glutamatergic neurotransmission in the human brain, thereby influencing prefrontal cortex function and associated cognitive processes. While association, neuroanatomical and cellular studies indicate that DTNBP1 might be one of several susceptibility genes for schizophrenia, the effect of dysbindin on prefrontal brain function at an underlying neurophysiological level has not yet been explored for these patients. The NoGo-anteriorization (NGA) is a topographical event-related potential measure, which has been established as a valid neurophysiological marker of prefrontal brain function. In the present study, we investigated the influence of seven dysbindin gene variants on the NGA in a group of 44 schizophrenic patients. In line with our a priori hypothesis, one DTNBP1 polymorphism previously linked to schizophrenia (rs2619528) was found to be associated with changes in the NGA; however, the direction of this association directly contrasts with our previous findings in a healthy control sample. This differential impact of DTNBP1 gene variation on prefrontal functioning in schizophrenic patients vs. healthy controls is discussed in terms of abnormal glutamatergic baseline levels in patients suffering from schizophrenic illnesses. This is the first report on a role of DTNBP1 gene variation for prefrontal functioning at a basic neurophysiological level in schizophrenic patients. An impact on fundamental processes of cognitive response control may be one mechanism by which DTNBP1 gene variants via glutamatergic transmission contribute to the pathophysiology underlying schizophrenic illnesses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
181Biol. Psychiatry 2010 Dec 68: 1126-33
PMID21130223
TitleMeta-analysis of genetic variation in DTNBP1 and general cognitive ability.
AbstractThe human dystrobrevin binding protein 1 (DTNBP1) gene has been linked to risk for schizophrenia. Recent studies indicate that several single nucleotide polymorphisms (SNPs) in the DTNBP1 gene may also influence general cognitive ability in both schizophrenic patients and healthy control subjects. We examined the relationship between DTNBP1 SNPs and general cognitive ability in nonpsychiatric healthy samples via meta-analysis.
MEDLINE search (12/31/09) yielded 11 articles examining DTNBP1 variation and general cognitive ability, of which 8 studies had data available encompassing 10 independent cohorts (total n = 7592). The phenotype was defined as either the first principal component score from multiple neuropsychological tests (Spearman's g) or full-scale IQ. Meta-analyses were conducted for nine SNPs for which cognitive data were available from at least three cohorts. For each SNP in each cohort, effect size was computed between major allele homozygotes and minor allele carriers; effect size was then pooled across studies using a random effect model.
Pooled effect sizes from two of the nine SNPs (rs1018381 and rs2619522) were -.123 and -.083, ps < .01, respectively, suggesting that the minor allele carriers of these SNPs had lower cognitive ability scores than the major allele homozygotes. Results remained significant after examining heterogeneity among samples and potential publication biases. Other SNPs did not show significant effects on general cognitive ability.
Genetic variation in DTNBP1 modestly influences general cognitive ability. Further studies are needed to elucidate the biological mechanisms that may account for this relationship.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
182Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Apr 153B: 766-74
PMID19859905
TitleMutation screening of the DTNBP1 exonic sequence in 669 schizophrenics and 710 controls using high-resolution melting analysis.
AbstractA large number of independent studies have reported evidence for association between the dysbindin gene (DTNBP1) and schizophrenia; however, specific risk alleles have been not been implicated as causal. In this study we set out to perform a comprehensive assessment of DNA variation within the exonic sequence of DTNBP1. To achieve this we optimized a high-resolution melting analysis (HRMA) protocol and applied it to screen all 11 DTNBP1 exons for DNA variants in a sample of 669 cases and 710 controls from the UK. Despite identifying seven exonic variants with a minor allele frequency (MAF) >0.01, none was significantly associated with schizophrenia (minimum P = 0.054), showing that the strong association we previously reported in this sample is not the result of association to a common functional variant located within the exonic sequence of any of the three major DTNBP1 transcripts. We also sought additional support for DTNBP1 as a susceptibility gene for schizophrenia by testing the hypothesis that rare exonic highly penetrant variants exist at the DTNBP1 locus. Our analysis failed to identify an enrichment of rare functional variants in the patients compared to the controls. Taken as a whole, this data demonstrate that if DTNBP1 is a risk gene for schizophrenia then risk is not conferred by mutations that affect the structure of the dysbindin protein.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
183Genes Brain Behav. 2010 Jul 9: 489-97
PMID20180862
TitleDTNBP1 (dysbindin) gene variants modulate prefrontal brain function in schizophrenic patients--support for the glutamate hypothesis of schizophrenias.
AbstractDysbindin (DTNBP1) is a recently characterized protein that seems to be involved in the modulation of glutamatergic neurotransmission in the human brain, thereby influencing prefrontal cortex function and associated cognitive processes. While association, neuroanatomical and cellular studies indicate that DTNBP1 might be one of several susceptibility genes for schizophrenia, the effect of dysbindin on prefrontal brain function at an underlying neurophysiological level has not yet been explored for these patients. The NoGo-anteriorization (NGA) is a topographical event-related potential measure, which has been established as a valid neurophysiological marker of prefrontal brain function. In the present study, we investigated the influence of seven dysbindin gene variants on the NGA in a group of 44 schizophrenic patients. In line with our a priori hypothesis, one DTNBP1 polymorphism previously linked to schizophrenia (rs2619528) was found to be associated with changes in the NGA; however, the direction of this association directly contrasts with our previous findings in a healthy control sample. This differential impact of DTNBP1 gene variation on prefrontal functioning in schizophrenic patients vs. healthy controls is discussed in terms of abnormal glutamatergic baseline levels in patients suffering from schizophrenic illnesses. This is the first report on a role of DTNBP1 gene variation for prefrontal functioning at a basic neurophysiological level in schizophrenic patients. An impact on fundamental processes of cognitive response control may be one mechanism by which DTNBP1 gene variants via glutamatergic transmission contribute to the pathophysiology underlying schizophrenic illnesses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
184Neuropsychopharmacol Hung 2011 Dec 13: 205-10
PMID22184188
TitleGenetic predisposition to schizophrenia: what did we learn and what does the future hold?
Abstractschizophrenia 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
185PLoS ONE 2011 -1 6: e18113
PMID21448290
TitleCorrelated alterations in serotonergic and dopaminergic modulations at the hippocampal mossy fiber synapse in mice lacking dysbindin.
AbstractDysbindin-1 (dystrobrevin-binding protein 1, DTNBP1) is one of the promising schizophrenia susceptibility genes. Dysbindin protein is abundantly expressed in synaptic regions of the hippocampus, including the terminal field of the mossy fibers, and this hippocampal expression of dysbindin is strongly reduced in patients with schizophrenia. In the present study, we examined the functional role of dysbindin in hippocampal mossy fiber-CA3 synaptic transmission and its modulation using the sandy mouse, a spontaneous mutant with deletion in the dysbindin gene. Electrophysiological recordings were made in hippocampal slices prepared from adult male sandy mice and their wild-type littermates. Basic properties of the mossy fiber synaptic transmission in the mutant mice were generally normal except for slightly reduced frequency facilitation. Serotonin and dopamine, two major neuromodulators implicated in the pathophysiology of schizophrenia, can potentiate mossy fiber synaptic transmission probably via an increase in cAMP levels. Synaptic potentiation induced by serotonin and dopamine was very variable in magnitude in the mutant mice, with some mice showing prominent enhancement as compared with the wild-type mice. In addition, the magnitude of potentiation induced by these monoamines significantly correlated with each other in the mutant mice, indicating that a subpopulation of sandy mice has marked hypersensitivity to both serotonin and dopamine. While direct activation of the cAMP cascade by forskolin induced robust synaptic potentiation in both wild-type and mutant mice, this forskolin-induced potentaition correlated in magnitude with the serotonin-induced potentiation only in the mutant mice, suggesting a possible change in coupling of receptor activation to downstream signaling. These results suggest that the dysbindin deficiency could be an essential genetic factor that causes synaptic hypersensitivity to dopamine and serotonin. The altered monoaminergic modulation at the mossy fiber synapse could be a candidate pathophysiological basis for impairment of hippocampus-dependent brain functions in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
186Mol. Psychiatry 2011 Nov 16: 1105-16
PMID21502952
TitleDysbindin-1, a schizophrenia-related protein, facilitates neurite outgrowth by promoting the transcriptional activity of p53.
AbstractGenetic 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.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
187Behav Brain Funct 2011 -1 7: 43
PMID21981786
TitleThe genetic validation of heterogeneity in schizophrenia.
Abstractschizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV.
Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p < 0.0005) were selected from DRD2, DRD4, GRIN2B, TPH1, MTHFR, and DTNBP1 (February, 2007). 407 schizophrenia cases and 384 controls participated in this study. To aggregate the vulnerability of the disorder based on the participants' genetic information, we calculated the "risk-index" by adding the number of genetic risk factors.
No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5+/-1.57) was slightly lower than among controls (6.6+/-1.39).
The current work illustrates the difficulty in identifying universal and definitive risk-conferring polymorphisms for schizophrenia. Our employed number of samples was small, so we can not preclude the possibility that some or all of these variants are minor risk factors for schizophrenia in the Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
188Nihon Shinkei Seishin Yakurigaku Zasshi 2011 Feb 31: 35-40
PMID21409843
Title[Possible relationship of the function of dysbindin-1 with the pathophysiology of schizophrenia].
Abstractschizophrenia is a psychiatric disorder with a prevalence of about 1%. Genetic factors are known to be important in the etiology of schizophrenia and several susceptibility genes have been identified in linkage or association studies. Although the pathophysiology is yet to be determined, unusual neurotransmissions such as dopaminergic and glutamatergic systems have been suggested for the mechanism of schizophrenia symptoms. On the other hand, the concept that schizophrenia is a neurite malformation illness has arisen, based on the observations that DISC1 is involved in neuronal development. The gene for dysbindin-1 (DTNBP1) is situated at chromosome 6, the location of one of the most established linkages to schizophrenia. Interestingly, significant haplotypic associations between DTNBP1 and schizophrenia have been found in several studies in independent populations of schizophrenic cases. In addition, reduction of the gene and the protein of dysbindin-1 have been reported in brains from schizophrenic cases. Hence, genetic variations in DTNBP1 might be a major risk factor for schizophrenia. In the present review, we focus on the function of dysbindin-1 and its potential contributions to the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
189Neuropharmacology 2011 Dec 61: 1345-53
PMID21856316
TitleIncreased expression of dysbindin-1A leads to a selective deficit in NMDA receptor signaling in the hippocampus.
AbstractThe effects of the major schizophrenia susceptibility gene disease DTNBP1 on disease risk are likely to be mediated through changes in expression level of the gene product, dysbindin-1. How such changes might influence pathogenesis is, however, unclear. One possible mechanism is suggested by recent work establishing a link between altered dysbindin-1 expression and changes in surface levels of N-methyl-d-aspartate receptors (NMDAR), although neither the precise nature of this relationship, nor the mechanism underlying it, are understood. Using organotypic slices of rat hippocampus, we show that increased expression of dysbindin-1A in pyramidal neurons causes a severe and selective hypofunction of NMDARs and blocks induction of LTP. Cell surface, but not cytoplasmic, expression of the NR1 subunit of the NMDAR is decreased, suggesting dysregulation of NMDAR trafficking and, consistent with this, pharmacological inhibition of clathrin-dependent endocytosis is sufficient to reverse the deficit in NMDAR signaling. These results support the idea that the level of the NMDAR at the plasma membrane is modulated by changes in dysbindin-1 expression and offer further insight into the role of dysbindin-1 at an important cellular pathway implicated in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
190Mol. Neurobiol. 2011 Aug 44: 53-64
PMID21520000
TitleCell biology of the BLOC-1 complex subunit dysbindin, a schizophrenia susceptibility gene.
AbstractThere is growing interest in the biology of dysbindin and its genetic locus (DTNBP1) due to genetic variants associated with an increased risk of schizophrenia. Reduced levels of dysbindin mRNA and protein in the hippocampal formation of schizophrenia patients further support involvement of this locus in disease risk. Here, we discuss phylogenetically conserved dysbindin molecular interactions that define its contribution to the assembly of the biogenesis of lysosome-related organelles complex-1 (BLOC-1). We explore fundamental cellular processes where dysbindin and the dysbindin-containing BLOC-1 complex are implicated. We propose that cellular, tissue, and system neurological phenotypes from dysbindin deficiencies in model genetic organisms, and likely individuals affected with schizophrenia, emerge from abnormalities in few core cellular mechanisms controlled by BLOC-1-dysbindin-containing complex rather than from defects in dysbindin itself.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
191Proc. Natl. Acad. Sci. U.S.A. 2011 Oct 108: E962-70
PMID21969553
TitleDysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia.
AbstractDTNBP1 (dystrobrevin binding protein 1) is a leading candidate susceptibility gene in schizophrenia and is associated with working memory capacity in normal subjects. In schizophrenia, the encoded protein dystrobrevin-binding protein 1 (dysbindin-1) is often reduced in excitatory cortical limbic synapses. We found that reduced dysbindin-1 in mice yielded deficits in auditory-evoked response adaptation, prepulse inhibition of startle, and evoked ?-activity, similar to patterns in schizophrenia. In contrast to the role of dysbindin-1 in glutamatergic transmission, ?-band abnormalities in schizophrenia are most often attributed to disrupted inhibition and reductions in parvalbumin-positive interneuron (PV cell) activity. To determine the mechanism underlying electrophysiological deficits related to reduced dysbindin-1 and the potential role of PV cells, we examined PV cell immunoreactivity and measured changes in net circuit activity using voltage-sensitive dye imaging. The dominant circuit impact of reduced dysbindin-1 was impaired inhibition, and PV cell immunoreactivity was reduced. Thus, this model provides a link between a validated candidate gene and an auditory endophenotypes. Furthermore, these data implicate reduced fast-phasic inhibition as a common underlying mechanism of schizophrenia-associated intermediate phenotypes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
192PLoS ONE 2011 -1 6: e16886
PMID21390302
TitleSynaptic dysbindin-1 reductions in schizophrenia occur in an isoform-specific manner indicating their subsynaptic location.
AbstractAn increasing number of studies report associations between variation in DTNBP1, a top candidate gene in schizophrenia, and both the clinical symptoms of the disorder and its cognitive deficits. DTNBP1 encodes dysbindin-1, reduced levels of which have been found in synaptic fields of schizophrenia cases. This study determined whether such synaptic reductions are isoform-specific.
Using Western blotting of tissue fractions, we first determined the synaptic localization of the three major dysbindin-1 isoforms (A, B, and C). All three were concentrated in synaptosomes of multiple brain areas, including auditory association cortices in the posterior half of the superior temporal gyrus (pSTG) and the hippocampal formation (HF). Tests on the subsynaptic tissue fractions revealed that each isoform is predominantly, if not exclusively, associated with synaptic vesicles (dysbindin-1B) or with postsynaptic densities (dysbindin-1A and -1C). Using Western blotting on pSTG (n?=?15) and HF (n?=?15) synaptosomal fractions from schizophrenia cases and their matched controls, we discovered that synaptic dysbindin-1 is reduced in an isoform-specific manner in schizophrenia without changes in levels of synaptophysin or PSD-95. In pSTG, about 92% of the schizophrenia cases displayed synaptic dysbindin-1A reductions averaging 48% (p?=?0.0007) without alterations in other dysbindin-1 isoforms. In the HF, by contrast, schizophrenia cases displayed normal levels of synaptic dysbindin-1A, but 67% showed synaptic reductions in dysbindin-1B averaging 33% (p?=?0.0256), while 80% showed synaptic reductions in dysbindin-1C averaging 35% (p?=?0.0171).
Given the distinctive subsynaptic localization of dysbindin-1A, -1B, and -1C across brain regions, the observed pSTG reductions in dysbindin-1A are postsynaptic and may promote dendritic spine loss with consequent disruption of auditory information processing, while the noted HF reductions in dysbindin-1B and -1C are both presynaptic and postsynaptic and could promote deficits in spatial working memory.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
193J Child Psychol Psychiatry 2011 Dec 52: 1287-94
PMID21639861
TitleEffects of DTNBP1 genotype on brain development in children.
Abstractschizophrenia is a neurodevelopmental disorder, and risk genes are thought to act through disruption of brain development. Several genetic studies have identified dystrobrevin-binding protein 1 (DTNBP1, also known as dysbindin) as a potential susceptibility gene for schizophrenia, but its impact on brain development is poorly understood. The present investigation examined for the first time the effects of DTNBP1 on brain structure in children. Our hypothesis was that a genetic variation in DTNBP1 (i.e., the single nucleotide polymorphism rs2619538) would be associated with differences in both gray and white matter brain regions previously implicated in schizophrenia.
Magnetic resonance imaging and voxel-based morphometry were used to examine brain structure in 52 male children aged between 10 and 12 years. Statistical inferences on the effects of DTNBP1 genotype on gray and white matter volume (GMV and WMV) were made at p < .05 after family-wise error correction for multiple comparisons across the whole brain.
Individuals homozygous for the schizophrenia high-risk allele (AA) compared with those homozygous for the low-risk allele (TT) expressed reduced GMV in the left anterior cingulate gyrus and reduced WMV in the left medial frontal area.
Our results suggest that genetic variation in DTNBP1 is associated with differences in gray and white matter; and that these effects are already evident in children as young as 10-12 years. These findings are consistent with the notion that the DTNBP1 genotype influences brain development and may thereby modulate vulnerability to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
194J Psychiatr Res 2011 May 45: 588-95
PMID20951386
TitleDysbindin (DTNBP1)--a role in psychotic depression?
AbstractPrevious studies yielded evidence for dysbindin (DTNBP1) to impact the pathogenesis of schizophrenia on the one hand and affective disorders such as bipolar or major depressive disorder (MDD) on the other. Thus, in the present study we investigated whether DTNBP1 variation was associated with psychotic depression as a severe clinical manifestation of MDD possibly constituting an overlapping phenotype between affective disorders and schizophrenia. A sample of 243 Caucasian inpatients with MDD (SCID-I) was genotyped for 12 SNPs spanning 92% of the DTNBP1 gene region. Differences in DTNBP1 genotype distributions across diagnostic subgroups of psychotic (N = 131) vs. non-psychotic depression were estimated by Pearson Chi(2) test and logistic regression analyses adjusted for age, gender, Beck Depression Inventory (BDI) and the Global Assessment of Functioning Scale (GAF). Overall, patients with psychotic depression presented with higher BDI and lower GAF scores expressing a higher severity of the illness as compared to depressed patients without psychotic features. Four DTNBP1 SNPs, particularly rs1997679 and rs9370822, and the corresponding haplotypes, respectively, were found to be significantly associated with the risk of psychotic depression in an allele-dose fashion. In summary, the present results provide preliminary support for dysbindin (DTNBP1) gene variation, particularly SNPs rs1997679 and rs9370822, to be associated with the clinical phenotype of psychotic depression suggesting a possible neurobiological mechanism for an intermediate trait on the continuum between affective disorders and schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
195ASN Neuro 2011 -1 3: -1
PMID21504412
TitleDysbindin-containing complexes and their proposed functions in brain: from zero to (too) many in a decade.
AbstractDysbindin (also known as dysbindin-1 or dystrobrevin-binding protein 1) was identified 10 years ago as a ubiquitously expressed protein of unknown function. In the following years, the protein and its encoding gene, DTNBP1, have become the focus of intensive research owing to genetic and histopathological evidence suggesting a potential role in the pathogenesis of schizophrenia. In this review, we discuss published results demonstrating that dysbindin function is required for normal physiology of the mammalian central nervous system. In tissues other than brain and in non-neuronal cell types, the protein has been characterized as a stable component of a multi-subunit complex, named BLOC-1 (biogenesis of lysosome-related organelles complex-1), which has been implicated in intracellular protein trafficking and the biogenesis of specialized organelles of the endosomal-lysosomal system. In the brain, however, dysbindin has been proposed to associate into multiple complexes with alternative binding partners, and to play a surprisingly wide variety of functions including transcriptional regulation, neurite and dendritic spine formation, synaptic vesicle biogenesis and exocytosis, and trafficking of glutamate and dopamine receptors. This puzzling array of molecular and functional properties ascribed to the dysbindin protein from brain underscores the need of further research aimed at ascertaining its biological significance in health and disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
196Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Apr 156B: 322-33
PMID21305691
TitleDysbindin-1 gene contributes differentially to early- and adult-onset forms of functional psychosis.
AbstractDysbindin-1 is a relatively ubiquitous protein in the brain which is involved in the modulation of synaptic homeostasis. The dysbindin-1 gene (DTNBP1) has been associated with schizophrenia and bipolar disorder diagnoses. However, its contribution to the severity of the clinical and neurocognitive expression of these disorders remains controversial. We aimed to explore the association between DTNBP1 and the phenotypes which are more directly linked with the underlying biology, such as age at onset and neurocognitive impairment. The present family sample comprised 894 Caucasian individuals: 268 patients affected by functional psychosis [58% with illness onset before 18 years, mean age at onset (SD): 14.71 (2.10)], 483 parents and 143 siblings. Ten DTNBP1 single nucleotide polymorphisms were genotyped in all individuals and their transmission disequilibrium was tested in relation to: (i) the risk for psychosis; (ii) patients' age at onset; and (iii) familial neurocognitive performance (including IQ estimation and executive functioning). In early-onset families a 5-marker haplotype encompassing exons 2-4 and the surrounding introns was significantly over-transmitted to cases, while in adult-onset families two haplotypes corresponding to the region between introns 4 and 7 were over-transmitted to cases. Estimated IQ was associated with the rs760666 marker in the whole sample, whereas a significant association between executive functioning and the rs2619522 marker appeared in early-onset families. Our findings confirm the role of the dysbindin-1 gene in the risk for functional psychosis and show a differential haplotypic risk pattern in families with early as opposed to adult onset in the affected offspring.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
197Mol. Psychiatry 2011 Feb 16: 145-55
PMID20010894
TitleDysbindin-1 genotype effects on emotional working memory.
AbstractWe combined functional imaging and genetics to investigate the behavioral and neural effects of a dysbindin-1 (DTNBP1) genotype associated with the expression level of this important synaptic protein, which has been implicated in schizophrenia. On a working memory (WM) task for emotional faces, participants with the genotype related to increased expression showed higher WM capacity for happy faces compared with the genotype related to lower expression. Activity in several task-related brain areas with known DTNBP1 expression was increased, including hippocampal, temporal and frontal cortex. Although these increases occurred across emotions, they were mostly observed in areas whose activity correlated with performance for happy faces. This suggests effects of variability in DTNBP1 on emotion-specific WM capacity and region-specific task-related brain activation in humans. Synaptic effects of DTNBP1 implicate that altered dopaminergic and/or glutamatergic neurotransmission may be related to the increased WM capacity. The combination of imaging and genetics thus allows us to bridge the gap between the cellular/molecular and systems/behavioral level and extend the cognitive neuroscience approach to a comprehensive biology of cognition.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
198Mol. Psychiatry 2011 Nov 16: 1117-29
PMID20838396
TitleGWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia.
AbstractWe conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ?0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3?828?611-rs10043986, r(2)=0.008; rs10043986-rs4704591, r(2)=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11?380 cases and 15?021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 10(-4) and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 10(-4)). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
199Nihon Shinkei Seishin Yakurigaku Zasshi 2011 Feb 31: 35-40
PMID21409843
Title[Possible relationship of the function of dysbindin-1 with the pathophysiology of schizophrenia].
Abstractschizophrenia is a psychiatric disorder with a prevalence of about 1%. Genetic factors are known to be important in the etiology of schizophrenia and several susceptibility genes have been identified in linkage or association studies. Although the pathophysiology is yet to be determined, unusual neurotransmissions such as dopaminergic and glutamatergic systems have been suggested for the mechanism of schizophrenia symptoms. On the other hand, the concept that schizophrenia is a neurite malformation illness has arisen, based on the observations that DISC1 is involved in neuronal development. The gene for dysbindin-1 (DTNBP1) is situated at chromosome 6, the location of one of the most established linkages to schizophrenia. Interestingly, significant haplotypic associations between DTNBP1 and schizophrenia have been found in several studies in independent populations of schizophrenic cases. In addition, reduction of the gene and the protein of dysbindin-1 have been reported in brains from schizophrenic cases. Hence, genetic variations in DTNBP1 might be a major risk factor for schizophrenia. In the present review, we focus on the function of dysbindin-1 and its potential contributions to the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
200Mol. Psychiatry 2012 Sep 17: 887-905
PMID22584867
TitleConvergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction.
AbstractWe have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
201Psychol Med 2012 Mar 42: 607-16
PMID21854684
TitleHypothesis-driven candidate genes for schizophrenia compared to genome-wide association results.
AbstractCandidate gene studies have been a key approach to the genetics of schizophrenia (SCZ). However, the results of these studies are confusing and no genes have been unequivocally implicated. The hypothesis-driven candidate gene literature can be appraised by comparison with the results of genome-wide association studies (GWAS).
We describe the characteristics of hypothesis-driven candidate gene studies from the SZGene database, and use pathway analysis to compare hypothesis-driven candidate genes with GWAS results from the International schizophrenia Consortium (ISC).
SZGene contained 732 autosomal genes evaluated in 1374 studies. These genes had poor statistical power to detect genetic effects typical for human diseases, assessed only 3.7% of genes in the genome, and had low marker densities per gene. Most genes were assessed once or twice (76.9%), providing minimal ability to evaluate consensus across studies. The ISC studies had 89% power to detect a genetic effect typical for common human diseases and assessed 79% of known autosomal common genetic variation. Pathway analyses did not reveal enrichment of smaller ISC p values in hypothesis-driven candidate genes, nor did a comprehensive evaluation of meta-hypotheses driving candidate gene selection (SCZ as a disease of the synapse or neurodevelopment). The most studied hypothesis-driven candidate genes (COMT, DRD3, DRD2, HTR2A, NRG1, BDNF, DTNBP1 and SLC6A4) had no notable ISC results.
We did not find support for the idea that the hypothesis-driven candidate genes studied in the literature are enriched for the common genetic variation involved in the etiology of SCZ. Larger samples are required to evaluate this conclusion definitively.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
202Neuropharmacology 2012 Mar 62: 1204-20
PMID21557953
TitleMouse models of genetic effects on cognition: relevance to schizophrenia.
AbstractCognitive dysfunction is a core feature of schizophrenia. Growing evidence indicates that a wide variety of genetic mutations and polymorphisms impact cognition and may thus be implicated in various aspects of this mental disorder. Despite differences between human and rodent brain structure and function, genetic mouse models have contributed critical information about brain mechanisms involved in cognitive processes. Here, we summarize discoveries of genetic modifications in mice that impact cognition. Based on functional hypotheses, gene modifications within five model systems are described: 1) dopamine (D1, D2, D3, D4, D5, DAT, COMT, MAO); 2) glutamate (GluR-A, NR1, NR2A, NR2B, GRM2, GRM3, GLAST); 3) GABA (?(5), ?(2), ?(4), ?GABA(A), GABA(B(1)), GAT1); 4) acetylcholine (nAChR?2, ?7, CHRM1); and 5) calcium (CaMKII-?, neurogranin, CaMKK?, CaMKIV). We also consider other risk-associated genes for schizophrenia such as dysbindin (DTNBP1), neuregulin (NRG1), disrupted-in-schizophrenia1 (DISC1), reelin and proline dehydrogenase (PRODH). Because of the presumed importance of environmental factors, we further consider genetic modifications within the stress-sensitive systems of corticotropin-releasing factor (CRF), brain-derived neurotrophic factor (BDNF) and the endocannabinoid systems. We highlight the missing information and limitations of cognitive assays in genetically modified mice models relevant to schizophrenia pathology.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
203Neuroimage 2012 Aug 62: 120-9
PMID22584233
TitleStructural and functional neuroimaging phenotypes in dysbindin mutant mice.
Abstractschizophrenia is a highly heritable psychiatric disorder that is associated with a number of structural and functional neurophenotypes. DTNBP1, the gene encoding dysbindin-1, is a promising candidate gene for schizophrenia. Use of a mouse model carrying a large genomic deletion exclusively within the dysbindin gene permits a direct investigation of the gene in isolation. Here, we use manganese-enhanced magnetic resonance imaging (MEMRI) to explore the regional alterations in brain structure and function caused by loss of the gene encoding dysbindin-1. We report novel findings that uniquely inform our understanding of the relationship of dysbindin-1 to known schizophrenia phenotypes. First, in mutant mice, analysis of the rate of manganese uptake into the brain over a 24-hour period, putatively indexing basal cellular activity, revealed differences in dopamine rich brain regions, as well as in CA1 and dentate subregions of the hippocampus formation. Finally, novel tensor-based morphometry techniques were applied to the mouse MRI data, providing evidence for structural volume deficits in cortical regions, subiculum and dentate gyrus, and the striatum of dysbindin mutant mice. The affected cortical regions were primarily localized to the sensory cortices in particular the auditory cortex. This work represents the first application of manganese-enhanced small animal imaging to a mouse model of schizophrenia endophenotypes, and a novel combination of functional and structural measures. It revealed both hypothesized and novel structural and functional neural alterations related to dysbindin-1.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
204J. Neurosci. 2012 Mar 32: 3697-711
PMID22423091
TitleQuantitative proteomic and genetic analyses of the schizophrenia susceptibility factor dysbindin identify novel roles of the biogenesis of lysosome-related organelles complex 1.
AbstractThe Biogenesis of Lysosome-Related Organelles Complex 1 (BLOC-1) is a protein complex containing the schizophrenia susceptibility factor dysbindin, which is encoded by the gene DTNBP1. However, mechanisms engaged by dysbindin defining schizophrenia susceptibility pathways have not been quantitatively elucidated. Here, we discovered prevalent and novel cellular roles of the BLOC-1 complex in neuronal cells by performing large-scale Stable Isotopic Labeling of Cells in Culture (SILAC) quantitative proteomics combined with genetic analyses in dysbindin-null mice (Mus musculus) and the genome of schizophrenia patients. We identified 24 proteins that associate with the BLOC-1 complex, many of which were altered in content/distribution in cells or tissues deficient in BLOC-1. New findings include BLOC-1 interactions with the COG complex, a Golgi apparatus tether, and antioxidant enzymes peroxiredoxins 1-2. Importantly, loci encoding eight of the 24 proteins are affected by genomic copy number variation in schizophrenia patients. Thus, our quantitative proteomic studies expand the functional repertoire of the BLOC-1 complex and provide insight into putative molecular pathways of schizophrenia susceptibility.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
205Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Oct 159B: 841-9
PMID22911901
TitleAssociation of genetic variations in DTNBP1 with cognitive function in schizophrenia patients and healthy subjects.
AbstractThe dystrobrevin-binding protein 1 gene (DTNBP1) has been regarded as a susceptibility gene for schizophrenia. Recent studies have investigated its role on cognitive function that is frequently impaired in schizophrenia patients, and generated inconsistent results. The present study was performed to elucidate effects of genetic variations in DTNBP1 on various cognitive domains in both schizophrenia patients and healthy subjects. Comprehensive neuropsychological tests were administered to 122 clinically stable schizophrenia patients and 119 healthy subjects. Based on positive findings reported in previous association studies, six SNPs were selected and genotyped. Compared to healthy subjects, schizophrenia patients showed expected lower performance for all of the cognitive domains. After adjusting for age, gender, and educational level, four SNPs showed a nominally significant association with cognitive domains. The association of rs760761 and rs1018381 with the attention and vigilance domain remained significant after applying the correction for multiple testing (P?DTNBP1 not only in the development of attention deficit of schizophrenia, but also in the inter-individual variability of this cognitive domain within the normal functional range.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
206Acta Neuropsychiatr 2012 Jun 24: 155-9
PMID26953008
TitleAssociation of P1635 and P1655 polymorphisms in dysbindin (DTNBP1) gene with schizophrenia.
Abstractschizophrenia (SCZ) is a severe psychiatric disorder with a lifetime prevalence of approximately 1% in most of the populations studied. SCZ is multifactorial with the contribution of multiple susceptibility genes that could act in conjunction with epigenetic processes and environmental factors. There is some evidence supporting the association between genetic variants in dysbindin (DTNBP1) gene and SCZ in populations. In this study, we investigated the association between polymorphisms P1635 and P1655 in dysbindin gene with SCZ.
Totally, 115 unrelated patients with SCZ and 117 unrelated healthy volunteers were studied. Genomic DNA was extracted from blood. Genotyping was done with the PCR-RFLP method. The allele and genotype associations were analysed with X 2 test. The Benjamini-Hochberg procedure was used to correct p values for multiple comparisons.
The results showed no significant difference between patients and controls in allelic frequencies or genotypic distributions of SNP P1635 (p = 0.809), but a significant difference between the case and control groups for SNP P1655 (p = 0.009) was found. We could also find a significant positive association between A-C haplotype and SCZ (OR = 1.7, 95% CI 1.18-2.42; p = 0.004, p c = 0.02) and a protective effect for A-G haplotype (p = 0.003, OR = 0.57, 95% CI 1.18-2.42; p = 0.003, p c = 0.02).
This study may provide further support for the association between SNP polymorphisms in DTNBP1 and SCZ in the Iranian population. Studies with more markers and subjects for various populations will be necessary to understand the genetic contribution of the gene to the development of SCZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
207Curr Pharm Biotechnol 2012 Jun 13: 1513-21
PMID22283763
TitleDTNBP1 (dysbindin) gene variants: in vivo evidence for effects on hippocampal glutamate status.
AbstractIn linkage and association studies the DTNBP1 gene has been identified as a major susceptibility gene for schizophrenia. Reduced expression of DTNBP1 was found in the hippocampus and prefrontal cortex in post mortem brains of schizophrenic patients. In vitro and animal models provide evidence that the DTNBP1 gene product dysbindin modulates the activity of the neurotransmitter glutamate in hippocampal neurons and is crucial for cell functioning and synaptogenesis. This study is the first to investigate the effects of genetic variants of DTNBP1 on the status of the glutamate system as well as neuronal integrity (N-acetylaspartate, NAA) in the hippocampus and a cortical region, the anterior cingulate cortex (ACC), in humans.
In 79 healthy subjects, the association of single nucleotide polymorphisms (SNPs) rs760665 and rs909706 with absolute concentrations of glutamate and NAA in the left hippocampus and the ACC were investigated, using proton magnetic resonance spectroscopy (MRS) at 3 Tesla and a well established quantification procedure.
Hippocampal glutamate concentration was significantly affected by genotype of rs760665 (F=4.406, df=2,p=0.016) and rs909706 (F=3.171,df=2,p=0.048). For the concentration of NAA, a weak association with rs760665 was observed in the contrast analysis. None of the metabolites measured in the ACC showed a significant connection with either genotype.
The results support a role of DTNBP1 gene variants in the glutamate neurotransmission system in the human brain at least in the hippocampus. This is compatible to growing evidence of a crucial role of glutamate in the pathobiology of schizophrenia. In addition, the weak association between DTNBP1 genotype and NAA is in line with a regulatory influence of dysbindin on synaptogenesis and neuronal survival.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
208Curr Pharm Biotechnol 2012 Jun 13: 1513-21
PMID22283763
TitleDTNBP1 (dysbindin) gene variants: in vivo evidence for effects on hippocampal glutamate status.
AbstractIn linkage and association studies the DTNBP1 gene has been identified as a major susceptibility gene for schizophrenia. Reduced expression of DTNBP1 was found in the hippocampus and prefrontal cortex in post mortem brains of schizophrenic patients. In vitro and animal models provide evidence that the DTNBP1 gene product dysbindin modulates the activity of the neurotransmitter glutamate in hippocampal neurons and is crucial for cell functioning and synaptogenesis. This study is the first to investigate the effects of genetic variants of DTNBP1 on the status of the glutamate system as well as neuronal integrity (N-acetylaspartate, NAA) in the hippocampus and a cortical region, the anterior cingulate cortex (ACC), in humans.
In 79 healthy subjects, the association of single nucleotide polymorphisms (SNPs) rs760665 and rs909706 with absolute concentrations of glutamate and NAA in the left hippocampus and the ACC were investigated, using proton magnetic resonance spectroscopy (MRS) at 3 Tesla and a well established quantification procedure.
Hippocampal glutamate concentration was significantly affected by genotype of rs760665 (F=4.406, df=2,p=0.016) and rs909706 (F=3.171,df=2,p=0.048). For the concentration of NAA, a weak association with rs760665 was observed in the contrast analysis. None of the metabolites measured in the ACC showed a significant connection with either genotype.
The results support a role of DTNBP1 gene variants in the glutamate neurotransmission system in the human brain at least in the hippocampus. This is compatible to growing evidence of a crucial role of glutamate in the pathobiology of schizophrenia. In addition, the weak association between DTNBP1 genotype and NAA is in line with a regulatory influence of dysbindin on synaptogenesis and neuronal survival.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
209Exp. Eye Res. 2013 Nov 116: 1-8
PMID23954924
TitleDevelopmental expression of dysbindin in Muller cells of rat retina.
AbstractDysbindin, the product of the DTNBP1 gene, was identified by yeast two hybrid assay as a binding partner of dystrobrevin, a cytosolic component of the dystrophin protein complex. Although its functional role has not yet been completely elucidated, the finding that dysbindin assembles into the biogenesis of lysosome related organelles complex 1 (BLOC-1) suggests that it participates in intracellular trafficking and biogenesis of organelles and vesicles. Dysbindin is ubiquitous and in brain is expressed primarily in neurons. Variations at the dysbindin gene have been associated with increased risk for schizophrenia. As anomalies in retinal function have been reported in patients suffering from neuropsychiatric disorders, we investigated the expression of dysbindin in the retina. Our results show that differentially regulated dysbindin isoforms are expressed in rat retina during postnatal maturation. Interestingly, we found that dysbindin is mainly localized in Mller cells. The identification of dysbindin in glial cells may open new perspectives for a better understanding of the functional involvement of this protein in visual alterations associated to neuropsychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
210Neuropsychiatr Dis Treat 2013 -1 9: 1573-82
PMID24143106
TitleEvidence for single nucleotide polymorphisms and their association with bipolar disorder.
AbstractBipolar disorder (BD) is a complex disorder with a number of susceptibility genes and environmental risk factors involved in its pathogenesis. In recent years, huge progress has been made in molecular techniques for genetic studies, which have enabled identification of numerous genomic regions and genetic variants implicated in BD across populations. Despite the abundance of genetic findings, the results have often been inconsistent and not replicated for many candidate genes/single nucleotide polymorphisms (SNPs). Therefore, the aim of the review presented here is to summarize the most important data reported so far in candidate gene and genome-wide association studies. Taking into account the abundance of association data, this review focuses on the most extensively studied genes and polymorphisms reported so far for BD to present the most promising genomic regions/SNPs involved in BD. The review of association data reveals evidence for several genes (SLC6A4/5-HTT [serotonin transporter gene], BDNF [brain-derived neurotrophic factor], DAOA [D-amino acid oxidase activator], DTNBP1 [dysbindin], NRG1 [neuregulin 1], DISC1 [disrupted in schizophrenia 1]) to be crucial candidates in BD, whereas numerous genome-wide association studies conducted in BD indicate polymorphisms in two genes (CACNA1C [calcium channel, voltage-dependent, L type, alpha 1C subunit], ANK3 [ankyrin 3]) replicated for association with BD in most of these studies. Nevertheless, further studies focusing on interactions between multiple candidate genes/SNPs, as well as systems biology and pathway analyses are necessary to integrate and improve the way we analyze the currently available association data.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
211Nat. Neurosci. 2013 Nov 16: 1627-36
PMID24121738
TitleAge-dependent regulation of synaptic connections by dopamine D2 receptors.
AbstractDopamine D2 receptors (D2R) are G protein-coupled receptors that modulate synaptic transmission and are important for various brain functions, including learning and working memory. Abnormal D2R signaling has been implicated in psychiatric disorders such as schizophrenia. Here we report a new function of D2R in dendritic spine morphogenesis. Activation of D2R reduced spine number via GluN2B- and cAMP-dependent mechanisms in mice. Notably, this regulation occurred only during adolescence. During this period, D2R overactivation caused by mutations in the schizophrenia risk gene DTNBP1 led to spine deficiency, dysconnectivity in the entorhinal-hippocampal circuit and impairment of spatial working memory. Notably, these defects could be ameliorated by D2R blockers administered during adolescence. Our findings suggest an age-dependent function of D2R in spine development, provide evidence that D2R dysfunction during adolescence impairs neuronal circuits and working memory, and indicate that adolescent interventions to prevent aberrant D2R activity protect against cognitive impairment.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
212Schizophr Bull 2013 Jul 39: 766-75
PMID23512949
TitleClinical and molecular genetics of psychotic depression.
AbstractThis review provides a comprehensive overview of clinical and molecular genetic as well as pharmacogenetic studies regarding the clinical phenotype of "psychotic depression." Results are discussed with regard to the long-standing debate on categorical vs dimensional disease models of affective and psychotic disorders on a continuum from unipolar depression over bipolar disorder and schizoaffective disorder to schizophrenia. Clinical genetic studies suggest a familial aggregation and a considerable heritability (39%) of psychotic depression partly shared with schizoaffective disorder, schizophrenia, and affective disorders. Molecular genetic studies point to potential risk loci of psychotic depression shared with schizoaffective disorder (1q42, 22q11, 19p13), depression, bipolar disorder, and schizophrenia (6p, 8p22, 10p13-12, 10p14, 13q13-14, 13q32, 18p, 22q11-13) and several vulnerability genes possibly contributing to an increased risk of psychotic symptoms in depression (eg, BDNF, DBH, DTNBP1, DRD2, DRD4, GSK-3beta, MAO-A). Pharmacogenetic studies implicate 5-HTT, TPH1, and DTNBP1 gene variation in the mediation of antidepressant treatment response in psychotic depression. Genetic factors are suggested to contribute to the disease risk of psychotic depression in partial overlap with disorders along the affective-psychotic spectrum. Thus, genetic research focusing on psychotic depression might inspire a more dimensional, neurobiologically and symptom-oriented taxonomy of affective and psychotic disorders challenging the dichotomous Kraepelinian view. Additionally, pharmacogenetic studies might aid in the development of a more personalized treatment of psychotic depression with an individually tailored antidepressive/antipsychotic pharmacotherapy according to genotype.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
213Acta Neuropsychiatr 2013 Aug 25: 215-20
PMID25287634
TitleAbnormalities in extracellular glycine and glutamate levels in the striatum of sandy mice.
AbstractGlycine regulates glutamatergic neurotransmission, and several papers have reported the relationship between glycine and schizophrenia. The dysbindin-1 (DTNBP1: dystrobrevin-binding protein 1) gene is related to glutamatergic neurotransmission and has been found to be a strong candidate gene for schizophrenia. In this study, we clarified the relationship between dysbindin, glutamate, and glycine with in vivo microdialysis methods.
We measured extracellular glycine and glutamate levels in the striatum of sandy (sdy) mice using in vivo microdialysis methods. Sdy mice express no dysbindin protein owing to a deletion in the dysbindin-1 gene. In addition, we measured changes in those amino acids after methamphetamine (METH) administration.
The basal levels of extracellular glycine and glutamate in the striatum of sdy mice were elevated. These extracellular glutamate levels decreased gradually after METH administration and were not subsequently different from those of wild-type mice.
These results suggest that dysbindin might modulate glycine and glutamate release in vivo.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
214Schizophr. Res. 2013 May 146: 254-63
PMID23473812
TitlePotential molecular mechanisms for decreased synaptic glutamate release in dysbindin-1 mutant mice.
AbstractBehavioral genetic studies of humans have associated variation in the DTNBP1 gene with schizophrenia and its cognitive deficit phenotypes. The protein encoded by DTNBP1, dysbindin-1, is expressed in forebrain neurons where it interacts with proteins mediating vesicular trafficking and exocytosis. It has been shown that loss of dysbindin-1 results in a decrease in glutamate release in the prefrontal cortex; however the mechanisms underlying this decrease are not fully understood. In order to investigate this question, we evaluated dysbindin-1 null mutant mice, using electrophysiological recordings of prefrontal cortical neurons, imaging studies of vesicles, calcium dynamics and Western blot measures of synaptic proteins and Ca(2+) channels. Dysbindin-1 null mice showed a decrease in the ready releasable pool of synaptic vesicles, decreases in quantal size, decreases in the probability of release and deficits in the rate of endo- and exocytosis compared with wild-type controls. Moreover, the dysbindin-1 null mice show decreases in the [Ca(2+)]i,expression of L- and N-type Ca(2+)channels and several proteins involved in synaptic vesicle trafficking and priming. Our results provide new insights into the mechanisms of action of dysbindin-1.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
215Schizophr Bull 2013 May 39: 518-26
PMID22499782
TitleBrain vs behavior: an effect size comparison of neuroimaging and cognitive studies of genetic risk for schizophrenia.
AbstractGenetic 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 Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
216Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Oct 46: 64-9
PMID23778016
TitleGenetic analysis of common variants in the CMYA5 (cardiomyopathy-associated 5) gene with schizophrenia.
AbstractRecently, CMYA5 was suggested as a susceptibility gene for schizophrenia based on two independent studies utilizing different ethnic samples. We designed a case-control study to examine whether 21 SNPs contained within CMYA5 were associated with the disorder in a western Han Chinese sample comprised of 488 schizophrenia patients and 516 healthy control subjects. The allele distribution of SNPs rs7714250, rs16877135 and rs13158477 showed significant association with schizophrenia (Puncorrected=0.008, Puncorrected=0.04, and Puncorrected=0.009, respectively) as well as the genotype distribution in the Cochran-Armitage trend test (Puncorrected=0.008, Puncorrected=0.037 and Puncorrected=0.011, respectively). After Bonferroni correction, rs7714250 showed a trend of association with schizophrenia both in allele distribution (Pcorrected=0.088) and genotype distribution (Pcorrected=0.088). Furthermore, significant associations were found in several two-, three-, four-, and five-SNP tests of haplotype analyses. Replications of the association of CMYA5 with schizophrenia across various studies suggest that it is very likely a potential common schizophrenia-related gene worldwide. Functional studies correlating CMYA5 with DTNBP1 and PKA warrant further investigation of the molecular basis of this gene in relationship to the signal transduction pathway(s) underlying the pathogenesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
217BMC Med. Genet. 2013 -1 14: 33
PMID23497497
TitleSchizophrenia susceptibility and NMDA-receptor mediated signalling: an association study involving 32 tagSNPs of DAO, DAOA, PPP3CC, and DTNBP1 genes.
AbstractRecent studies supported associations between four NMDA-receptor-mediated signalling genes (D-amino acid oxidase, DAO; D-amino acid oxidase activator, DAOA; protein phosphatase 3 catalytic subunit gamma isoform, PPP3CC; dystrobrevin-binding protein 1, DTNBP1) and schizophrenia susceptibility, even though with contrasting results.
In an attempt to replicate these findings for the first time in an Italian population, a panel of 32 tagSNPs was analysed in a representative case-control sample involving 879 subjects.
An association in the allele frequency was observed for the estimated PPP3CC CAG triplotype in the SNP window rs4872499 T/C-rs11780915 A/G-rs13271367 G/A (pcorrect = 0.001). Similarly, the clustered genotype frequencies of the estimated/phased CAG triplotype differed between cases and controls (p = 0.004), with the carriers having a higher frequency in the control population (p = 0.002, odd ratio OR = 0.59, 95% confident interval CI: 0.43-0.82).Following the phenotypic dissection strategy, the analysis of single SNPs evidenced a protective effect in males of rs11780915 and rs13271367 in PPP3CC gene (pcorrect = 0.02, pcorrect = 0.04 respectively). Moreover the estimated/phased GT diplotype (rs2070586A/G-rs3741775G/T) carriers of the DAO gene were more highly represented in female controls (p = 0.017, OR = 0.58, 95% CI: 0.37-0.90), as were the estimated/phased CAG triplotype carriers of the PPP3CC gene in females (p = 0.01, OR = 0.53, 95% CI: 0.32-0.87). In addition, we performed an interaction analysis, and a 66% (p = 0.003, OR = 0.34, 95% CI: 0.17-0.70) lower risk of developing schizophrenia for female (CAG + GT) carriers versus non-CAG or -GT carriers was observed. For DTNBP1, we found a protective effect in males for the rs6459409 (pcorrect = 0.02) and the estimated/phased CT diplotype (rs6459409-rs9476886) carriers (p = 3x10-4, OR = 0.46, 95% CI: 0.30-0.70).In relation to diagnostic subtypes, the estimated/phased DAO GT diplotype and PPP3CC CAG triplotype female carriers were found to show relative risk ratio (RRR) values of 0.52 and 0.54 lower risk for a paranoid phenotype respectively.
Although the results are preliminary and needed replication in a larger sample, this study suggests that NMDA receptor-mediated signalling genes (DAO, PPP3CC, DTNBP1) might be involved in schizophrenia pathogenic mechanisms related to gender.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
218Behav. Brain Res. 2013 Mar 241: 173-84
PMID23261874
TitleLoss of dysbindin-1 in mice impairs reward-based operant learning by increasing impulsive and compulsive behavior.
AbstractThe dystrobrevin-binding protein 1 (DTNBP1) gene, which encodes the dysbindin-1 protein, is a potential schizophrenia susceptibility gene. Polymorphisms in the DTNBP1 gene have been associated with altered cognitive abilities. In the present study, dysbindin-1 null mutant (dys-/-), heterozygous (dys+/-), and wild-type (dys+/+) mice, on a C57BL/6J genetic background, were tested in either a match to sample or nonmatch to sample visual discrimination task. This visual discrimination task was designed to measure rule learning and detect any changes in response timing over the course of testing. Dys-/- mice displayed significant learning deficits and required more trials to acquire this task. However, once criterion was reached, there were no differences between the genotypes on any behavioral measures. Dys-/- mice exhibited increased compulsive and impulsive behaviors compared to control littermates suggesting the inability to suppress incorrectly-timed responses underlies their increased time to acquisition. Indeed, group comparisons of behavior differences between the first and last day of testing showed that only dys-/- mice consistently decreased measures of perseverative, premature, timeout, and total responses. These findings illustrate how some aspects of altered cognitive performance in dys-/- mice might be related to increased impulsive and compulsive behaviors, analogous to cognitive deficits in some individuals with psychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
219Eur Arch Psychiatry Clin Neurosci 2013 Feb 263: 53-63
PMID22580710
TitleThe DTNBP1 (dysbindin-1) gene variant rs2619522 is associated with variation of hippocampal and prefrontal grey matter volumes in humans.
AbstractDTNBP1 is one of the most established susceptibility genes for schizophrenia, and hippocampal volume reduction is one of the major neuropathological findings in this severe disorder. Consistent with these findings, the encoded protein dysbindin-1 has been shown to be diminished in glutamatergic hippocampal neurons in schizophrenic patients. The aim of this study was to investigate the effects of two single nucleotide polymorphisms of DTNBP1 on grey matter volumes in human subjects using voxel-based morphometry. Seventy-two subjects were included and genotyped with respect to two single nucleotide polymorphisms of DTNBP1 (rs2619522 and rs1018381). All participants underwent structural magnetic resonance imaging (MRI). MRI data were preprocessed and statistically analysed using standard procedures as implemented in SPM5 (Statistical Parametric Mapping), in particular the voxel-based morphometry (VBM) toolbox. We found significant effects of the DTNBP1 SNP rs2619522 bilaterally in the hippocampus as well as in the anterior middle frontal gyrus and the intraparietal cortex. Carriers of the G allele showed significantly higher grey matter volumes in these brain regions than T/T homozygotes. Compatible with previous findings on a role of dysbindin in hippocampal functions as well as in major psychoses, the present study provides first direct in vivo evidence that the DTNBP1 SNP rs2619522 is associated with variation of grey matter volumes bilaterally in the hippocampus.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
220Zh Nevrol Psikhiatr Im S S Korsakova 2013 -1 113: 54-60
PMID23612411
Title[SNAP-25 and DTNBP1 as candidate genes for cognitive reserve in schizophrenia].
AbstractCognitive reserve (CR) postulates that individual differences in the cognitive processes or neural networks underlying task performance allow some people to cope better than others with brain damage. An aim of the study was to search for candidate genes for CR in schizophrenia. We propose that higher frequencies of low risk alleles is observed in healthy relatives of schizophrenic patients compared to patients and controls and in patients without neurocognitive deficit and with less severity of the disease compared to other patients and controls. Besides, frequencies of these alleles in patients should be similar to those in general population. Authors studied SNAP-25 and DTNBP1 genes. The polymorphism T1065G of SNAP-25 was genotyped in 278 patients with schizophrenia, 126 their relatives and 207 controls and the polymorphism P1763 of DTNBP1 was genotyped in 202 patients, 229 relatives and 262 controls. There was a trend towards the increase in the frequency of an G allele of SNAP-25 in siblings of patients. The frequency of this allele was higher in patients without neurocognitive deficit compared to patients with cognitive deficit (p=0.003) and controls (p=0.002). The allele was associated with index of cognitive functioning in patients (p=0.012) and controls (p=0.006) and with the severity of negative symptoms in patients (p=0.023). At the same time, the polymorphism T1065G was not associated with schizophrenia. Therefore, an allele G may be considered as a marker for higher CR.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
221Eur Arch Psychiatry Clin Neurosci 2013 Feb 263: 53-63
PMID22580710
TitleThe DTNBP1 (dysbindin-1) gene variant rs2619522 is associated with variation of hippocampal and prefrontal grey matter volumes in humans.
AbstractDTNBP1 is one of the most established susceptibility genes for schizophrenia, and hippocampal volume reduction is one of the major neuropathological findings in this severe disorder. Consistent with these findings, the encoded protein dysbindin-1 has been shown to be diminished in glutamatergic hippocampal neurons in schizophrenic patients. The aim of this study was to investigate the effects of two single nucleotide polymorphisms of DTNBP1 on grey matter volumes in human subjects using voxel-based morphometry. Seventy-two subjects were included and genotyped with respect to two single nucleotide polymorphisms of DTNBP1 (rs2619522 and rs1018381). All participants underwent structural magnetic resonance imaging (MRI). MRI data were preprocessed and statistically analysed using standard procedures as implemented in SPM5 (Statistical Parametric Mapping), in particular the voxel-based morphometry (VBM) toolbox. We found significant effects of the DTNBP1 SNP rs2619522 bilaterally in the hippocampus as well as in the anterior middle frontal gyrus and the intraparietal cortex. Carriers of the G allele showed significantly higher grey matter volumes in these brain regions than T/T homozygotes. Compatible with previous findings on a role of dysbindin in hippocampal functions as well as in major psychoses, the present study provides first direct in vivo evidence that the DTNBP1 SNP rs2619522 is associated with variation of grey matter volumes bilaterally in the hippocampus.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
222Zh Nevrol Psikhiatr Im S S Korsakova 2013 -1 113: 54-60
PMID23612411
Title[SNAP-25 and DTNBP1 as candidate genes for cognitive reserve in schizophrenia].
AbstractCognitive reserve (CR) postulates that individual differences in the cognitive processes or neural networks underlying task performance allow some people to cope better than others with brain damage. An aim of the study was to search for candidate genes for CR in schizophrenia. We propose that higher frequencies of low risk alleles is observed in healthy relatives of schizophrenic patients compared to patients and controls and in patients without neurocognitive deficit and with less severity of the disease compared to other patients and controls. Besides, frequencies of these alleles in patients should be similar to those in general population. Authors studied SNAP-25 and DTNBP1 genes. The polymorphism T1065G of SNAP-25 was genotyped in 278 patients with schizophrenia, 126 their relatives and 207 controls and the polymorphism P1763 of DTNBP1 was genotyped in 202 patients, 229 relatives and 262 controls. There was a trend towards the increase in the frequency of an G allele of SNAP-25 in siblings of patients. The frequency of this allele was higher in patients without neurocognitive deficit compared to patients with cognitive deficit (p=0.003) and controls (p=0.002). The allele was associated with index of cognitive functioning in patients (p=0.012) and controls (p=0.006) and with the severity of negative symptoms in patients (p=0.023). At the same time, the polymorphism T1065G was not associated with schizophrenia. Therefore, an allele G may be considered as a marker for higher CR.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
223Transl Psychiatry 2014 -1 4: e339
PMID24399042
TitleGenome-wide DNA methylation analysis of human brain tissue from schizophrenia patients.
AbstractRecent studies suggest that genetic and environmental factors do not account for all the schizophrenia risk, and epigenetics also has a role in disease susceptibility. DNA methylation is a heritable epigenetic modification that can regulate gene expression. Genome-wide DNA methylation analysis was performed on post-mortem human brain tissue from 24 patients with schizophrenia and 24 unaffected controls. DNA methylation was assessed at over 485,000 CpG sites using the Illumina Infinium HumanMethylation450 Bead Chip. After adjusting for age and post-mortem interval, 4641 probes corresponding to 2929 unique genes were found to be differentially methylated. Of those genes, 1291 were located in a CpG island and 817 were in a promoter region. These include NOS1, AKT1, DTNBP1, DNMT1, PPP3CC and SOX10, which have previously been associated with schizophrenia. More than 100 of these genes overlap with a previous DNA methylation study of peripheral blood from schizophrenia patients in which 27,000 CpG sites were analysed. Unsupervised clustering analysis of the top 3000 most variable probes revealed two distinct groups with significantly more people with schizophrenia in cluster one compared with controls (P=1.74 10(-4)). The first cluster composed of 88% of patients with schizophrenia and only 12% controls, whereas the second cluster composed of 27% of patients with schizophrenia and 73% controls. These results strongly suggest that differential DNA methylation is important in schizophrenia etiology and add support for the use of DNA methylation profiles as a future prognostic indicator of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
224Mol. Cell. Neurosci. 2014 Jan 58: 76-84
PMID24321452
TitleThe schizophrenia susceptibility gene DTNBP1 modulates AMPAR synaptic transmission and plasticity in the hippocampus of juvenile DBA/2J mice.
AbstractThe dystrobrevin binding protein (DTNBP) 1 gene has emerged over the last decade as a potential susceptibility locus for schizophrenia. While no causative mutations have been found, reduced expression of the encoded protein, dysbindin, was reported in patients. Dysbindin likely plays a role in the neuronal trafficking of proteins including receptors. One important pathway suspected to be affected in schizophrenia is the fast excitatory glutamatergic transmission mediated by AMPA receptors. Here, we investigated excitatory synaptic transmission and plasticity in hippocampal neurons from dysbindin-deficient sandy mice bred on the DBA/2J strain. In cultured neurons an enhancement of AMPAR responses was observed. The enhancement of AMPAR-mediated transmission was confirmed in hippocampal CA3-CA1 synapses, and was not associated with changes in the expression of GluA1-4 subunits or an increase in GluR2-lacking receptor complexes. Lastly, an enhancement in LTP was also found in these mice. These data provide compelling evidence that dysbindin, a widely suspected susceptibility protein in schizophrenia, is important for AMPAR-mediated synaptic transmission and plasticity in the developing hippocampus.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
225Asian J Psychiatr 2014 Aug 10: 62-8
PMID25042954
TitleAn exploratory association study of the influence of dysbindin and neuregulin polymorphisms on brain morphometry in patients with schizophrenia and healthy subjects from South India.
AbstractMultiple genetic risk variants may act in a convergent manner leading on to the pathophysiological alterations of brain structure and function in schizophrenia. We examined the effect of polymorphisms of two candidate genes that mediate glutamatergic signaling, viz., dysbindin (rs1011313) and neuregulin (rs35753505), on brain morphometry in patients with schizophrenia (N=38) and healthy subjects (N=37) from South India. Patients with schizophrenia showed trend-level (p<0.001 uncorrected, 20 voxel extent correction) volumetric reductions in multiple brain regions when compared to healthy control subjects. Trend-level volumetric differences were also noted between homozygotes of the risk allele (AA) of the neuregulin (NRG1) polymorphism and heterozygotes (AG), as well as homozygotes of the risk allele (CC) of the dysbindin (DTNBP1) polymorphism and heterozygotes (TC), irrespective of diagnosis. Moreover, an additive effect of the risk alleles on brain morphometry was also noted. These preliminary findings highlight the possible influence of polymorphisms of risk genes on brain morphometry in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
226Prog. Brain Res. 2014 -1 211: 79-112
PMID24968777
TitleDopaminergic function in relation to genes associated with risk for schizophrenia: translational mutant mouse models.
AbstractMutant mice play an increasingly important role in understanding disease processes at multiple levels. In particular, they illuminate the impact of risk genes for disease on such processes. This article reviews recent advances in the application of mutant mice to study the intricacies of dopaminergic (DAergic) function in relation to the putative pathophysiology of psychotic illness, particularly schizophrenia, and antipsychotic drug action. It considers models for understanding the role(s) of risk genes, with a particular focus on DTNBP1 and NRG1, their interactions with environmental factors, and with each other (epistasis). In overview, it considers new schemas for understanding psychotic illness that integrate DAergic pathophysiology with developmental, social, and cognitive processes, and how mutant mouse models can reflect and inform on such schemas.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
227Hippocampus 2014 Feb 24: 204-13
PMID24446171
TitleDysbindin-1 loss compromises NMDAR-dependent synaptic plasticity and contextual fear conditioning.
AbstractGenetic variants in DTNBP1 encoding the protein dysbindin-1 have often been associated with schizophrenia and with the cognitive deficits prominent in that disorder. Because impaired function of the hippocampus is thought to play a role in these memory deficits and because NMDAR-dependent synaptic plasticity in this region is a proposed biological substrate for some hippocampal-dependent memory functions in schizophrenia, we hypothesized that reduced dysbindin-1 expression would lead to impairments in NMDAR-dependent synaptic plasticity and in contextual fear conditioning. Acute slices from male mice carrying 0, 1, or 2 null mutant alleles of the DTNBP1 gene were prepared, and field recordings from the CA1 striatum radiatum were obtained before and after tetanization of Schaffer collaterals of CA3 pyramidal cells. Mice homozygous for the null mutation in DTNBP1 exhibited significantly reduced NMDAR-dependent synaptic potentiation compared to wild type mice, an effect that could be rescued by bath application of the NMDA receptor coagonist glycine (10 ?M). Behavioral testing in adult mice revealed deficits in hippocampal memory processes. Homozygous null mice exhibited lower conditional freezing, without a change in the response to shock itself, indicative of a learning and memory deficit. Taken together, these results indicate that a loss of dysbindin-1 impairs hippocampal plasticity which may, in part, explain the role dysbindin-1 plays in the cognitive impairments of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
228J. Biol. Chem. 2014 Oct 289: 29060-72
PMID25157109
TitleDysbindin-1C is required for the survival of hilar mossy cells and the maturation of adult newborn neurons in dentate gyrus.
AbstractDTNBP1 (dystrobrevin-binding protein 1), which encodes dysbindin-1, is one of the leading susceptibility genes for schizophrenia. Both dysbindin-1B and -1C isoforms are decreased, but the dysbindin-1A isoform is unchanged in schizophrenic hippocampal formation, suggesting dysbindin-1 isoforms may have distinct roles in schizophrenia. We found that mouse dysbindin-1C, but not dysbindin-1A, is localized in the hilar glutamatergic mossy cells of the dentate gyrus. The maturation rate of newborn neurons in sandy (sdy) mice, in which both dysbindin-1A and -1C are deleted, is significantly delayed when compared with that in wild-type mice or with that in muted (mu) mice in which dysbindin-1A is destabilized but dysbindin-1C is unaltered. Dysbindin-1C deficiency leads to a decrease in mossy cells, which causes the delayed maturation of newborn neurons. This suggests that dysbindin-1C, rather than dysbindin-1A, regulates adult hippocampal neurogenesis in a non-cell autonomous manner.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
229Neurosci. Lett. 2014 Oct 582: 120-4
PMID25196196
TitleDysbindin-1, a schizophrenia-related protein, interacts with HDAC3.
AbstractDTNBP1 is a key candidate gene associated with schizophrenia. The expression of its protein product, dysbindin-1, is altered in the brains of schizophrenic patients; however, the physiological functions of dysbindin-1 in the central nervous system are unclear. Several studies have shown that both dysbindin-1 and histone deacetylase 3 (HDAC3) can be phosphorylated by the DNA-dependent protein kinase complex. In this study, we investigated the relationship between dysbindin-1 and HDAC3. We found that dysbindin-1 formed a protein complex with HDAC3 in human neuroblastoma cells and in mouse brain. The interaction between dysbindin-1 and HDAC3 occurred in an isoform-specific manner: HDAC3 coupled with dysbindin-1A and -1B, but not -1C. We also found that dysbindin-1B expression was increased in the nucleus in the presence of HDAC3, and, conversely, that the phosphorylation level of HDAC3 increased in the presence of dysbindin-1B. Taken together, these results identify a novel binding partner for dysbindin-1, which may potentially provide a new avenue for research into the neurological mechanisms of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
230Neurochem. Int. 2014 Dec 79: 65-9
PMID25445987
TitleOxidative stress reduces levels of dysbindin-1A via its PEST domain.
AbstractOxidative stress resulting from the generation of reactive oxygen species has been proposed as an etiological factor in schizophrenia. The present study tests the hypothesis that oxidative stress can affect levels of dysbindin-1A, encoded by DTNBP1, a genetic risk factor for schizophrenia, via its PEST domain. In vitro studies on SH-SY5Y cells indicate that oxidative stress triggers proteasomal degradation of dysbindin-1A, and that this requires interactions with its PEST domain, which may be a TRIM32 target. We specifically found (a) that oxidative stress induced in SH-SY5Y cells by 500 M hydrogen peroxide reduced levels of full-length dysbindin-1, but did not reduce levels of that protein lacking its PEST domain and (b) that levels of full-length dysbindin-1, but not dysbindin-1 lacking its PEST domain, were higher in cells treated with the proteasome inhibitor MG132. Oxidative stress thus emerges as the first known cellular factor regulating dysbindin-1 isoforms with PEST domains. These findings are consistent with the previously noted fact that phosphorylation of PEST domains often marks proteins for proteasomal degradation, and raises the possibility that treatments reducing oxidative stress in the brain, especially during development, may lower schizophrenia risk.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
231Mol Brain 2014 -1 7: 74
PMID25298178
TitleBehavioral characterization of mice overexpressing human dysbindin-1.
AbstractThe dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) is a promising schizophrenia susceptibility gene, known to localize almost exclusively to neurons in the brain, and participates in the regulation of neurotransmitter release, membrane-surface receptor expression, and synaptic plasticity. Sandy mice, with spontaneous DTNBP1 deletion, display behavioral abnormalities relevant to symptoms of schizophrenia. However, it remains unknown if dysbindin-1 gain-of-function is beneficial or detrimental.
To answer this question and gain further insight into the pathophysiology and therapeutic potential of dysbindin-1, we developed transgenic mice expressing human DTNBP1 (Dys1A-Tg) and analyzed their behavioral phenotypes. Dys1A-Tg mice were born viable in the expected Mendelian ratios, apparently normal and fertile. Primary screening of behavior and function showed a marginal change in limb grasping in Dys1A-Tg mice. In addition, Dys1A-Tg mice exhibited increased hyperlocomotion after methamphetamine injection. Transcriptomic analysis identified several up- and down-regulated genes, including the immediate-early genes Arc and Egr2, in the prefrontal cortex of Dys1A-Tg mice.
The present findings in Dys1A-Tg mice support the role of dysbindin-1 in psychiatric disorders. The fact that either overexpression (Dys1A-Tg) or underexpression (Sandy) of dysbindin-1 leads to behavioral alterations in mice highlights the functional importance of dysbindin-1 in vivo.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
232World J. Biol. Psychiatry 2014 Sep 15: 553-60
PMID24988482
TitleThe CMYA5 gene confers risk for both schizophrenia and major depressive disorder in the Han Chinese population.
AbstractA recent genome-wide association study (GWAS) of the European population implicated the CMYA5 gene in schizophrenia. Previous functional studies showed that the CMYA5 protein can interact with DTNBP1 and PKA, providing further support for a role of CMYA5 in the pathogenesis of schizophrenia. However, this association requires additional validation in independent populations.
To validate the association between CMYA5 and schizophrenia and major depressive disorder, we genotyped 16 SNPs within the CMYA5 gene and performed case-control studies in 1330 schizophrenia patients, 1045 patients with major depressive disorder, and 1235 normal controls. All patients were of Han Chinese origin.
rs6883197 and rs259127 were significantly associated with schizophrenia, and rs12514461, rs259127, and rs7343 were associated with major depressive disorder. Additionally, one risk haplotype of rs16877109-rs3828611 (G-G) was associated with both schizophrenia (P = 0.0000784, after correction) and major depressive disorder (P = 0.00230, after correction).
Our findings support the idea that specific alleles and haplotype in the CMYA5 confer genetic risk for both schizophrenia and major depressive disorder in the Han Chinese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
233J. Proteome Res. 2014 Nov 13: 4567-80
PMID25198678
TitleDysbindin-associated proteome in the p2 synaptosome fraction of mouse brain.
AbstractThe gene DTNBP1 encodes the protein dysbindin and is among the most promising and highly investigated schizophrenia-risk genes. Accumulating evidence suggests that dysbindin plays an important role in the regulation of neuroplasticity. Dysbindin was reported to be a stable component of BLOC-1 complex in the cytosol. However, little is known about the endogenous dysbindin-containing complex in the brain synaptosome. In this study, we investigated the associated proteome of dysbindin in the P2 synaptosome fraction of mouse brain. Our data suggest that dysbindin has three isoforms associating with different complexes in the P2 fraction of mouse brain. To facilitate immunopurification, BAC transgenic mice expressing a tagged dysbindin were generated, and 47 putative dysbindin-associated proteins, including all components of BLOC-1, were identified by mass spectrometry in the dysbindin-containing complex purified from P2. The interactions of several selected candidates, including WDR11, FAM91A1, snapin, muted, pallidin, and two proteasome subunits, PSMD9 and PSMA4, were verified by coimmunoprecipitation. The specific proteasomal activity is significantly reduced in the P2 fraction of the brains of the dysbindin-null mutant (sandy) mice. Our data suggest that dysbindin is functionally interrelated to the ubiquitin-proteasome system and offer a molecular repertoire for future study of dysbindin functional networks in brain.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
234J. Biol. Chem. 2014 Oct 289: 29060-72
PMID25157109
TitleDysbindin-1C is required for the survival of hilar mossy cells and the maturation of adult newborn neurons in dentate gyrus.
AbstractDTNBP1 (dystrobrevin-binding protein 1), which encodes dysbindin-1, is one of the leading susceptibility genes for schizophrenia. Both dysbindin-1B and -1C isoforms are decreased, but the dysbindin-1A isoform is unchanged in schizophrenic hippocampal formation, suggesting dysbindin-1 isoforms may have distinct roles in schizophrenia. We found that mouse dysbindin-1C, but not dysbindin-1A, is localized in the hilar glutamatergic mossy cells of the dentate gyrus. The maturation rate of newborn neurons in sandy (sdy) mice, in which both dysbindin-1A and -1C are deleted, is significantly delayed when compared with that in wild-type mice or with that in muted (mu) mice in which dysbindin-1A is destabilized but dysbindin-1C is unaltered. Dysbindin-1C deficiency leads to a decrease in mossy cells, which causes the delayed maturation of newborn neurons. This suggests that dysbindin-1C, rather than dysbindin-1A, regulates adult hippocampal neurogenesis in a non-cell autonomous manner.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
235Neurosci. Lett. 2014 Oct 582: 120-4
PMID25196196
TitleDysbindin-1, a schizophrenia-related protein, interacts with HDAC3.
AbstractDTNBP1 is a key candidate gene associated with schizophrenia. The expression of its protein product, dysbindin-1, is altered in the brains of schizophrenic patients; however, the physiological functions of dysbindin-1 in the central nervous system are unclear. Several studies have shown that both dysbindin-1 and histone deacetylase 3 (HDAC3) can be phosphorylated by the DNA-dependent protein kinase complex. In this study, we investigated the relationship between dysbindin-1 and HDAC3. We found that dysbindin-1 formed a protein complex with HDAC3 in human neuroblastoma cells and in mouse brain. The interaction between dysbindin-1 and HDAC3 occurred in an isoform-specific manner: HDAC3 coupled with dysbindin-1A and -1B, but not -1C. We also found that dysbindin-1B expression was increased in the nucleus in the presence of HDAC3, and, conversely, that the phosphorylation level of HDAC3 increased in the presence of dysbindin-1B. Taken together, these results identify a novel binding partner for dysbindin-1, which may potentially provide a new avenue for research into the neurological mechanisms of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
236Hum. Mol. Genet. 2015 Oct 24: 5512-23
PMID26199316
TitleNeuronal copper homeostasis susceptibility by genetic defects in dysbindin, a schizophrenia susceptibility factor.
AbstractEnvironmental factors and susceptible genomes interact to determine the risk of neurodevelopmental disorders. Although few genes and environmental factors have been linked, the intervening cellular and molecular mechanisms connecting a disorder susceptibility gene with environmental factors remain mostly unexplored. Here we focus on the schizophrenia susceptibility gene DTNBP1 and its product dysbindin, a subunit of the BLOC-1 complex, and describe a neuronal pathway modulating copper metabolism via ATP7A. Mutations in ATP7A result in Menkes disease, a disorder of copper metabolism. Dysbindin/BLOC-1 and ATP7A genetically and biochemically interact. Furthermore, disruption of this pathway causes alteration in the transcriptional profile of copper-regulatory and dependent factors in the hippocampus of dysbindin/BLOC-1-null mice. Dysbindin/BLOC-1 loss-of-function alleles do not affect cell and tissue copper content, yet they alter the susceptibility to toxic copper challenges in both mammalian cells and Drosophila. Our results demonstrate that perturbations downstream of the schizophrenia susceptibility gene DTNBP1 confer susceptibility to copper, a metal that in excess is a neurotoxin and whose depletion constitutes a micronutrient deficiency.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
237Biol. Psychiatry 2015 Aug -1: -1
PMID26386481
TitleRegulation of Brain-Derived Neurotrophic Factor Exocytosis and Gamma-Aminobutyric Acidergic Interneuron Synapse by the Schizophrenia Susceptibility Gene Dysbindin-1.
AbstractGenetic variations in dystrobrevin binding protein 1 (DTNBP1 or dysbindin-1) have been implicated as risk factors in the pathogenesis of schizophrenia. The encoded protein dysbindin-1 functions in the regulation of synaptic activity and synapse development. Intriguingly, a loss of function mutation in DTNBP1 in mice disrupted both glutamatergic and gamma-aminobutyric acidergic transmission in the cerebral cortex; pyramidal neurons displayed enhanced excitability due to reductions in inhibitory synaptic inputs. However, the mechanism by which reduced dysbindin-1 activity causes inhibitory synaptic deficits remains unknown.
We investigated the role of dysbindin-1 in the exocytosis of brain-derived neurotrophic factor (BDNF) from cortical excitatory neurons, organotypic brain slices, and acute slices from dysbindin-1 mutant mice and determined how this change in BDNF exocytosis transsynaptically affected the number of inhibitory synapses formed on excitatory neurons via whole-cell recordings, immunohistochemistry, and live-cell imaging using total internal reflection fluorescence microscopy.
A decrease in dysbindin-1 reduces the exocytosis of BDNF from cortical excitatory neurons, and this reduction in BDNF exocytosis transsynaptically resulted in reduced inhibitory synapse numbers formed on excitatory neurons. Furthermore, application of exogenous BDNF rescued the inhibitory synaptic deficits caused by the reduced dysbindin-1 level in both cultured cortical neurons and slice cultures.
Taken together, our results demonstrate that these two genes linked to risk for schizophrenia (BDNF and dysbindin-1) function together to regulate interneuron development and cortical network activity. This evidence supports the investigation of the association between dysbindin-1 and BDNF in humans with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
238Mol. Psychiatry 2015 May 20: 555-62
PMID25754081
TitleEvaluating historical candidate genes for schizophrenia.
AbstractPrior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
239Front Behav Neurosci 2015 -1 9: 72
PMID25859193
TitleLoss of dysbindin-1, a risk gene for schizophrenia, leads to impaired group 1 metabotropic glutamate receptor function in mice.
AbstractThe expression of dysbindin-1, a protein coded by the risk gene DTNBP1, is reduced in the brains of schizophrenia patients. Evidence indicates a role of dysbindin-1 in dopaminergic and glutamatergic transmission. Glutamatergic transmission and plasticity at excitatory synapses is critically regulated by G-protein coupled metabotropic glutamate receptor (mGluR) family members, that have been implicated in schizophrenia. Here, we report a role of dysbindin-1 in hippocampal group 1 mGluR (mGluRI) function in mice. In hippocampal synaptoneurosomal preparations from sandy (sdy) mice, that have a loss of function mutation in dysbindin-1 gene, we observed a striking reduction in mGluRI agonist [(S)-3, 5-dihydroxyphenylglycine] (DHPG)-induced phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2). This mGluR-ERK1/2 deficit occurred in the absence of significant changes in protein levels of the two members of the mGluRI family (i.e., mGluR1 and mGluR5) or in another mGluRI signaling pathway, i.e., protein kinase C (PKC). Aberrant mGluRI-ERK1/2 signaling affected hippocampal synaptic plasticity in the sdy mutants as DHPG-induced long-term depression (LTD) at CA1 excitatory synapses was significantly reduced. Behavioral data suggest that the mGluRI hypofunction may underlie some of the cognitive abnormalities described in sdy mice as the administration of CDPPB (3-cyano-N-(1, 3-diphenyl-1H-pyrazol-5-yl benzamide), a positive allosteric modulator of mGluR5, rescued short-term object recognition and spatial learning and memory deficits in these mice. Taken together, our data suggest a novel role of dysbindin-1 in regulating mGluRI functions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
240Neuroscience 2015 Apr 291: 301-16
PMID25704251
TitlePropagation of dysbindin-1B aggregates: exosome-mediated transmission of neurotoxic deposits.
AbstractGiven the detection of aggregated deposits in chronic mental diseases (CMD), the disturbance of proteostasis in those diseases is receiving increasing attention. The study of aggregated proteins can contribute to our understanding of the chronic and progressive condition of such diseases. Dysbindin, encoded by the schizophrenia susceptibility gene DTNBP1, has been reported to co-aggregate with DISC1. However, there has been no evidence to date on the aggregation tendency of dysbindin. Therefore, we investigated the isoform-specific aggregation of dysbindin. We found that dysbindin-1B aggregated into cell-invasive deposits in mice. Because of the efficient propagation of dysbindin-1B, we further studied the mechanism of propagation and identified it as exosome-mediated transmission of the aggregates. In addition, aggregates of dysbindin-1B were toxic. Through exosome-mediated propagation, the deposits of dysbindin-1B exerted toxic effects on recipient neurons a long distance away from the initial aggregation site in mice brain. The rapid long distance propagation of neurotoxic deposits of dysbindin-1B in affected neuronal circuitry indicates a possible mechanism for the progressive deterioration of neurons and cognitive function in CMD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
241PLoS ONE 2015 -1 10: e0132639
PMID26171858
TitleThe Schizophrenia-Related Protein Dysbindin-1A Is Degraded and Facilitates NF-Kappa B Activity in the Nucleus.
AbstractDystrobrevin-binding protein 1 (DTNBP1), a gene encoding dysbindin-1, has been identified as a susceptibility gene for schizophrenia. Functioning with partners in synapses or the cytoplasm, this gene regulates neurite outgrowth and neurotransmitter release. Loss of dysbindin-1 affects schizophrenia pathology. Dysbindin-1 is also found in the nucleus, however, the characteristics of dysbindin in the nucleus are not fully understood. Here, we found that dysbindin-1A is degraded in the nucleus via the ubiquitin-proteasome system and that amino acids 2-41 at the N-terminus are required for this process. By interacting with p65, dysbindin-1A promotes the transcriptional activity of NF-kappa B in the nucleus and positively regulates MMP-9 expression. Taken together, the data obtained in this study demonstrate that dysbindin-1A protein levels are highly regulated in the nucleus and that dysbindin-1A regulates transcription factor NF-kappa B activity to promote the expression of MMP-9 and TNF-?.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
242Schizophr Res Cogn 2015 Jun 2: 56-63
PMID26346124
TitleHierarchical Classes Analysis (HICLAS): A novel data reduction method to examine associations between biallelic SNPs and perceptual organization phenotypes in schizophrenia.
AbstractThe power of SNP association studies to detect valid relationships with clinical phenotypes in schizophrenia is largely limited by the number of SNPs selected and non-specificity of phenotypes. To address this, we first assessed performance on two visual perceptual organization tasks designed to avoid many generalized deficit confounds, Kanizsa shape perception and contour integration, in a schizophrenia patient sample. Then, to reduce the total number of candidate SNPs analyzed in association with perceptual organization phenotypes, we employed a two-stage strategy: first a priori SNPs from three candidate genes were selected (GAD1, NRG1 and DTNBP1); then a Hierarchical Classes Analysis (HICLAS) was performed to reduce the total number of SNPs, based on statistically related SNP clusters. HICLAS reduced the total number of candidate SNPs for subsequent phenotype association analyses from 6 to 3. MANCOVAs indicated that rs10503929 and rs1978340 were associated with the Kanizsa shape perception filling in metric but not the global shape detection metric. rs10503929 was also associated with altered contour integration performance. SNPs not selected by the HICLAS model were unrelated to perceptual phenotype indices. While the contribution of candidate SNPs to perceptual impairments requires further clarification, this study reports the first application of HICLAS as a hypothesis-independent mathematical method for SNP data reduction. HICLAS may be useful for future larger scale genotype-phenotype association studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
243Genet. Mol. Biol. 2015 May 38: 138-46
PMID26273215
TitleGenetic association of single nucleotide polymorphisms in dystrobrevin binding protein 1 gene with schizophrenia in a Malaysian population.
AbstractDystrobrevin binding protein 1 (DTNBP1) gene is pivotal in regulating the glutamatergic system. Genetic variants of the DTNBP1 affect cognition and thus may be particularly relevant to schizophrenia. We therefore evaluated the association of six single nucleotide polymorphisms (SNPs) with schizophrenia in a Malaysian population (171 cases; 171 controls). Associations between these six SNPs and schizophrenia were tested in two stages. Association signals with p < 0.05 and minor allele frequency > 0.05 in stage 1 were followed by genotyping the SNPs in a replication phase (stage 2). Genotyping was performed with sequenced specific primer (PCR-SSP) and restriction fragment length polymorphism (PCR-RFLP). In our sample, we found significant associations between rs2619522 (allele p = 0.002, OR = 1.902, 95%CI = 1.266 - 2.859; genotype p = 0.002) and rs2619528 (allele p = 0.008, OR = 1.606, 95%CI = 1.130 - 2.281; genotype p = 6.18 10(-5)) and schizophrenia. Given that these two SNPs may be associated with the pathophysiology of schizophrenia, further studies on the other DTNBP1 variants are warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
244Genes Brain Behav. 2015 Nov 14: 618-24
PMID26294018
TitleRecognition deficits in mice carrying mutations of genes encoding BLOC-1 subunits pallidin or dysbindin.
AbstractNumerous studies have implicated DTNBP1, the gene encoding dystrobrevin-binding protein or dysbindin, as a candidate risk gene for schizophrenia, though this relationship remains somewhat controversial. Variation in dysbindin, and its location on chromosome 6p, has been associated with cognitive processes, including those relying on a complex system of glutamatergic and dopaminergic interactions. Dysbindin is one of the seven protein subunits that comprise the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin protein levels are lower in mice with null mutations in pallidin, another gene in the BLOC-1, and pallidin levels are lower in mice with null mutations in the dysbindin gene, suggesting that multiple subunit proteins must be present to form a functional oligomeric complex. Furthermore, pallidin and dysbindin have similar distribution patterns in a mouse and human brain. Here, we investigated whether the apparent correspondence of pallid and dysbindin at the level of gene expression is also found at the level of behavior. Hypothesizing a mutation leading to underexpression of either of these proteins should show similar phenotypic effects, we studied recognition memory in both strains using the novel object recognition task (NORT) and social novelty recognition task (SNRT). We found that mice with a null mutation in either gene are impaired on SNRT and NORT when compared with wild-type controls. These results support the conclusion that deficits consistent with recognition memory impairment, a cognitive function that is impaired in schizophrenia, result from either pallidin or dysbindin mutations, possibly through degradation of BLOC-1 expression and/or function.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
245Behav. Brain Res. 2015 May 284: 58-68
PMID25677649
TitleConstant light uncovers behavioral effects of a mutation in the schizophrenia risk gene Dtnbp1 in mice.
AbstractVarious psychiatric disorders, including schizophrenia, are comorbid with sleep and circadian rhythm disruptions. To understand the links between circadian rhythms and schizophrenia, we analyzed wheel-running behavior of Sandy (Sdy) mice, which have a loss-of-function mutation in the schizophrenia risk gene DTNBP1, and exhibit several behavioral features of schizophrenia. While rhythms of Sdy mice were mainly normal under light-dark conditions (LD) or in constant darkness (DD), they had a significantly longer free-running period under constant light (LL) compared to wild-type (WT) littermates. The mutant mice also had a higher subjective day/subjective night ratio of activity under LL, indicating lower amplitude, and a lower precision of their onsets of activity under all three lighting conditions. These observations are reminiscent of the circadian disruptions observed in schizophrenia patients. This prompted us to assess schizophrenia-relevant behavioral abnormalities in Sdy mice following alteration of the circadian rhythms by presentation of constant light. Spontaneous locomotor activity, prepulse inhibition (PPI) of acoustic startle and anxiety-like behavior were assessed under baseline LD conditions, then in LL, and then again in LD. Under LL, the Sdy mice showed significantly increased spontaneous locomotion as well as deficits in PPI compared to WT mice. Strikingly, these behavioral deficits persisted even after the mice were returned in LD conditions. While LL led to an increase in anxiety-like behavior in WT animals that was fully reversed after 3 weeks in LD, this effect was not observed in the Sdy mutants. Overall, these results suggest that DTNBP1 deficiency may lead to increased vulnerability to schizophrenia under environmental conditions where circadian rhythms are altered.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
246J Genet Genomics 2015 Jan 42: 1-8
PMID25619597
TitleImpaired autophagy in hilar mossy cells of the dentate gyrus and its implication in schizophrenia.
Abstractschizophrenia (SCZ) is a complex disease that has been regarded as a neurodevelopmental, synaptic or epigenetic disorder. Here we provide evidence that neurodegeneration is implicated in SCZ. The DTNBP1 (dystrobrevin-binding protein 1) gene encodes dysbindin-1 and is a leading susceptibility gene of SCZ. We previously reported that the dysbindin-1C isoform regulates the survival of the hilar glutamatergic mossy cells in the dentate gyrus, which controls the adult hippocampal neurogenesis. However, the underlying mechanism of hilar mossy cell loss in the dysbindin-1-deficient sandy (sdy) mice (a mouse model of SCZ) is unknown. In this study, we did not observe the apoptotic signals in the hilar mossy cells of the sdy mice by using the TUNEL assay and immunostaining of cleaved caspase-3 or necdin, a dysbindin-1- and p53-interacting protein required for neuronal survival. However, we found that the steady-state level of LC3-II, a marker of autophagosomes, was decreased in the hippocampal formation in the mice lacking dysbindin-1C. Furthermore, we observed a significant reduction of the cytosolic LC3-II puncta in the mossy cells of sdy mice. In addition, overexpression of dysbindin-1C, but not 1A, in cultured cells increased LC3-II level and the LC3 puncta in the transfected cells. These results suggest that dysbindin-1C deficiency causes impaired autophagy, which is likely implicated in the pathogenesis of SCZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
247J. Neurosci. 2015 May 35: 7643-53
PMID25972187
TitleThe N-ethylmaleimide-sensitive factor and dysbindin interact to modulate synaptic plasticity.
AbstractDysbindin is a schizophrenia susceptibility factor and subunit of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) required for lysosome-related organelle biogenesis, and in neurons, synaptic vesicle assembly, neurotransmission, and plasticity. Protein networks, or interactomes, downstream of dysbindin/BLOC-1 remain partially explored despite their potential to illuminate neurodevelopmental disorder mechanisms. Here, we conducted a proteome-wide search for polypeptides whose cellular content is sensitive to dysbindin/BLOC-1 loss of function. We identified components of the vesicle fusion machinery as factors downregulated in dysbindin/BLOC-1 deficiency in neuroectodermal cells and iPSC-derived human neurons, among them the N-ethylmaleimide-sensitive factor (NSF). Human dysbindin/BLOC-1 coprecipitates with NSF and vice versa, and both proteins colocalized in a Drosophila model synapse. To test the hypothesis that NSF and dysbindin/BLOC-1 participate in a pathway-regulating synaptic function, we examined the role for NSF in dysbindin/BLOC-1-dependent synaptic homeostatic plasticity in Drosophila. As previously described, we found that mutations in dysbindin precluded homeostatic synaptic plasticity elicited by acute blockage of postsynaptic receptors. This dysbindin mutant phenotype is fully rescued by presynaptic expression of either dysbindin or Drosophila NSF. However, neither reduction of NSF alone or in combination with dysbindin haploinsufficiency impaired homeostatic synaptic plasticity. Our results demonstrate that dysbindin/BLOC-1 expression defects result in altered cellular content of proteins of the vesicle fusion apparatus and therefore influence synaptic plasticity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
248Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Dec 168: 687-96
PMID26285059
TitleAntipsychotic drugs attenuate aberrant DNA methylation of DTNBP1 (dysbindin) promoter in saliva and post-mortem brain of patients with schizophrenia and Psychotic bipolar disorder.
AbstractDue to the lack of genetic association between individual genes and schizophrenia (SCZ) pathogenesis, the current consensus is to consider both genetic and epigenetic alterations. Here, we report the examination of DNA methylation status of DTNBP1 promoter region, one of the most credible candidate genes affected in SCZ, assayed in saliva and post-mortem brain samples. The Illumina DNA methylation profiling and bisulfite sequencing of representative samples were used to identify methylation status of the DTNBP1 promoter region. Quantitative methylation specific PCR (qMSP) was employed to assess methylation of DTNBP1 promoter CpGs flanking a SP1 binding site in the saliva of SCZ patients, their first-degree relatives and control subjects (30, 15, and 30/group, respectively) as well as in post-mortem brains of patients with SCZ and bipolar disorder (BD) versus controls (35/group). qRT-PCR was used to assess DTNBP1 expression. We found DNA hypermethylation of DTNBP1 promoter in the saliva of SCZ patients (?12.5%, P?=?0.036), particularly in drug-nave patients (?20%, P?=?0.011), and a trend toward hypermethylation in their first-degree relatives (P?=?0.085) versus controls. Analysis of post-mortem brain samples revealed an inverse correlation between DTNBP1 methylation and expression, and normalization of this epigenetic change by classic antipsychotic drugs. Additionally, BD patients with psychotic depression exhibited higher degree of methylation versus other BD patients (?80%, P?=?0.025). DTNBP1 promoter DNA methylation may become a key element in a panel of biomarkers for diagnosis, prevention, or therapy in SCZ and at risk individuals pending confirmatory studies with larger sample sizes to attain a higher degree of significance.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
249Eur. Psychiatry 2015 Jun 30: 486-91
PMID25697573
TitleDysbindin (DTNBP1) variants are associated with hallucinations in schizophrenia.
AbstractDystrobrevin binding protein 1 (DTNBP1) is a schizophrenia susceptibility gene involved with neurotransmission regulation (especially dopamine and glutamate) and neurodevelopment. The gene is known to be associated with cognitive deficit phenotypes within schizophrenia. In our previous studies, DTNBP1 was found associated not only with schizophrenia but with other psychiatric disorders including psychotic depression, post-traumatic stress disorder, nicotine dependence and opiate dependence. These findings suggest that DNTBP1 may be involved in pathways that lead to multiple psychiatric phenotypes. In this study, we explored the association between DTNBP1 SNPs (single nucleotide polymorphisms) and multiple psychiatric phenotypes included in the Diagnostic Interview of Psychosis (DIP).
Five DTNBP1 SNPs, rs17470454, rs1997679, rs4236167, rs9370822 and rs9370823, were genotyped in 235 schizophrenia subjects screened for various phenotypes in the domains of depression, mania, hallucinations, delusions, subjective thought disorder, behaviour and affect, and speech disorder. SNP-phenotype association was determined with ANOVA under general, dominant/recessive and over-dominance models.
Post hoc tests determined that SNP rs1997679 was associated with visual hallucination; SNP rs4236167 was associated with general auditory hallucination as well as specific features including non-verbal, abusive and third-person form auditory hallucinations; and SNP rs9370822 was associated with visual and olfactory hallucinations. SNPs that survived correction for multiple testing were rs4236167 for third-person and abusive form auditory hallucinations; and rs9370822 for olfactory hallucinations.
These data suggest that DTNBP1 is likely to play a role in development of auditory related, visual and olfactory hallucinations which is consistent with evidence of DTNBP1 activity in the auditory processing regions, in visual processing and in the regulation of glutamate and dopamine activity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
250Cogn Neuropsychiatry 2015 -1 20: 144-56
PMID25530342
TitleDysbindin gene variability is associated with cognitive abnormalities in first-episode non-affective psychosis.
AbstractDystrobrevin-binding protein 1 gene (dysbindin or DTNBP1) has been associated with schizophrenia and cognitive performance. Its expression in areas implicated in cognition such as the dorsolateral prefrontal cortex, as well as its role in dopaminergic and glutamatergic system, has been replicated by several studies. The main aim of this study was to examine the association between DTNBP1 variability and cognitive performance in a sample of 238 patients with a first episode of a non-affective psychosis.
Patients, and a comparison sample of 47 healthy subjects, completed an extensive neuropsychological battery. Five single nucleotide polymorphisms (SNPs) within DTNBP1 (rs2619528, rs2619538, rs3213207, rs2619539 and rs760761) and three haplotypes (GACAC, GAGAC and GTGAC) were analysed.
In the group of patients, we found a significant association between two of the DTNBP1 SNPs and one of the haplotypes (rs2619539, rs3213207 and GACAC) and a measure of premorbid IQ [Wechsler Adult Intelligence Scale-3rd Edition (WAIS-III) Vocabulary subtest]. Moreover, one of these SNPs, rs2619539, was also associated with our measure of working memory (WAIS-III Backward digits subtest) and two haplotypes, GAGAC and GTGAC, with our measure of verbal memory (Rey Auditory Verbal Learning Test), of visual memory (Rey Complex Figure Test) in the case of GAGAC, and of speed of processing (WAIS-III Digit Symbol-coding) in the case of GTGAC.
Our findings add further evidence suggesting an association between dysbindin gene variability and cognitive abnormalities in schizophrenia, providing preliminary evidence of this association since the time of illness onset among minimally medicated patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
251Biochim. Biophys. Acta 2016 Aug 1862: 1383-91
PMID27130439
TitleSchizophrenia susceptibility gene product dysbindin-1 regulates the homeostasis of cyclin D1.
AbstractDysbindin-1 (dystrobrevin binding protein-1, DTNBP1) is now widely accepted as a potential schizophrenia susceptibility gene and accumulating evidence indicates its functions in the neural development. In this study, we tried to identify new binding partners for dysbindin-1 to clarify the novel function of this molecule. When consulted with BioGRID protein interaction database, cyclin D3 was found to be a possible binding partner for dysbindin-1. We then examined the interaction between various dysbindin-1 isoforms (dysbindin-1A, -1B and -1C) and all three D-type cyclins (cyclin D1, D2, and D3) by immunoprecipitation with the COS7 cell expression system, and found that dysbindin-1A preferentially interacts with cyclin D1. The mode of interaction between these molecules was considered as direct binding since recombinant dysbindin-1A and cyclin D1 formed a complex in vitro. Mapping analyses revealed that the C-terminal region of dysbindin-1A binds to the C-terminal of cyclin D1. Consistent with the results of the biochemical analyses, endogenous dysbindin-1was partially colocalized with cyclin D1 in NIH3T3 fibroblast cells and in neuronal stem and/or progenitor cells in embryonic mouse brain. While co-expression of dysbindin-1A with cyclin D1 changed the localization of the latter from the nucleus to cytosol, cyclin D1-binding partner CDK4 inhibited the dysbindin-cyclin D1 interaction. Meanwhile, depletion of endogenous dysbindin-1A increased cyclin D1 expression. These results indicate that dysbindin-1A may control the cyclin D1 function spatiotemporally and might contribute to better understanding of the pathophysiology of dysbindin-1-associated disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
252Schizophr Res Cogn 2016 Jun 4: 4-9
PMID27069875
TitleKynurenine pathway and cognitive impairments in schizophrenia: Pharmacogenetics of galantamine and memantine.
AbstractThe Measurement and Treatment Research to Improve Cognition in schizophrenia (MATRICS) project designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia, identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. Galantamine is an acetylcholinesterase inhibitor and a positive allosteric modulator of the ?7 nicotinic receptors. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist. There is evidence to suggest that the combination of galantamine and memantine may be effective in the treatment of cognitive impairments in schizophrenia. There is a growing body of evidence that excess kynurenic acid (KYNA) is associated with cognitive impairments in schizophrenia. The ?-7 nicotinic and the NMDA receptors may counteract the effects of kynurenic acid (KYNA) resulting in cognitive enhancement. Galantamine and memantine through its ?-7 nicotinic and NMDA receptors respectively may counteract the effects of KYNA thereby improving cognitive impairments. The Single Nucleotide Polymorphisms in the Cholinergic Receptor, Nicotinic, Alpha 7 gene (CHRNA7), Glutamate (NMDA) Receptor, Metabotropic 1 (GRM1) gene, Dystrobrevin Binding Protein 1 (DTNBP1) and kynurenine 3-monooxygenase (KMO) gene may predict treatment response to galantamine and memantine combination for cognitive impairments in schizophrenia in the kynurenine pathway.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
253J Neurodev Disord 2016 -1 8: 14
PMID27134685
TitleEffects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus.
AbstractNeurodevelopmental disorders such as autism spectrum disorders and schizophrenia differentially impact males and females and are highly heritable. The ways in which sex and genetic vulnerability influence the pathogenesis of these disorders are not clearly understood. The n-methyl-d-aspartate (NMDA) receptor pathway has been implicated in schizophrenia and autism spectrum disorders and changes dramatically across postnatal development at the level of the GluN2B-GluN2A subunit "switch" (a shift from reliance on GluN2B-containing receptors to reliance on GluN2A-containing receptors). We investigated whether sex and genetic vulnerability (specifically, null mutation of DTNBP1 [dysbindin; a possible susceptibility gene for schizophrenia]) influence the developmental GluN2B-GluN2A switch.
Subcellular fractionation to enrich for postsynaptic density (PSD), together with Western blotting and kinase assay, were used to investigate the GluN2B-GluN2A switch in the cortex and hippocampus of male and female DTNBP1 null mutant mice and their wild-type littermates. Main effects of sex and DTNBP1 genotype, and interactions with age, were assessed using factorial ANOVA.
Sex differences in the GluN2B-GluN2A switch emerged across development at the frontal cortical synapse, in parameters related to GluN2B. Males across genotypes displayed higher GluN2B:GluN2A and GluN2B:GluN1 ratios (p?DTNBP1 were evident exclusively in the hippocampus. The developmental trajectory of GluN2B was disrupted in DTNBP1 null mice (genotype??age interaction p?Sex and DTNBP1 mutation influence the GluN2B-GluN2A switch at the synapse in a brain-region-specific fashion involving pY1472-GluN2B, Fyn, and PLC?. This highlights the possible mechanisms through which risk factors may mediate their effects on vulnerability to disorders of NMDA receptor dysfunction.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal
254Mol. Neurobiol. 2016 Feb -1: -1
PMID26873854
TitleNeuronal Activity-Induced Sterol Regulatory Element Binding Protein-1 (SREBP1) is Disrupted in Dysbindin-Null Mice-Potential Link to Cognitive Impairment in Schizophrenia.
Abstractschizophrenia is a chronic debilitating neuropsychiatric disorder that affects about 1% of the population. Dystrobrevin-binding protein 1 (DTNBP1 or dysbindin) is one of the Research Domain Constructs (RDoC) associated with cognition and is significantly reduced in the brain of schizophrenia patients. To further understand the molecular underpinnings of pathogenesis of schizophrenia, we have performed microarray analyses of the hippocampi from dysbindin knockout mice, and found that genes involved in the lipogenic pathway are suppressed. Moreover, we discovered that maturation of a master transcriptional regulator for lipid synthesis, sterol regulatory element binding protein-1 (SREBP1) is induced by neuronal activity, and is required for induction of the immediate early gene ARC (activity-regulated cytoskeleton-associated protein), necessary for synaptic plasticity and memory. We found that nuclear SREBP1 is dramatically reduced in dysbindin-1 knockout mice and postmortem brain tissues from human patients with schizophrenia. Furthermore, activity-dependent maturation of SREBP1 as well as ARC expression were attenuated in dysbindin-1 knockout mice, and these deficits were restored by an atypical antipsychotic drug, clozapine. Together, results indicate an important role of dysbindin-1 in neuronal activity induced SREBP1 and ARC, which could be related to cognitive deficits in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypy, schizophrenias, schizotypal