1Genomics 2000 Jul 67: 69-77
PMID10945471
TitleChromosomal location and genomic structure of the human translin-associated factor X gene (TRAX; TSNAX) revealed by intergenic splicing to DISC1, a gene disrupted by a translocation segregating with schizophrenia.
AbstractTwo candidate genes, DISC1 and DISC2 on chromosome 1, are disrupted by a translocation that segregates with major psychiatric illness. Several DISC1 transcripts contain TRAX (HGMW-approved symbol TSNAX) sequence at the 5' end. These transcripts initiate at the 5' end of TRAX and terminate at the final exon of DISC1. Five species of transcript resulting from intergenic splicing have been identified; one encodes a novel TRAX/DISC1 fusion protein. The remaining four transcripts are bicistronic and encode a series of novel truncated isoforms of TRAX and DISC1. Demonstration that the various TRAX/DISC1 transcripts are translated awaits further experimentation. As a consequence of the observation of intergenic splicing, the human TRAX gene has been mapped at least 35 kb proximal to DISC1 and within approximately 150-250 kb of the translocation breakpoint at 1q42.1. The TRAX gene consists of six exons with a putative CpG island at the 5' end. Four major transcripts are produced from this gene, of which the smallest, at 2.7 kb, had previously been identified.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
2Hum. Mol. Genet. 2000 May 9: 1415-23
PMID10814723
TitleDisruption of two novel genes by a translocation co-segregating with schizophrenia.
AbstractA balanced (1;11)(q42.1;q14.3) translocation segregates with schizophrenia and related psychiatric disorders in a large Scottish family (maximum LOD = 6.0). We hypothesize that the translocation is the causative event and that it directly disrupts gene function. We previously reported a dearth of genes in the breakpoint region of chromosome 11 and it is therefore unlikely that the expression of any genes on this chromosome has been affected by the translocation. By contrast, the corresponding region on chromosome 1 is gene dense and, not one, but two novel genes are directly disrupted by the translocation. These genes have been provisionally named Disrupted-In-schizophrenia 1 and 2 ( DISC1 and DISC2 ). DISC1 encodes a large protein with no significant sequence homology to other known proteins. It is predicted to consist of a globular N-terminal domain(s) and helical C-terminal domain which has the potential to form a coiled-coil by interaction with another, as yet, unidentified protein(s). Similar structures are thought to be present in a variety of unrelated proteins that are known to function in the nervous system. The putative structure of the protein encoded by DISC1 is therefore compatible with a role in the nervous system. DISC2 apparently specifies a non-coding RNA molecule that is antisense to DISC1, an arrangement that has been observed at other loci where it is thought that the antisense RNA is involved in regulating expression of the sense gene. Altogether, these observations indicate that DISC1 and DISC2 should be considered formal candidate genes for susceptibility to psychiatric illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
3Psychiatr. Genet. 2001 Jun 11: 71-8
PMID11525420
TitleIdentification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder.
AbstractWe have undertaken a search for polymorphic sequence variation within Disrupted in schizophrenia 1 and Disrupted in schizophrenia 2 (DISC1 and DISC2), which are both novel genes that span a translocation breakpoint strongly associated with schizophrenia and related psychoses in a large Scottish family. A scan of the coding sequence, intron/exon boundaries, and part of the 5' and 3' untranslated regions of DISC1, plus 2.7 kb at the 3' end of DISC2, has revealed a novel microsatellite and 15 novel single nucleotide polymorphisms (SNPs). We have tracked the inheritance of four of the SNPs through multiply affected families, and carried out case-control association studies using the microsatellite and four common SNPs on populations of patients with schizophrenia or bipolar affective disorder versus normal control subjects. Neither co-segregation with disease status nor significant association was detected; however, we could not detect linkage disequilibrium between all these markers in the control population, arguing that an even greater density of informative markers is required to test rigorously for association in this genomic region.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
4Mol. Psychiatry 2001 Mar 6: 173-8
PMID11317219
TitleGenomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia.
AbstractTwo overlapping and antiparallel genes on chromosome 1, Disrupted In schizophrenia 1 and 2 (DISC1 and DISC2), are disrupted by a (1;11)(q42.1;q14.3) translocation which segregates with schizophrenia through at least four generations of a large Scottish family. Consequently, these genes are worthy of further investigation as candidate genes potentially involved in the aetiology of major psychiatric illness. We have constructed a contiguous clone map of PACs and cosmids extending across at least 400 kb of the chromosome 1 translocation breakpoint region and this has provided the basis for examination of the genomic structure of DISC1. The gene consists of thirteen exons, estimated to extend across at least 300 kb of DNA. The antisense gene DISC2 overlaps with exon 9. Exon 11 contains an alternative splice site that removes 66 nucleotides from the open reading frame. The final intron of DISC1 belongs to the rare AT-AC class of introns. We have also mapped marker DIS251 in close proximity to DISC1, localising the gene within a critical region identified by several independent studies. Information regarding the structure of the DISC1 gene will facilitate assessment of its involvement in the aetiology of major mental illness in psychotic individuals unrelated to carriers of the translocation.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
5Neurosci. Res. 2001 Jun 40: 105-13
PMID11377748
TitleMolecular genetics of bipolar disorder.
AbstractAlteration of monoaminergic neurotransmission is implicated in the pathophysiology of bipolar disorder (manic-depressive illness). Candidate genes participating in monoaminergic neurotransmission, especially serotonin transporter and monoamine oxidase A, may be associated with bipolar disorder. And the regulating regions of these genes and the molecules participating in intracellular signal transduction are now under investigation. To date, 13 whole genome positional cloning studies have been performed and many candidate loci identified. Using patients from a pedigree in which schizophrenia, depression or bipolar disorder have been linked with a balanced translocation at 1 and 11, candidate pathogenetic genes were cloned as DISC1 (disrupted in schizophrenia-1) and DISC2. Recently, pathogenetic mutations have been identified in two genetic diseases frequently co-morbid with mood disorder; WFS1 for Wolfram syndrome and ATP2A2 (SERCA2) for Darier's disease. Transmission of bipolar disorder may be characterized by anticipation and parent-of-origin effect, and extended CTG repeat at SEF2-1B gene was identified from a bipolar patient. However, its pathogenetic role was not supported by subsequent studies. Association of bipolar disorder with mitochondrial DNA has also been suggested. The role of genomic imprinting is also possible because linkage to 18p11 is limited to paternally transmitted pedigrees. These results warrant further study of molecular genetics of bipolar disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
6Hum. Mol. Genet. 2001 Jul 10: 1611-7
PMID11468279
TitleChromosome 1 loci in Finnish schizophrenia families.
AbstractWe have earlier reported evidence for linkage to two regions on chromosome 1q32--q42 in schizophrenia families collected for two separate studies in Finland. Here we report the results of a fine mapping effort aimed at further definition of the chromosomal region of interest using a large, population-based study sample (221 families, 557 affected individuals). Most affecteds (78%) had a DSM-IV schizophrenia diagnosis and the remaining had schizophrenia spectrum disorders. We genotyped a total of 147 microsatellite markers on a wide 45 cM region of chromosome 1q. The results were analyzed separately for families originating from an internal isolate of Finland and for families from the rest of Finland, as well as for all families jointly. We used traditional two-point linkage analysis, SimWalk2 multipoint analysis and a novel gamete-competition association/linkage method. Evidence for linkage was obtained for one locus in the combined sample (Z(max) = 2.71, D1S2709) and in the nuclear families from outside the internal isolate (Z(max) = 3.21, D1S2709). In the families from the internal isolate the strongest evidence for linkage was obtained with markers located 22 cM centromeric from this marker (Z(max) = 2.30, D1S245). Multipoint analysis also indicated these loci. Some evidence for association with several markers was observed using the gamete-competition method. Interestingly, the strongest evidence for linkage in the combined study sample was obtained for marker D1S2709, which is an intragenic marker of the DISC1 gene, previously suggested as a susceptibility gene for schizophrenia. These results are consistent with the presence of susceptibility gene(s) in this chromosomal region, a result also implied in other recent family studies of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
7Am. J. Hum. Genet. 2001 Aug 69: 428-33
PMID11443544
TitleSchizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family.
AbstractA family with a (1;11)(q42;q14.3) translocation significantly linked to a clinical phenotype that includes schizophrenia and affective disorders is described. This translocation generates a LOD score of 3.6 when the disease phenotype is restricted to schizophrenia, of 4.5 when the disease phenotype is restricted to affective disorders, of 7.1 when relatives with recurrent major depression, with bipolar disorder, or with schizophrenia are all classed as affected. This evidence for linkage is among the strongest reported for a psychiatric disorder. Family members showed no distinctive features by which the psychiatric phenotype could be distinguished from unrelated cases of either schizophrenia or affective disorders, and no physical, neurological, or dysmorphic conditions co-occurred with psychiatric symptoms. Translocation carriers and noncarriers had the same mean intelligence quotient. Translocation carriers were similar to subjects with schizophrenia and different from noncarriers and controls, in showing a significant reduction in the amplitude of the P300 event-related potential (ERP). Furthermore, P300 amplitude reduction and latency prolongation were measured in some carriers of the translocation who had no psychiatric symptoms-a pattern found in other families with multiple members with schizophrenia, in which amplitude of and latency of P300 appear to be trait markers of risk. The results of karyotypic, clinical, and ERP investigations of this family suggest that the recently described genes DISC1 and DISC2, which are directly disrupted by the breakpoint on chromosome 1, may have a role in the development of a disease phenotype that includes schizophrenia as well as unipolar and bipolar affective disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
8Genomics 2002 Dec 80: 662-72
PMID12504857
TitleCloning and characterization of Disc1, the mouse ortholog of DISC1 (Disrupted-in-Schizophrenia 1).
AbstractWe cloned the mouse ortholog of DISC1 (Disrupted-in-schizophrenia 1), a candidate gene for schizophrenia. DISC1 is 3163 nucleotides long and has 60% identity with the human DISC1. DISC1 encodes 851 amino acids and has 56% identity with the human protein. DISC1 maps to the DISC1 syntenic region in the mouse, and genomic structure is conserved. A DISC1 splice variant deletes a portion of DISC1 beginning at amino acids orthologous to the human truncation. Bioinformatic analysis and cross-species comparisons revealed sequence conservation distributed across the genes and conservation of leucine zipper and coiled-coil domains in both orthologs. In situ hybridization in adult mouse brain revealed a restricted expression pattern, with highest levels in the dentate gyrus of the hippocampus and lower expression in CA1-CA3 of the hippocampus, cerebellum, cerebral cortex, and olfactory bulbs. Identification of DISC1 will facilitate the study of DISC1's function and creation of mouse models of DISC1 disruption.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
9Genomics 2003 Jan 81: 67-77
PMID12573262
TitleEvolutionary constraints on the Disrupted in Schizophrenia locus.
AbstractThe Disrupted in schizophrenia (DISC) locus on human chromosome 1q42 has been strongly implicated by genetic studies as a susceptibility locus for major mental illnesses. In humans the locus is transcriptionally complex, with multiple alternate splicing events, antisense transcription, and intergenic splicing all evident. We have compared the genomic sequence and transcription maps of this locus between human, mouse, pufferfish (Fugu rubripes), and, in part, zebrafish (Danio rerio). The order and orientation of EGLN1, TSNAX, and DISC1 genes are conserved between mammals and F. rubripes. Intergenic splicing and short intergenic transcripts are not found to be conserved features. DISC2, a putative noncoding transcript partially antisense to DISC1, is not conserved in mouse or F. rubripes. Alternate splice forms of the protein-coding DISC1 gene are conserved even though the genomic structure is not. The amino acid sequence of DISC1 is diverging rapidly, although a putative nuclear localization signal and discrete blocks of coiled coil are specifically conserved features.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
10Neuroreport 2003 May 14: 951-4
PMID12802181
TitleDISC1 (Disrupted in Schizophrenia-1) is expressed in limbic regions of the primate brain.
AbstractDisrupted in schizophrenia-1 (DISC1) was identified as truncated by a balanced translocation segregating with schizophrenia and other major mental illness in a large Scottish family. As a step in evaluating the function of DISC1 and its potential role in human schizophrenia, we have determined its regional expression in the primate brain by in situ hybridization. DISC1 expression is highly localized, with most prominent expression in the dentate gyrus of the hippocampus and lateral septum, and lower levels of expression in the cerebral cortex, amygdala, paraventricular hypothalamus, cerebellum, interpeduncular nucleus, and subthalamic nucleus. Given that many of these regions have been implicated in schizophrenia pathogenesis, these results suggest brain circuits through which DISC1 truncation may predispose to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
11Mol. Psychiatry 2003 Jul 8: 685-94
PMID12874605
TitleDisrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth.
AbstractDisrupted-In-schizophrenia 1 (DISC1) was identified as a novel gene disrupted by a (1;11)(q42.1;q14.3) translocation that segregated with schizophrenia in a Scottish family. Predicted DISC1 product has no significant homology to other known proteins. Here, we demonstrated the existence of DISC1 protein and identified fasciculation and elongation protein zeta-1 (FEZ1) as an interacting partner of DISC1 by a yeast two-hybrid study. FEZ1 and its nematode homolog are reported to represent a new protein family involved in axonal outgrowth and fasciculation. In cultured hippocampal neurons, DISC1 and FEZ1 colocalized in growth cones. Interactions of these proteins were associated with F-actin. In the course of neuronal differentiation of PC12 cells, upregulation of DISC1/FEZ1 interaction was observed as along with enhanced extension of neurites by overexpression of DISC1. The present study shows that DISC1 participates in neurite outgrowth through its interaction with FEZ1. Recent studies have provided reliable evidence that schizophrenia is a neurodevelopmental disorder. As there is a high level of DISC1 expression in developing rat brain, dysfunction of DISC1 may confer susceptibility to psychiatric illnesses through abnormal development of the nervous system.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
12Biochem. Biophys. Res. Commun. 2003 Nov 311: 1019-25
PMID14623284
TitleYeast two-hybrid screens implicate DISC1 in brain development and function.
AbstractDISC1 is a candidate gene for involvement in the aetiology of major psychiatric illnesses including schizophrenia. We report here the results of DISC1 yeast two-hybrid screens using human foetal and adult brain libraries. Twenty-one proteins from a variety of subcellular locations were identified, consistent with observations that DISC1 occupies multiple subcellular compartments. The cellular roles of the proteins identified implicate DISC1 in several aspects of central nervous system development and function, including gene transcription, mitochondrial function, modulation of the actin cytoskeleton, neuronal migration, glutamate transmission, and signal transduction. Intriguingly, mutations in one of the proteins identified, WKL1, have been previously suggested to underlie the aetiology of catatonic schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
13Hum. Mol. Genet. 2003 Jul 12: 1591-608
PMID12812986
TitleDISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation.
AbstractDisrupted-In-schizophrenia 1 (DISC1) is a novel gene associated with schizophrenia by multiple genetic studies. In order to determine how mutations in DISC1 might cause susceptibility to schizophrenia, we undertook a comprehensive study of the cellular biology of DISC1 in its full-length and disease-associated mutant forms. DISC1 interacts by yeast two-hybrid, mammalian two-hybrid, and co-immunoprecipitation assays with multiple proteins of the centrosome and cytoskeletal system, including MIPT3, MAP1A and NUDEL; proteins which localize receptors to membranes, including alpha-actinin2 and beta4-spectrin; and proteins which transduce signals from membrane receptors, including ATF4 and ATF5. Truncated mutant DISC1 fails to interact with ATF4, ATF5 or NUDEL. Deletion mapping demonstrated that DISC1 has distinct interaction domains: MAP1A interacts via its LC2 domain with the N-terminus of DISC1, whereas MIPT3 and NUDEL bind via their C-terminal domains to the central coiled-coil domain of DISC1, and ATF4/5 bind via their C-terminal domains to the C-terminus of DISC1. In its full-length form, DISC1 protein localizes to predominantly perinuclear punctate structures which extend into neurites in some cells; mutant truncated DISC1, by contrast, is seen in a diffuse pattern throughout the cytoplasm and abundantly in neurites. Both forms co-localize with the centrosomal complex, although truncated less abundantly than full-length DISC1. Although both full-length and mutant DISC1 are found in microtubule fractions, neither form of DISC1 appears to bind directly to microtubules, but rather do so in a MIPT3-dependent fashion that is stabilized by taxol. Based on these data, we propose that DISC1 is a multifunctional protein whose truncation contributes to schizophrenia susceptibility by disrupting intracellular transport, neurite architecture and/or neuronal migration, all of which have been hypothesized to be pathogenic in the schizophrenic brain.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
14Hum. Mol. Genet. 2003 Jul 12: 1591-608
PMID12812986
TitleDISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation.
AbstractDisrupted-In-schizophrenia 1 (DISC1) is a novel gene associated with schizophrenia by multiple genetic studies. In order to determine how mutations in DISC1 might cause susceptibility to schizophrenia, we undertook a comprehensive study of the cellular biology of DISC1 in its full-length and disease-associated mutant forms. DISC1 interacts by yeast two-hybrid, mammalian two-hybrid, and co-immunoprecipitation assays with multiple proteins of the centrosome and cytoskeletal system, including MIPT3, MAP1A and NUDEL; proteins which localize receptors to membranes, including alpha-actinin2 and beta4-spectrin; and proteins which transduce signals from membrane receptors, including ATF4 and ATF5. Truncated mutant DISC1 fails to interact with ATF4, ATF5 or NUDEL. Deletion mapping demonstrated that DISC1 has distinct interaction domains: MAP1A interacts via its LC2 domain with the N-terminus of DISC1, whereas MIPT3 and NUDEL bind via their C-terminal domains to the central coiled-coil domain of DISC1, and ATF4/5 bind via their C-terminal domains to the C-terminus of DISC1. In its full-length form, DISC1 protein localizes to predominantly perinuclear punctate structures which extend into neurites in some cells; mutant truncated DISC1, by contrast, is seen in a diffuse pattern throughout the cytoplasm and abundantly in neurites. Both forms co-localize with the centrosomal complex, although truncated less abundantly than full-length DISC1. Although both full-length and mutant DISC1 are found in microtubule fractions, neither form of DISC1 appears to bind directly to microtubules, but rather do so in a MIPT3-dependent fashion that is stabilized by taxol. Based on these data, we propose that DISC1 is a multifunctional protein whose truncation contributes to schizophrenia susceptibility by disrupting intracellular transport, neurite architecture and/or neuronal migration, all of which have been hypothesized to be pathogenic in the schizophrenic brain.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
15Hum. Mol. Genet. 2003 Dec 12: 3151-9
PMID14532331
TitleHaplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects.
AbstractWe have previously reported a linkage peak on 1q42 in a Finnish schizophrenia sample. In this study we genotyped 28 single nucleotide polymorphisms (SNPs) from 1q42 covering the three candidate genes TRAX, DISC1 and DISC2, using a study sample of 458 Finnish families ascertained for schizophrenia. Two-point and haplotype association analysis revealed a significant region of interest within the DISC1 gene. A common haplotype (HEP3) was observed to be significantly under-transmitted to affected individuals (P=0.0031). HEP3 represents a two SNP haplotype spanning from intron 1 to exon 2 of DISC1. This haplotype also displayed sex differences in transmission distortion, the under-transmission being significant only to affected females (P=0.00024). Three other regions of interest were observed in the TRAX and DISC genes. However, analysis of only those families with complete genotype information specifically highlights the HEP3 haplotype as a true observation. The finding of a common under-transmitted SNP haplotype might imply that this particular allele offers some protection from the development of schizophrenia. Analysis of component-traits of schizophrenia, derived from the Operational Criteria Checklist of Psychotic Illness (OCCPI), displayed association of HEP3 to features of the general phenotype of schizophrenia, including traits representing delusions, hallucinations and negative symptoms. This study provides further evidence for the hypothesis that the DISC1 gene is involved in the aetiology of schizophrenia, and implies a putative sex difference for the effect of the gene. Our findings would also encourage more detailed analyses of the effect of DISC1 on the component-traits of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
16Neurosci. Lett. 2004 Sep 368: 41-5
PMID15342131
TitleAssociation study of polymorphisms in the 5' upstream region of human DISC1 gene with schizophrenia.
AbstractDisrupted-in-schizophrenia-1 (DISC1) is a gene in which a mutant truncation by a balanced t(1;11)(p42.1;q14.3) translocation is segregated with major psychiatric illness with a predominance of schizophrenic symptomatology in a large Scottish family. However, no functional polymorphisms have been detected that are associated with schizophrenia in general populations. As prior polymorphism searches in DISC1 have been focused on coding exons and flanking introns, the present study examined sequence variations in the 5' upstream region of DISC1. Screening of exon 1 through to approximately 1.0 kb upstream of exon 1 identified 6 polymorphisms, including 2 novel variants, -94C>A and -199(CG)(n). We tested these variants for associations with schizophrenia in the first set of a case (n = 198) and control (n = 198) panel, and found significant results with -274G>C (genotypic P = 0.01) and -215(TG)(n) (genotypic P = 0.039). However, we failed to replicate these associations in a second, larger independent patient (n = 532) and control (n = 519) sample. These results suggest that the genomic interval of DISC1 probably involved in transcriptional regulation does not display major genetic relevance in Japanese schizophrenia patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
17Mol. Psychiatry 2004 Dec 9: 1100-10
PMID15381924
TitleExpression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment.
AbstractDisrupted in schizophrenia 1 (DISC1) was identified as a potential susceptibility gene for schizophrenia due to its disruption by a balanced t(1;11) (q42;q14) translocation, which has been shown to cosegregate with major psychiatric disease in a large Scottish family. We have recently presented evidence that DISC1 exists in a neurodevelopmentally regulated protein complex with Nudel. In this study, we report the protein expression profile of DISC1 in the adult and developing mouse brain utilizing immunohistochemistry and quantitative Western blot. In the adult mouse brain, DISC1 is expressed in neurons within various brain areas including the olfactory bulb, cortex, hippocampus, hypothalamus, cerebellum and brain stem. During development, DISC1 protein is detected at all stages, from E10 to 6 months old, with two significant peaks of protein expression of a DISC1 isoform at E13.5 and P35. Interestingly, these time points correspond to critical stages during mouse development, the active neurogenesis period in the developing brain and the period of puberty. Together, these results suggest that DISC1 may play a critical role in brain development, consistent with the neurodevelopmental hypothesis of the etiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
18Ann. Med. 2004 -1 36: 367-78
PMID15478311
TitleDISC1 and DISC2: discovering and dissecting molecular mechanisms underlying psychiatric illness.
AbstractA balanced (1;11)(q42;q14) translocation co-segregates with schizophrenia and major affective disorders in a large Scottish family. The translocation breakpoint on chromosome 1 is located within the Disrupted in schizophrenia 1 and 2 genes (DISC1 and DISC2). Consequently loss of normal function of these genes is likely to underlie the susceptibility to developing psychiatric disorders that is conferred by inheritance of the translocation. Additionally, a number of independent genetic studies highlight the region of chromosome 1q containing DISC1 and DISC2 as a likely susceptibility locus for both schizophrenia and affective disorders. These genes are thus implicated in the aetiology of major psychiatric disorders in several populations. Although the function of DISC1 was initially unknown, several recent reports have made significant progress towards understanding its role in the central nervous system. Intriguingly, all data obtained to date point towards an involvement in processes critical to neurodevelopment and function. DISC2 has not been studied in detail, but is likely to modulate DISC1 expression. Overall, it is clear from the combination of genetic and functional data that DISC1 and/or DISC2 are emerging as important factors in the molecular genetics of psychiatric illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
19Mol. Psychiatry 2004 Dec 9: 1083-90
PMID15249933
TitleA genome scan and follow-up study identify a bipolar disorder susceptibility locus on chromosome 1q42.
AbstractIn this study, we report a genome scan for psychiatric disease susceptibility loci in 13 Scottish families. We follow up one of the linkage peaks on chromosome 1q in a substantially larger sample of 22 families affected by schizophrenia (SCZ) or bipolar affective disorder (BPAD). To minimise the effect of genetic heterogeneity, we collected mainly large extended families (average family size >18). The families collected were Scottish, carried no chromosomal abnormalities and were unrelated to the large family previously reported as segregating a balanced (1:11) translocation with major psychiatric disease. In the genome scan, we found linkage peaks with logarithm of odds (LOD) scores >1.5 on chromosomes 1q (BPAD), 3p (SCZ), 8p (SCZ), 8q (BPAD), 9q (BPAD) and 19q (SCZ). In the follow-up sample, we obtained most evidence for linkage to 1q42 in bipolar families, with a maximum (parametric) LOD of 2.63 at D1S103. Multipoint variance components linkage gave a maximum LOD of 2.77 (overall maximum LOD 2.47 after correction for multiple tests), 12 cM from the previously identified SCZ susceptibility locus DISC1. Interestingly, there was negligible evidence for linkage to 1q42 in the SCZ families. These results, together with results from a number of other recent studies, stress the importance of the 1q42 region in susceptibility to both BPAD and SCZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
20Am. J. Hum. Genet. 2004 Nov 75: 862-72
PMID15386212
TitleDisrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder.
Abstractschizophrenia, schizoaffective disorder, and bipolar disorder are common psychiatric disorders with high heritabilities and variable phenotypes. The Disrupted in schizophrenia 1 (DISC1) gene, on chromosome 1q42, was originally discovered and linked to schizophrenia in a Scottish kindred carrying a balanced translocation that disrupts DISC1 and DISC2. More recently, DISC1 was linked to schizophrenia, broadly defined, in the general Finnish population, through the undertransmission to affected women of a common haplotype from the region of intron 1/exon 2. We present data from a case-control study of a North American white population, confirming the underrepresentation of a common haplotype of the intron 1/exon 2 region in individuals with schizoaffective disorder. Multiple haplotypes contained within four haplotype blocks extending between exon 1 and exon 9 are associated with schizophrenia, schizoaffective disorder, and bipolar disorder. We also find overrepresentation of the exon 9 missense allele Phe607 in schizoaffective disorder. These data support the idea that these apparently distinct disorders have at least a partially convergent etiology and that variation at the DISC1 locus predisposes individuals to a variety of psychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
21Neurosci. Lett. 2004 Sep 368: 41-5
PMID15342131
TitleAssociation study of polymorphisms in the 5' upstream region of human DISC1 gene with schizophrenia.
AbstractDisrupted-in-schizophrenia-1 (DISC1) is a gene in which a mutant truncation by a balanced t(1;11)(p42.1;q14.3) translocation is segregated with major psychiatric illness with a predominance of schizophrenic symptomatology in a large Scottish family. However, no functional polymorphisms have been detected that are associated with schizophrenia in general populations. As prior polymorphism searches in DISC1 have been focused on coding exons and flanking introns, the present study examined sequence variations in the 5' upstream region of DISC1. Screening of exon 1 through to approximately 1.0 kb upstream of exon 1 identified 6 polymorphisms, including 2 novel variants, -94C>A and -199(CG)(n). We tested these variants for associations with schizophrenia in the first set of a case (n = 198) and control (n = 198) panel, and found significant results with -274G>C (genotypic P = 0.01) and -215(TG)(n) (genotypic P = 0.039). However, we failed to replicate these associations in a second, larger independent patient (n = 532) and control (n = 519) sample. These results suggest that the genomic interval of DISC1 probably involved in transcriptional regulation does not display major genetic relevance in Japanese schizophrenia patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
22Mol. Cell. Neurosci. 2004 Jan 25: 42-55
PMID14962739
TitleDisrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders.
AbstractDisrupted In schizophrenia 1 (DISC1) was identified as a potential susceptibility gene for schizophrenia due to its disruption by a balanced t(1;11) (q42;q14) translocation, which has been shown to cosegregate with major psychiatric disease in a large Scottish family. We have demonstrated that DISC1 exists in a neurodevelopmentally regulated protein complex with Nudel. The complex is abundant at E17 and in early postnatal life but is greatly reduced in the adult. Nudel has previously been shown to bind Lis1, a gene underlying lissencephaly in humans. Critically, we show that the predicted peptide product resulting from the Scottish translocation removes the interaction domain for Nudel. DISC1 interacts with Nudel through a leucine zipper domain and binds to a novel DISC1-interaction domain on Nudel, which is independent from the Lis1 binding site. We show that Nudel is able to act as a bridge between DISC1 and Lis1 to allow formation of a trimolecular complex. Nudel has been implicated to play a role in neuronal migration, together with the developmental variation in the abundance of the DISC1-Nudel complex, may implicate a defective DISC1-Nudel complex as a neurodevelopmental cause of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
23Mol. Psychiatry 2004 Nov 9: 1037-41
PMID15197400
TitleReplication of 1q42 linkage in Finnish schizophrenia pedigrees.
AbstractChromosome 1q has been implicated in the etiology of schizophrenia in several independent studies. However, the peak linkage findings have been dispersed over a large chromosomal region, with negative findings in this region also being reported. Our group has previously observed linkage on chromosome 1q42, maximizing within the DISC1 gene, which has also been implied in the etiology of schizophrenia based on functional studies. In the study presented here, we genotyped 300 polymorphic markers on chromosome 1 using a study sample of 70 families with multiple individuals affected with schizophrenia or related conditions, independent of the study samples in our previous reports. We again found evidence for linkage on 1q42 maximizing within the DISC1 gene (rs1000731, lod=2.70). Further, a haplotype containing the most strongly linked markers showed some evidence of association with the disease. This replicates the previous linkage finding in the same region and constitutes supportive evidence for a susceptibility gene in this region.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
24Mol. Cell. Neurosci. 2004 May 26: 112-22
PMID15121183
TitleDisrupted in Schizophrenia 1 (DISC1) is a multicompartmentalized protein that predominantly localizes to mitochondria.
AbstractDISC1 is disrupted by a chromosomal translocation cosegregating with schizophrenia and recurrent major depression in a large Scottish family and has also been reported as a potential susceptibility locus in independent populations. We reveal a widespread and complex pattern of DISC1 expression, with at least five forms of Disrupted in schizophrenia 1 DISC1 detectable. Mitochondria are the predominant site of DISC1 expression with additional nuclear, cytoplasmic, and actin-associated locations evident. Although the subcellular targeting of DISC1 is clearly complex, the association with mitochondria is of interest as many mitochondrial deficits have been reported in schizophrenia and other neuropsychiatric illnesses. Moreover, of the many cellular functions performed by mitochondria, their role in oxidative phosphorylation, calcium homeostasis, and apoptosis may hold particular relevance for the neuronal disturbances believed to be involved in the pathogenesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
25Brain Res. Mol. Brain Res. 2004 Mar 122: 89-92
PMID14992819
TitleExpression of fasciculation and elongation protein zeta-1 (FEZ1) in the developing rat brain.
AbstractFasciculation and elongation protein zeta-1 (FEZ1) is a mammalian homologue of the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth and fasciculation. Recently, we reported that FEZ1 interacts with Disrupted-In-schizophrenia 1 (DISC1), a product of the candidate gene for schizophrenia, and that the interaction between these proteins has a role in neurite outgrowth. This time, we investigated the expression of FEZ1 and DISC1 in the developing rat brain using in situ hybridization. Both FEZ1 and DISC1 showed high levels of expression, especially in developing hippocampal neurons. These findings suggest the potential involvement of FEZ1 and DISC1 in the formation of hippocampal neural circuits.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
26Nihon Shinkei Seishin Yakurigaku Zasshi 2004 Apr 24: 87-91
PMID15164617
Title[DISC1 and schizophrenia].
AbstractMolecular mechanisms underlying the pathogenesis of schizophrenia remains elusive. The difficulty in accessing the mechanisms stems from, at least in part, multiple etiologies for schizophrenia. We have studied DISC1, as it was identified as a candidate gene for a schizophrenia-associated mental condition with the single etiology. Thus far, we have obtained evidence that DISC1 may have implications in neurodevelopment. This concept fits with many historical observations found for schizophrenia in association with neurodevelopmental abnormalities. DISC1 may become one of the key molecules in studying the pathogenesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
27Biochem. Biophys. Res. Commun. 2004 May 317: 1195-9
PMID15094396
TitleDISC1 localizes to the centrosome by binding to kendrin.
AbstractDisrupted-In-schizophrenia 1 (DISC1) was identified as a novel gene disrupted by a (1;11)(q42.1;q14.3) translocation that segregated with major mental disorders in a Scottish family. Using the yeast two-hybrid system, we screened a human brain cDNA library for interactors of the DISC1 protein. One of the positive clones encoded kendrin/pericentrin-B, a giant protein known to localize specifically to the centrosome. The interaction between DISC1 and kendrin in mammalian cells was demonstrated by an immunoprecipitation assay. Residues 446-533 of DISC1 were essential for the interaction with kendrin. Immunocytochemical analysis revealed the colocalization of DISC1 and kendrin to the centrosome. These data indicate that DISC1 localizes to the centrosome by binding to kendrin. Kendrin has been reported to anchor the gamma-tubulin complex to the centrosome, providing microtubule nucleation sites. The present study suggests the possible involvement of DISC1 in the pathophysiology of mental disorders due to its putative effect on centrosomal function.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
28Biol. Psychiatry 2004 Nov 56: 683-90
PMID15522253
TitleAssociation analysis of FEZ1 variants with schizophrenia in Japanese cohorts.
AbstractDISC1 has been suggested as a causative gene for psychoses in a large Scottish family. We recently identified FEZ1 as an interacting partner for DISC1. To investigate the role of FEZ1 in schizophrenia and bipolar disorder, case-control association analyses were conducted in Japanese cohorts.
We performed a mutation screen of the FEZ1 gene and detected 15 polymorphisms. Additional data on informative polymorphisms were obtained from public databases. Eight single nucleotide polymorphisms (SNPs) were analyzed in 119 bipolar disorder and 360 schizophrenic patients and age- and gender-matched control subjects. All genotypes were determined with the TaqMan assay, and selected samples were confirmed by sequencing.
The two adjacent polymorphisms displayed a nominally significant association with schizophrenia (IVS2+ 1587G>A, p = .014; 396Tschizophrenia patients but not in control subjects or bipolar patients. Conversely, no SNPs displayed allelic, genotypic, or haplotypic associations with bipolar disorder.
A modest association between FEZ1 and schizophrenia suggests that this gene and the DISC1-mediated molecular pathway might play roles in the development of schizophrenia, with FEZ1 affecting only a small subset of Japanese schizophrenia patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
29Neurotox Res 2004 -1 6: 35-41
PMID15184103
TitleClinical phenotypes associated with DISC1, a candidate gene for schizophrenia.
AbstractGenetic factors play an important part in the development of schizophrenia and bipolar disorder, and linkage analyses in families have successfully identified several chromosomal regions containing candidate genes. A single large pedigree has been described in which schizophrenia and depression segregate with a balanced chromosomal translocation involving the long arm of chromosome 1 and the short arm of chromosome 11. The gene named DISC1, disrupted at the chromosome 1 breakpoint, is a novel candidate gene that may have a role in the pathogenesis of schizophrenia. The cellular location and function of the protein coded by DISC1 is currently being investigated. The phenotype associated with DISC1 in the t (1;11) translocation family includes schizophrenia, schizoaffective disorder, recurrent major depression and bipolar disorder. Hence this locus is one of several now reported apparently showing linkage to both schizophrenia and bipolar disorder. The study of intermediate phenotypes or "endophenotypes" may clarify the relations between phenotype and genotype. Auditory event related potentials are EEG based physiological measures widely studied in schizophrenia. In particular the cognitive evoked potential, the P300 response generated during an "odd-ball" two-tone discrimination task consistently shows reduced amplitude in schizophrenia compared to controls. In members of the family with the t (1;11) translocation, P300 amplitude was reduced in relatives who carried the translocation compared to relatives with a normal karyotype. Furthermore the amplitude reduction was independent of the presence or absence of symptoms because asymptomatic translocation carriers showed similar P300 amplitude reduction as was found in translocation carriers who were diagnosed with schizophrenia, bipolar disorder or unipolar depression. The results confirm that subjects with schizophrenia who carry the t (1;11) translocation have similar phenotype to unrelated subjects with schizophrenia and a normal karyotype. Furthermore P300 amplitude may be a useful intermediate phenotype detecting the neuropathology of schizophrenia in "at risk" individuals even in the absence of clinical symptoms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
30Biol. Psychiatry 2004 Nov 56: 683-90
PMID15522253
TitleAssociation analysis of FEZ1 variants with schizophrenia in Japanese cohorts.
AbstractDISC1 has been suggested as a causative gene for psychoses in a large Scottish family. We recently identified FEZ1 as an interacting partner for DISC1. To investigate the role of FEZ1 in schizophrenia and bipolar disorder, case-control association analyses were conducted in Japanese cohorts.
We performed a mutation screen of the FEZ1 gene and detected 15 polymorphisms. Additional data on informative polymorphisms were obtained from public databases. Eight single nucleotide polymorphisms (SNPs) were analyzed in 119 bipolar disorder and 360 schizophrenic patients and age- and gender-matched control subjects. All genotypes were determined with the TaqMan assay, and selected samples were confirmed by sequencing.
The two adjacent polymorphisms displayed a nominally significant association with schizophrenia (IVS2+ 1587G>A, p = .014; 396Tschizophrenia patients but not in control subjects or bipolar patients. Conversely, no SNPs displayed allelic, genotypic, or haplotypic associations with bipolar disorder.
A modest association between FEZ1 and schizophrenia suggests that this gene and the DISC1-mediated molecular pathway might play roles in the development of schizophrenia, with FEZ1 affecting only a small subset of Japanese schizophrenia patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
31Neuroscience 2004 -1 124: 3-10
PMID14960334
TitleExpression of Disrupted-In-Schizophrenia-1, a schizophrenia-associated gene, is prominent in the mouse hippocampus throughout brain development.
AbstractDISC1 (Disrupted-In-schizophrenia 1) has been associated with schizophrenia in multiple genetic studies. Studies from our laboratory have shown that DISC1, the mouse ortholog of DISC1, is highly expressed in the dentate gyrus of the hippocampus in the adult mouse brain. Because developmental dysfunction of the hippocampus is thought to play a major role in schizophrenia pathogenesis, and the dentate gyrus is a major locus for adult neurogenesis in the mouse, we investigated DISC1 expression during mouse brain development. Strikingly, DISC1 is strongly expressed in the hippocampus during all stages of hippocampal development, from embryonic day 14 through adulthood. DISC1 mRNA was detected in the dentate gyrus at all stages in which this structure was identifiable, as well as in the cornu ammonis (CA) fields of the hippocampus, the subiculum and adjacent entorhinal cortex, and the developing cerebral neocortex, hypothalamus, and olfactory bulbs, all of which also express DISC1 in the adult mouse brain. In addition, DISC1 mRNA was seen in regions of the developing mouse brain which do not express DISC1 during adulthood, regions including the bed nucleus of the stria terminalis, reticular thalamic nucleus and reuniens thalamic nucleus. These results demonstrate that DISC1 marks the hippocampus from its earliest stages, and suggest that developmental DISC1 dysfunction may lead to defects in hippocampal function that are associated with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
32Br. 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, schizophrenias
33J. 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, schizophrenias
34Science 2005 Nov 310: 1187-91
PMID16293762
TitleDISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling.
AbstractThe disrupted in schizophrenia 1 (DISC1) gene is a candidate susceptibility factor for schizophrenia, but its mechanistic role in the disorder is unknown. Here we report that the gene encoding phosphodiesterase 4B (PDE4B) is disrupted by a balanced translocation in a subject diagnosed with schizophrenia and a relative with chronic psychiatric illness. The PDEs inactivate adenosine 3',5'-monophosphate (cAMP), a second messenger implicated in learning, memory, and mood. We show that DISC1 interacts with the UCR2 domain of PDE4B and that elevation of cellular cAMP leads to dissociation of PDE4B from DISC1 and an increase in PDE4B activity. We propose a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated cAMP.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
35Trends 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, schizophrenias
36Biochem. Biophys. Res. Commun. 2005 Dec 338: 771-6
PMID16243297
TitleA functional link between Disrupted-In-Schizophrenia 1 and the eukaryotic translation initiation factor 3.
AbstractDisrupted-In-schizophrenia 1 (DISC1) was identified as a candidate gene for schizophrenia. DISC1 is disrupted by a balanced t(1;11)(q42.1;q14.3) translocation segregating with schizophrenia and related psychiatric illness in a large Scottish family. Here, we show that DISC1 interacts via its globular domain with the p40 subunit of the eukaryotic translation initiation factor 3. Furthermore, we found that overexpression of DISC1 in SH-SY5Y cells induces the assembly of eIF3- and TIA-1-positive stress granules (SGs), discrete cytoplasmic granules formed in response to environmental stresses. Our findings suggest that DISC1 may function as a translational regulator and may be involved in stress response.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
37Nat. Cell Biol. 2005 Dec 7: 1167-78
PMID16299498
TitleA schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development.
AbstractDisrupted-In-schizophrenia-1 (DISC1), originally identified at the breakpoint of a chromosomal translocation that is linked to a rare familial schizophrenia, has been genetically implicated in schizophrenia in other populations. schizophrenia involves subtle cytoarchitectural abnormalities that arise during neurodevelopment, but the underlying molecular mechanisms are unclear. Here, we demonstrate that DISC1 is a component of the microtubule-associated dynein motor complex and is essential for maintaining the complex at the centrosome, hence contributing to normal microtubular dynamics. Carboxy-terminal-truncated mutant DISC1 (mutDISC1), which results from a chromosomal translocation, functions in a dominant-negative manner by redistributing wild-type DISC1 through self-association and by dissociating the DISC1-dynein complex from the centrosome. Consequently, either depletion of endogenous DISC1 or expression of mutDISC1 impairs neurite outgrowth in vitro and proper development of the cerebral cortex in vivo. These results indicate that DISC1 is involved in cerebral cortex development, and suggest that loss of DISC1 function may underlie neurodevelopmental dysfunction in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
38Mol. Cell. Neurosci. 2005 Dec 30: 477-84
PMID16209927
TitleDisrupted in schizophrenia 1 (DISC1): subcellular targeting and induction of ring mitochondria.
AbstractSeveral independent studies have identified Disrupted In schizophrenia 1 (DISC1) as a potential susceptibility factor in the pathogenesis of schizophrenia and severe recurrent major depression. To identify potential mechanisms by which DISC1 may influence development of psychiatric illness, we investigated the cellular consequences of recombinant DISC1 expression in COS-7 cells. We show that the N-terminal head domain is sufficient for DISC1 mitochondrial and nuclear targeting, while sequence from the C-terminus facilitates centrosomal association. Loss of C-terminal sequence alters DISC1 subcellular distribution, significantly increasing nuclear localization. DISC1 over-expression produces striking mitochondrial reorganization in some cells, with formation of mitochondrial ring-like structures, indicating a potential involvement of DISC1 in mitochondrial fusion and/or fission.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
39Neuroreport 2005 Aug 16: 1399-402
PMID16056147
TitleDISC1 and neurocognitive function in schizophrenia.
AbstractWe recently reported an association between DISC1 and schizophrenia, schizoaffective disorder, and bipolar disorder. Convergent evidence suggests that DISC1 has a direct effect on central nervous system functioning. However, there is a paucity of data investigating the effects of DISC1 on neurocognition. Thus, we analyzed the relationship between five single-nucleotide polymorphisms that influenced risk for schizophrenia in our previous study and neurocognition in 250 patients with schizophrenia. DISC1 genotype was related to neurocognitive performance on measures of rapid visual search and verbal working memory, when controlling for age and premorbid intellectual capacity, and explained 3%-4% of the variance. These data suggest that DISC1 is associated with neurocognitive functioning in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
40Neurosci. Lett. 2005 Nov 389: 41-5
PMID16054297
TitleAssociation between genotype at an exonic SNP in DISC1 and normal cognitive aging.
AbstractDISC1 is expressed in the hippocampus and has been identified as a possible genetic risk factor for both schizophrenia and bipolar disorder. These psychiatric illnesses are associated with impaired learning and memory. This study investigates the association of variation in DISC1 with cognitive function on the same general mental ability test (Moray House Test) at age 11 and age 79, and cognitive change between ages 11 and 79, in 425 people from the Lothian Birth Cohort 1921 (LBC1921). Tests of memory, non-verbal reasoning and executive function were also administered at age 79. The effect of genotype at a non-synonymous single nucleotide polymorphism in exon 11, rs821616, was studied. There was no direct effect of DISC1 genotype on any cognitive measure. However, there was a significant DISC1 genotype by sex interaction on Moray House Test scores at age 79, both before and after adjustment for cognitive ability at age 11 (p = 0.034 and 0.043, respectively). Women homozygous for the Cys allele had significantly lower cognitive ability scores than men at age 79, p = 0.003. Variation in DISC1 may therefore affect cognitive aging especially in women.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
41Schizophr. Res. 2005 Nov 79: 175-80
PMID16039834
TitleAssociation study of the DISC1/TRAX locus with schizophrenia in a Japanese population.
AbstractDisrupted-in-schizophrenia-1 (DISC1), identified by cytogenetic approaches in a pedigree with familial psychosis, is considered a candidate susceptibility gene for schizophrenia in some populations. In the pedigree, the TRAX gene, located adjacent to DISC1 on the disrupted chromosome 1, may also contribute to the pathophysiology of the familial schizophrenia. We studied association of the DISC1 and TRAX genes with schizophrenia in 338 Japanese by analyzing 15 single nucleotide polymorphisms (SNPs), including 12 SNPs in DISC1 and three in TRAX, respectively. No significant difference was observed between the patients and controls in allelic frequencies or genotypic distributions of 15 SNPs. A weak trend for the association in genotypic distribution of one SNP in TRAX (major homo/hetero/minor homo: 0.324/0.431/0.245 vs. 0.293/0.526/0.181 for patients vs controls, p = 0.039 in the 2 x 3 comparison) turned out to be insignificant after Bonferroni correction. Haplotype analysis did not support the association between the patients and controls. The present study suggests that the DISC1/TRAX locus may not have a major role in Japanese schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
42Curr Opin Psychiatry 2005 Mar 18: 135-40
PMID16639165
TitleThe inheritance of intermediate phenotypes for schizophrenia.
AbstractWhile schizophrenia is substantially heritable, the mode of inheritance is complex, involving numerous genes of small effect and a non-trivial environmental component. The 'endophenotype' approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes in the context of complexly inherited traits. Here we review recent studies applying this method to measures of brain structure, physiology, and function in samples of schizophrenia patients and their non-ill first-degree relatives (siblings and co-twins).
The results suggest that there are multiple heritable dimensions of central nervous system pathology in schizophrenia, including disturbances in the structure and functioning of frontal lobe systems involved in working memory and executive processes, temporal lobe systems involved in episodic memory, auditory perception, and language processing, and cortical and sub-cortical systems mediating smooth pursuit eye movements and sensorimotor gating. A number of genetic loci that are suspected to play a role in predisposing to schizophrenia, including the DISC1, COMT, neuregulin, dysbindin, and alpha-7 nicotinic receptor genes, appear to affect quantitative variation on one or more of these indicators.
Future work is encouraged to address whether each of these neural system dysfunctions are under the influence of a partially distinct set of genes, to elucidate the manner in which multiple genes may coalesce in determining schizophrenia-promoting dysfunction in each neurobehavioral domain, and to clarify the degree of overlap in these quantitative trait loci-endophenotype relationships with other forms of psychosis, particularly bipolar disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
43Clin Ther 2005 -1 27 Suppl A: S8-15
PMID16198200
TitleGenetic mechanisms of psychosis: in vivo and postmortem genomics.
AbstractThe Clinical Brain Disorders Branch Sibling Study data set was initiated in 1996 to examine genetic associations and to identify biological traits associated with susceptibility gene effects. Characterizing genes--and translating their effects on brain development and function--has potential implications for improving the prevention and treatment of schizophrenia.
The goal of this article was to discuss the relationship between genetic variation and schizophrenia using in vivo and postmortem genomics.
Over the past 2 years, several specific genes have been convincingly associated with schizophrenia risk in a number of populations around the world. Some of the genes that have been studied more extensively include: catechol O-methyltransferase (COMT) (chromosome 22q), dysbindin-1 (chromosome 6p), neuregulin 1 (chromosome 8p), metabotropic glutamate receptor 3 (GRM-3) (chromosome 7q), glutamate decarboxylase 1 (chromosome 2q), and disrupted-in-schizophrenia 1 (DISC1) (chromosome 1q). A functional polymorphism in the COMT gene, which affects prefrontal cortical function by changing dopamine signaling in the prefrontal cortex, has been studied extensively. This gene impacts the regulation of dopamine neuronal activity in the brainstem, which is associated with psychosis. GRM-3 shows similar results on prefrontal function; in postmortem tissue, it has an effect on expression of various glutamate synaptic markers. DISC1 affects hippocampal anatomy and function, whereas dysbindin-1 appears to be a general cognitive capacity gene that is underexpressed in the schizophrenic cortex. Data suggest that these susceptibility genes influence the cortical information processing which characterizes the schizophrenic phenotype. These data add to the evidence that such genes contribute to the pathophysiology of schizophrenia and provide insights into their mechanisms. Thus, genetic variation and its influence on the biological processes underlying schizophrenia may be key to developing future prevention strategies and new treatments.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
44Mol. Psychiatry 2005 Jan 10: 40-68; image 5
PMID15263907
TitleSchizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.
AbstractThis review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
45Proc. Natl. Acad. Sci. U.S.A. 2005 Jan 102: 1187-92
PMID15657124
TitleA form of DISC1 enriched in nucleus: altered subcellular distribution in orbitofrontal cortex in psychosis and substance/alcohol abuse.
AbstractDisrupted-In-schizophrenia 1 (DISC1) was identified as the sole gene whose ORF is truncated and cosegregates with major mental illnesses in a Scottish family. DISC1 has also been suggested, by association and linkage studies, to be a susceptibility gene for schizophrenia (SZ) in independent populations. However, no analysis of DISC1 protein in human brains, especially those of patients with SZ, has yet been conducted. Here we performed a biochemical analysis of DISC1 protein in a well characterized set of autopsied brains, including brains of patients with SZ, bipolar disorder, and major depression (MD), as well as normal control brains. We identified an isoform of DISC1 by using MS and demonstrated that it is enriched in the nucleus of HeLa cells. In the orbitofrontal cortex, the subcellular distribution of this DISC1 isoform, assessed by the nuclear to cytoplasmic ratio in the immunoreactivity of the isoform, is significantly changed in brains from patients with SZ and MD. This altered distribution is also observed in those subjects with substance and alcohol abuse. The changes in MD brains are significantly influenced by substance/alcohol abuse as well as postmortem interval; however, the alteration in SZ brains is free from brain-associated confounding factors, although an interaction with substance/alcohol abuse cannot be completely ruled out. These results suggest that DISC1 may be implicated in psychiatric conditions in other populations than the unique Scottish family.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
46Mol. Psychiatry 2005 Aug 10: 758-64
PMID15940305
TitleA frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder.
AbstractIn a large Scottish pedigree, a balanced translocation t(1;11)(q42.1;q14.3) segregates with major mental illness, including schizophrenia, bipolar disorder, and recurrent major depression. The translocation is predicted to result in the loss of the C-terminal region of the protein product of Disrupted In schizophrenia 1 (DISC1), a gene located on 1q42.1. Since this initial discovery, DISC1 has been functionally implicated in several processes, including neurodevelopment. Based on the genetic and functional evidence that DISC1 may be associated with schizophrenia, we sequenced portions of DISC1 in 28 unrelated probands with schizophrenia and six unrelated probands with schizoaffective disorder, ascertained as part of a large sibpair study. We detected a 4 bp deletion at the extreme 3' end of exon 12 in a proband with schizophrenia. The mutation was also present in a sib with schizophrenia, a sib with schizoaffective disorder, and the unaffected father, while the mutation was not detected in 424 control individuals. The mutation is predicted to cause a frameshift and encode a truncated protein with nine abnormal C-terminal amino acids. The truncated transcript is detectable, but at a reduced level, in lymphoblastoid cell lines from three of four mutation carriers. These findings are consistent with the possibility that mutations in the DISC1 gene can increase the risk for schizophrenia and related disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
47Mol. Psychiatry 2005 Jul 10: 657-68, 616
PMID15838535
TitleAssociation between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population.
AbstractThe Translin-associated factor X/Disrupted in schizophrenia 1 (TRAX/DISC) region was first implicated as a susceptibility locus for schizophrenia by analysis of a large Scottish family in which a t(1;11) translocation cosegregates with schizophrenia, bipolar disorder and recurrent major depression. We now report evidence for association between bipolar disorder and schizophrenia and this locus in the general Scottish population. A systematic study of linkage disequilibrium in a representative sample of the Scottish population was undertaken across the 510 kb of TRAX and DISC1. SNPs representing each haplotype block were selected for case-control association studies of both schizophrenia and bipolar disorder. Significant association with bipolar disorder in women P=0.00026 (P=0.0016 in men and women combined) was detected in a region of DISC1. This same region also showed nominally significant association with schizophrenia in both men and women combined, P=0.0056. Two further regions, one in TRAX and the second in DISC1, showed weaker evidence for sex-specific associations of individual haplotypes with bipolar disorder in men and women respectively, P<0.01. Only the association between bipolar women and DISC1 remained significant after correction for multiple testing. This result provides further supporting evidence for DISC1 as a susceptibility factor for both bipolar disorder and schizophrenia, consistent with the diagnoses in the original Scottish translocation family.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
48Mol. Cell. Neurosci. 2005 Apr 28: 613-24
PMID15797709
TitleSubcellular targeting of DISC1 is dependent on a domain independent from the Nudel binding site.
AbstractDisrupted in schizophrenia 1 (DISC1) has been identified as a putative risk factor for schizophrenia and affective disorders through study of a Scottish family with a balanced (1;11) (q42.1;q14.3) translocation, which results in the disruption of the DISC1 locus and cosegregates with major psychiatric disease. Several other reports of genetic linkage and association between DISC1 and schizophrenia in a range of patient populations have added credibility to the DISC1-schizophrenia theory, but the function of the DISC1 protein is still poorly understood. Recent studies have suggested that DISC1 plays a role in neuronal outgrowth, possibly through reported interactions with the molecules Nudel and FEZ1. Here we have analyzed the DISC1 protein sequence to identify previously unknown regions that are important for the correct targeting of the protein and conducted imaging studies to identify DISC1 subcellular location. We have identified a central coiled-coil region and show it is critical for the subcellular targeting of DISC1. This domain is independent from the C-terminal Nudel binding domain highlighting the multidomain nature/functionality of the DISC1 protein. Furthermore, we have been able to provide the first direct evidence that DISC1 is localized to mitochondria in cultured cortical neurons that are dependent on an intact cytoskeleton. Surprisingly, Nudel is seen to differentially associate with mitochondrial markers in comparison to DISC1. Disruption of the cytoskeleton results in colocalization of Nudel and mitochondrial markers-the first observation of such a direct relationship. Mitochondrial dysfunction has been implicated to play a role in schizophrenia so we speculate that mutations in DISC1 or Nudel may impair mitochondrial transport or function, initiating a cascade of events culminating in psychiatric illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
49Mol. Psychiatry 2005 Dec 10: 1097-103
PMID16103888
TitleA haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia.
AbstractWe have previously reported evidence of linkage and association between markers on 1q42 and schizophrenia in a study sample of 498 multiply affected Finnish nuclear families, leading to the recent identification of four significantly associated haplotypes that specifically implicate the Translin-Associated Factor X (TRAX) and Disrupted in schizophrenia 1 and 2 (DISC1 and DISC2) genes in the genetic etiology of schizophrenia. Previously, the DISC genes were found to be disrupted by a balanced translocation (1;11)(q42.1;q14.3) that cosegregated with schizophrenia and related disorders in a large Scottish pedigree. Interestingly, we also reported earlier suggestive linkage between endophenotypic quantitative traits of visual and verbal memory and microsatellite markers in close proximity to TRAX/DISC, on 1q41. Here, we tested if the identified allelic haplotypes of TRAX/DISC would be associated with visual and/or verbal memory function impairments that are known to aggregate with schizophrenia in families. One haplotype of DISC1, HEP3, displayed association with poorer performance on tests assessing short-term visual memory and attention. Analysis of affected and unaffected offspring separately revealed that both samples contribute to the observed association to visual working memory. These results provide genetic support to the view that the DISC1 gene contributes to sensitivity to schizophrenia and associated disturbances and affects short-term visual memory functions. This finding should stimulate studies aiming at the molecular characterization of how the specific alleles of DISC1 affect the visual memory functions and eventually participates in the development of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
50Arch. Gen. Psychiatry 2005 Nov 62: 1205-13
PMID16275808
TitleAssociation of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory.
AbstractChromosome 1q42 is among several genomic regions showing replicated evidence of linkage with schizophrenia, but the specific susceptibility mechanisms underlying this relationship remain to be identified.
To examine a series of haplotype blocks of single-nucleotide polymorphic markers from a segment of 1q42 spanning the disrupted-in-schizophrenia 1 (DISC1) and translin-associated factor X (TRAX) genes for association with schizophrenia and several endophenotypic traits thought to be involved in disease pathogenesis.
Population-based twin cohort study.
Finland.
Two hundred thirty-six subjects, consisting of 7 twin pairs concordant for schizophrenia (6 monozygotic [MZ] and 1 dizygotic [DZ]), 52 pairs discordant for schizophrenia (20 MZ and 32 DZ), and 59 demographically balanced normal pairs (28 MZ and 31 DZ), were drawn from a twin cohort consisting of all of the same-sex twins born in Finland from 1940 through 1957.
Psychiatric diagnosis, performance on neurocognitive tests of short- and long-term memory, and gray matter volume measurements taken from high-resolution magnetic resonance images.
A common haplotype incorporating 3 single-nucleotide polymorphic markers near the translocation break point of DISC1 (odds ratio, 2.6 [P = .02]) and a rare haplotype incorporating 4 markers from the DISC1 and TRAX genes (odds ratio, 13.0 [P = .001]) were significantly overrepresented among individuals with schizophrenia. These haplotypes were also associated with several quantitative endophenotypic traits previously observed to covary with schizophrenia and genetic liability to schizophrenia, including impairments in short- and long-term memory functioning and reduced gray matter density in the prefrontal cortex, as demonstrated using a population-based brain atlas method, with a trend toward association with reduced hippocampal volume.
Specific alleles of the DISC1 and TRAX genes on 1q42 appear to contribute to genetic risk for schizophrenia through disruptive effects on the structure and function of the prefrontal cortex, medial temporal lobe, and other brain regions. These effects are consistent with their production of proteins that play roles in neuritic outgrowth, neuronal migration, synaptogenesis, and glutamatergic neurotransmission.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
51Arch. Gen. Psychiatry 2005 Oct 62: 1081-8
PMID16203953
TitleGenomewide linkage scan in schizoaffective disorder: significant evidence for linkage at 1q42 close to DISC1, and suggestive evidence at 22q11 and 19p13.
AbstractTraditionally, the search for genes involved in predisposition to major psychoses has proceeded with separate studies of schizophrenia and bipolar disorder. However, twin data suggest that, in addition to genes with specificity for these phenotypes, there exist genes that simultaneously influence susceptibility to schizophrenia, bipolar disorder, and schizoaffective disorder.
To undertake, to our knowledge, the first systematic search for such loci.
Genomewide linkage scan.
Affected individuals were ascertained in the United Kingdom and Ireland from general psychiatric inpatient and outpatient services.
The families were selected for linkage studies of either schizophrenia or bipolar disorder. Pedigrees were selected for the current analysis where there was at least 1 member with DSM-IV schizoaffective disorder, bipolar type. Within these pedigrees, individuals were coded as affected if they had been diagnosed with DSM-IV schizophrenia, schizoaffective disorder of bipolar type, or bipolar I disorder. A total of 24 pedigrees contributed 35 affected sibling pairs to the sample.
A 10-centimorgan genome scan using microsatellite markers was analyzed using MAPMAKER/SIBS software.
A genomewide significant signal (LOD = 3.54) was observed at chromosome 1q42 (near D1S2800), and suggestive LOD scores were observed at chromosomes 22q11 (LOD = 1.96) and 19p13 (LOD = 1.85). No linkage was observed in these regions in our original schizophrenia or bipolar scans in individuals from the United Kingdom.
Our linkage findings strongly support the existence of loci that influence susceptibility across the functional psychosis spectrum. The DISC1 gene lies within 2.5 megabases of our peak marker on chromosome 1q42 and has been previously implicated in schizophrenia, bipolar disorder, and, recently, schizoaffective disorder. Follow-up of this region should use samples enriched for cases of schizoaffective disorder. Our findings have similar implications for the search for genetic variation on chromosome 22q11 that influences susceptibility to psychosis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
52Proc. Natl. Acad. Sci. U.S.A. 2005 Jun 102: 8627-32
PMID15939883
TitleVariation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a promising schizophrenia candidate gene expressed predominantly within the hippocampus. We typed 12 single-nucleotide polymorphisms (SNPs) that covered the DISC1 gene. A three-SNP haplotype [hCV219779 (C)-rs821597 (G)-rs821616 (A)] spanning 83 kb of the gene was associated with schizophrenia in a family-based sample (P = 0.002). A common nonconservative SNP (Ser704Cys) (rs821616) within this haplotype was associated with schizophrenia (P = 0.004). Based on primary expression of DISC1 in hippocampus, we hypothesized that allelic variation at Ser704Cys would have a measurable impact on hippocampal structure and function as assayed via specific hippocampus-related intermediate phenotypes. In addition to overtransmission in schizophrenia, the Ser allele was associated with altered hippocampal structure and function in healthy subjects, including reduced hippocampal gray matter volume and altered engagement of the hippocampus during several cognitive tasks assayed with functional magnetic resonance imaging. These convergent data suggest that allelic variation within DISC1, either at Ser704Cys or haplotypes monitored by it, increases the risk for schizophrenia and that the mechanism of this effect involves structural and functional alterations in the hippocampal formation.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
53Proc. Natl. Acad. Sci. U.S.A. 2005 Mar 102: 3828-33
PMID15728732
TitleInhibition of NUDEL (nuclear distribution element-like)-oligopeptidase activity by disrupted-in-schizophrenia 1.
AbstractRecently, nuclear distribution element-like (NUDEL) has been implicated to play a role in lissencephaly and schizophrenia through interactions with the lissencephaly gene 1 (Lis1) and disrupted-in-schizophrenia 1 (DISC1) products, respectively. Interestingly, NUDEL is the same protein as endooligopeptidase A (EOPA), a thiol-activated peptidase involved in conversion and inactivation of a number of bioactive peptides. In this study, we have cloned EOPA from the human brain and have confirmed that it is equivalent to NUDEL, leading us to suggest a single name, NUDEL-oligopeptidase. In the brain, the monomeric form of NUDEL-oligopeptidase is responsible for the peptidase activity whose catalytic mechanism is likely to involve a reactive cysteine, because mutation of Cys-273 fully abolished NUDEL-oligopeptidase activity without disrupting the protein's secondary structure. Cys-273 is very close to the DISC1-binding site on NUDEL-oligopeptidase. Intriguingly, DISC1 inhibits NUDEL-oligopeptidase activity in a competitive fashion. We suggest that the activity of NUDEL-oligopeptidase is under tight regulation through protein-protein interactions and that disruption of these interactions, as postulated in a Scottish DISC1 translocation schizophrenia cohort, may lead to aberrant regulation of NUDEL-oligopeptidase, perhaps providing a substrate for the pathology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
54Clin Ther 2005 -1 27 Suppl A: S8-15
PMID16198200
TitleGenetic mechanisms of psychosis: in vivo and postmortem genomics.
AbstractThe Clinical Brain Disorders Branch Sibling Study data set was initiated in 1996 to examine genetic associations and to identify biological traits associated with susceptibility gene effects. Characterizing genes--and translating their effects on brain development and function--has potential implications for improving the prevention and treatment of schizophrenia.
The goal of this article was to discuss the relationship between genetic variation and schizophrenia using in vivo and postmortem genomics.
Over the past 2 years, several specific genes have been convincingly associated with schizophrenia risk in a number of populations around the world. Some of the genes that have been studied more extensively include: catechol O-methyltransferase (COMT) (chromosome 22q), dysbindin-1 (chromosome 6p), neuregulin 1 (chromosome 8p), metabotropic glutamate receptor 3 (GRM-3) (chromosome 7q), glutamate decarboxylase 1 (chromosome 2q), and disrupted-in-schizophrenia 1 (DISC1) (chromosome 1q). A functional polymorphism in the COMT gene, which affects prefrontal cortical function by changing dopamine signaling in the prefrontal cortex, has been studied extensively. This gene impacts the regulation of dopamine neuronal activity in the brainstem, which is associated with psychosis. GRM-3 shows similar results on prefrontal function; in postmortem tissue, it has an effect on expression of various glutamate synaptic markers. DISC1 affects hippocampal anatomy and function, whereas dysbindin-1 appears to be a general cognitive capacity gene that is underexpressed in the schizophrenic cortex. Data suggest that these susceptibility genes influence the cortical information processing which characterizes the schizophrenic phenotype. These data add to the evidence that such genes contribute to the pathophysiology of schizophrenia and provide insights into their mechanisms. Thus, genetic variation and its influence on the biological processes underlying schizophrenia may be key to developing future prevention strategies and new treatments.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
55Dialogues 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, schizophrenias
56Curr 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, schizophrenias
57Ann. N. Y. Acad. Sci. 2006 Nov 1086: 126-33
PMID17185511
TitleDisrupted-in-schizophrenia-1 (DISC1): a key susceptibility factor for major mental illnesses.
AbstractHere we overview Disrupted-in-schizophrenia-1 (DISC1), a promising lead in studying the pathophysiology of major mental conditions. Genetic association studies reproducibly suggest involvement of DISC1 in both schizophrenia and bipolar disorder in several ethnic groups. Different from several other susceptibility genes for schizophrenia, such as neuregulin-1 and dysbindin, there are two independent pedigrees in which genetic variations of DISC1 directly segregate with major mental conditions. This uniqueness has facilitated neurobiology of DISC1, which may hopefully lead to an important breakthrough in understanding of pathophysiology of major mental conditions. DISC1 is a multifunctional protein that plays a role in neurodevelopment and cell signaling. In autopsied brains from patients with psychosis and substance abuse, change in subcellular distribution of DISC1 is observed. DISC1 interacts with phosphodiesterase (PDE) 4B that degrades cyclic AMP (cAMP), which may be a regulatory molecule for working memory in the prefrontal cortex. Knockdown expression of DISC1 in developing cerebral cortex in mouse brains leads to changes that resemble, at least in part, the pathology found in patients with schizophrenia. These results support involvement of DISC1 in the pathophysiology of major mental conditions, including schizophrenia, in several mechanisms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
58Biol. Psychiatry 2006 Jun 59: 1189-97
PMID16797264
TitleA review of Disrupted-In-Schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions.
AbstractDisrupted-In-schizophrenia-1 (DISC1) is a promising candidate gene for schizophrenia (SZ) and bipolar disorder (BP), but its basic biology remains to be elucidated. Accumulating genetic evidence supports that DISC1 is associated with some aspects of cognitive functions relevant to SZ and BP. Here, we provide a summary of the current updates in biological studies of DISC1. Disrupted-In-schizophrenia-1, preferentially expressed in the forebrain, has multiple isoforms with potential posttranslational modifications. Disrupted-In-schizophrenia-1 protein occurs in multiple subcellular compartments, which include the centrosome, microtubule fractions, postsynaptic densities, actin cytoskeletal fractions, the mitochondria, and the nucleus. Recent studies have clarified that DISC1 mediates at least centrosome-dynein cascade and cyclic adenosine monophosphate (cAMP) signaling. Furthermore, both cytogenetic and cell biological studies consistently suggest that an overall loss of DISC1 function (either haploinsufficiency or dominant-negative, or both) may be associated with SZ and BP. On the basis of these findings, production of DISC1 genetically engineered mice is proposed as a promising animal model for SZ and BP. Several groups are currently generating DISC1 mice and starting to characterize them. In this review, the advantages and disadvantages of each animal model are discussed.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
59Neuron 2006 Oct 52: 139-53
PMID17015232
TitleNeurobiology of schizophrenia.
AbstractWith its hallucinations, delusions, thought disorder, and cognitive deficits, schizophrenia affects the most basic human processes of perception, emotion, and judgment. Evidence increasingly suggests that schizophrenia is a subtle disorder of brain development and plasticity. Genetic studies are beginning to identify proteins of candidate genetic risk factors for schizophrenia, including dysbindin, neuregulin 1, DAOA, COMT, and DISC1, and neurobiological studies of the normal and variant forms of these genes are now well justified. We suggest that DISC1 may offer especially valuable insights. Mechanistic studies of the properties of these candidate genes and their protein products should clarify the molecular, cellular, and systems-level pathogenesis of schizophrenia. This can help redefine the schizophrenia phenotype and shed light on the relationship between schizophrenia and other major psychiatric disorders. Understanding these basic pathologic processes may yield novel targets for the development of more effective treatments.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
60Neurosci. Res. 2006 Nov 56: 286-93
PMID16965828
TitlePrimate disrupted-in-schizophrenia-1 (DISC1): high divergence of a gene for major mental illnesses in recent evolutionary history.
AbstractHere we analyze the species conservation of disrupted-in-schizophrenia-1 (DISC1) gene, a susceptibility gene for schizophrenia. We cloned cDNA of DISC1 and characterized DISC1 protein in monkey brains and compared their features with those in a variety of species, including humans, rodents and lower vertebrates. Sequences of human and monkey DISC1 are very similar for both nucleotides and amino acids, in sharp contrast to those of rodents; this is reminiscent of G72, another gene involved in major mental illnesses. Bioinformatic cross-species comparisons identified a portion of DISC1 sequences in chicken and Caenorhabditis elegans, but failed to find DISC1 in Drosophila. In contrast to sequence differences, the regional expression profile of DISC1 is well conserved between rodents and primates in that levels of DISC1 mRNA and protein are higher in the hippocampus and the cerebral cortex, and much lower in cerebellum in adult brains. The findings of this study may suggest overall patterns of evolution of genes for psychiatric disorders, and thus assist in production of genetically-engineered mice, and the interpretation of the underlying mechanisms of psychiatric conditions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
61Proc. Natl. Acad. Sci. U.S.A. 2006 Mar 103: 3693-7
PMID16484369
TitleDisc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice.
AbstractDisrupted-In-schizophrenia (DISC1) is a leading candidate schizophrenia susceptibility gene. Here, we describe a deletion variant in mDISC1 specific to the 129S6/SvEv strain that introduces a termination codon at exon 7, abolishes production of the full-length protein, and impairs working memory performance when transferred to the C57BL/6J genetic background. Our findings provide insights into how DISC1 variation contributes to schizophrenia susceptibility in humans and the behavioral divergence between 129S6/SvEv and C57BL/6J mouse strains and have implications for modeling psychiatric diseases in mice.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
62J 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, schizophrenias
63Biol. Psychiatry 2006 Jul 60: 123-31
PMID16843095
TitleThe genetics and biology of DISC1--an emerging role in psychosis and cognition.
AbstractIn the developing field of biological psychiatry, DISC1 stands out by virtue of there being credible evidence, both genetic and biological, for a role in determining susceptibility to schizophrenia and related disorders. We highlight the methodologic paradigm that led to identification of DISC1 and review the supporting genetic and biological evidence. The original finding of DISC1 as a gene disrupted by a balanced translocation on chromosome 1q42 that segregates with schizophrenia, bipolar disorder, and recurrent major depression has sparked a number of confirmatory linkage and association studies. These indicate that DISC1 is a generalizable genetic risk factor for psychiatric illness that also influences cognition in healthy subjects. DISC1 has also been shown to interact with a number of proteins with neurobiological pedigrees, including Ndel1 (NUDEL), a key regulator of neuronal migration with endo-oligopeptidase activity, and PDE4B, a phosphodiesterase that is critical for cyclic adenosine monophosphate signaling and that is directly linked to learning, memory, and mood. Both are potential "drug" targets. DISC1 has thus emerged as a key molecular player in the etiology of major mental illness and in normal brain processes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
64Schizophr Bull 2006 Jul 32: 409-16
PMID16699061
TitleGenes and schizophrenia: beyond schizophrenia: the role of DISC1 in major mental illness.
Abstractschizophrenia and related disorders have a major genetic component, but despite much effort and many claims, few genes have been consistently replicated and fewer have biological support. One recent exception is "Disrupted in schizophrenia 1" (DISC1), which was identified at the breakpoint on chromosome 1 of the balanced translocation (1;11)(q42.1;q14.3) that co-segregated in a large Scottish family with a wide spectrum of major mental illnesses. Since then, genetic analysis has implicated DISC1 in schizophrenia, schizoaffective disorder, bipolar affective disorder, and major depression. Importantly, evidence is emerging from genetic studies for a causal relationship between DISC1 and directly measurable trait variables such as working memory, cognitive aging, and decreased gray matter volume in the prefrontal cortex, abnormalities in hippocampal structure and function, and reduction in the amplitude of the P300 event-related potential. Further, DISC1 binds a number of proteins known to be involved in essential processes of neuronal function, including neuronal migration, neurite outgrowth, cytoskeletal modulation, and signal transduction. Thus, both genetic and functional data provide evidence for a critical role for DISC1 in schizophrenia and related disorders, supporting the neurodevelopmental hypothesis for the molecular pathogenesis of these devastating illnesses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
65Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Mar 141B: 155-9
PMID16389590
TitleGenetic association between schizophrenia and the DISC1 gene in the Scottish population.
AbstractSeveral lines of evidence support the involvement of the disrupted in schizophrenia 1 (DISC1) gene in schizophrenia susceptibility, including its original identification in a schizophrenia family with a chromosome translocation, several genetic association studies, and functional characterization of the gene product. In the present study, we have genotyped multiple SNP and microsatellite markers in a large Scottish case-control sample. We identified two SNPs and one microsatellite that show significant association with schizophrenia. The strongest association is with a haplotype of SNPs rs751229 and rs3738401, located at the 5' end of the gene; the C-A haplotype of these SNPs is associated with a relative risk of schizophrenia of 5 in our population. We also observe association with a microsatellite in intron 7, but no association with markers toward the 3' end of the gene. The results are in broad agreement with those of other genetic studies, but there are differences in terms of the precise patterns of association. This analysis further strengthens the candidacy of DISC1 as a risk factor for schizophrenia in the general population, and suggests that more intensive searching for causative variants is justified.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
66Dialogues Clin Neurosci 2006 -1 8: 353-7
PMID17117617
TitleFunctional genomics in postmortem human brain: abnormalities in a DISC1 molecular pathway in schizophrenia.
AbstractThe disrupted in schizophrenia 1 (DISC1) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism (SNP) association studies and clinical data, suggesting that risk SNPs impact on hippocampal structure and function. We hypothesized that altered expression of DISC1 and/or its molecular partners (nuclear distribution element-like [NUDEL], fasciculation and elongation protein zeta-i [FEZ1], and lissencephaly 1 [LIS1]) may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and its binding partners in the hippocampus and dorsolateral prefrontal cortex of postmortem human brains of schizophrenic patients and controls. We found no difference in the expression of DISC1 mRNA in schizophrenia, and no association with previously identified risk SNPs. However, the expression of NUDEL, FEZ1, and LIS1 was significantly reduced in tissue from schizophrenic subjects, and the expression of each showed association with high-risk DISC1 polymorphisms. These data suggest involvement of genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
67Hum. Mol. Genet. 2006 Nov 15: 3313-23
PMID17035248
TitleDISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1.
AbstractDisrupted-In-schizophrenia-1 (DISC1) is a unique susceptibility gene for major mental conditions, because of the segregation of its genetic variant with hereditary psychosis in a Scottish pedigree. Genetic association studies reproducibly suggest involvement of DISC1 in both schizophrenia and bipolar disorder in several ethnic groups. The DISC1 protein is multifunctional, and a pool of DISC1 in the dynein motor complex is required for neurite outgrowth in PC12 cells as well as proper neuronal migration and dendritic arborization in the developing cerebral cortex in vivo. Here, we show that a specific interaction between DISC1 and nuclear distribution element-like (NDEL1/NUDEL) is required for neurite outgrowth in differentiating PC12 cells. Among several components of the dynein motor complex, DISC1 and NDEL1 are selectively upregulated during neurite outgrowth upon differentiation in PC12 cells. The NDEL1 binding site of DISC1 was narrowed down to a small portion of exon 13, corresponding to amino acids 802-835 of DISC1. We demonstrate that genetic variants of DISC1, proximal to the NDEL1 binding site, affect the interaction between DISC1 and NDEL1.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
68Biol. Psychiatry 2006 Nov 60: 929-35
PMID16814263
TitleDifferential expression of disrupted-in-schizophrenia (DISC1) in bipolar disorder.
AbstractThe disruption of the disrupted-in-schizophrenia (DISC1) gene segregates with major mental illnesses in a Scottish family. Association of DISC1 with schizophrenia has been reported in several ethnic groups, and now recently with mood disorder.
A family-based association study of DISC1 and bipolar disorder (BP) in 57 bipolar pedigrees was conducted. Then, we examined possible association of bipolar disorder with DISC1 mRNA expression in human lymphoblasts. We also studied the correlation of several clinical features with the levels of DISC1 mRNA expression.
Haplotype analysis identified one haplotype (HP1) that was overtransmitted to the BP phenotype (p = .01) and a second haplotype that was undertransmitted (HP2). There was a gender influence in the transmission distortion, with overtransmission of HP1 to affected females (p = .004). A significant decrease in DISC1 mRNA expression was observed in lymphoblasts from affected HP1 group compared to those from unaffected subjects with the HP2 (p = .006). Further, a higher number of manic symptoms correlated with lower levels of DISC1 expression (p = .008).
These results suggest that decreased mRNA levels of DISC1 expression, associating with the risk haplotype, may be implicated in the pathophysiology of bipolar disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
69Trends Mol Med 2006 Jun 12: 255-61
PMID16679065
TitleDisrupted in schizophrenia 1: building brains and memories.
Abstractschizophrenia and bipolar affective disorder are common, debilitating, and poorly understood and treated disorders. Both conditions are highly heritable. Recent genetic studies have suggested that the gene disrupted in schizophrenia 1 (DISC1) is an important risk factor. DISC1 seems to have a key role in building the brain and memories by interacting with other proteins, including nuclear distribution E-like protein and phosphodiesterase 4B. Here, we review the current knowledge, highlight some key unanswered questions and propose ways forward towards a better understanding of normal and abnormal brain development and function. In the long term, this might lead to the discovery of drugs that are more efficacious and safer than currently available ones.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
70J 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, schizophrenias
71J 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, schizophrenias
72Schizophr 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, schizophrenias
73Schizophr. Res. 2006 Sep 86: 1-14
PMID16842972
TitleSchizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability.
AbstractOver 130 genes have been associated with schizophrenia in genetic studies. None of these has reached a sufficient level of confidence to be accepted as a universal susceptibility gene and problems of replicability suggest that many may be false positives. Nevertheless, these genes can be grouped into distinct families related to glutamate transmission (in particular related to NMDA receptor function), the control of synaptic plasticity, dopaminergic transmission, oxidative stress, glutathione and quinone metabolism and oligodendrocyte viability. These families mirror the processes disrupted in the schizophrenic brain and certain gene families can be linked together to form a clearly defined signalling cascade involved in the phenomenon of NMDA receptor-dependent long-term potentiation and synaptic plasticity, that may be interconnected with oligodendrocyte and oxidative stress-related pathways. Many of the protein products of these genes interact with each other, forming complex integrated networks. Certain high-interest genes (for example DISC1, NRG1, COMT) may exert multiple effects on different areas of these pathways, while others exert more specific effects on certain branches. The convergence of a large number of genes on a definable signaling network raises the possibility of numerous interactions between gene candidates, and suggests that a targeted multigenic pathway approach would be useful in gene association studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
74NeuroRx 2006 Jan 3: 117-30
PMID16490418
TitleImaging genomics and response to treatment with antipsychotics in schizophrenia.
AbstractRecent important advancements in genomic research have opened the way to new strategies for public health management. One of these questions pertains to how individual genetic variation may be associated with individual variability in response to drug treatment. The field of pharmacogenetics may have a profound impact on treatment of complex psychiatric disorders like schizophrenia. However, pharmacogenetic studies in schizophrenia have produced conflicting results. The first studies examined potential associations between clinical response and drug receptor genes. Subsequent studies have tried to use more objective phenotypes still in association with drug receptor genes. More recently, other studies have sought the association between putative causative or modifier genes and intermediate phenotypes. Thus, conflicting results may be at least in part explained by variability and choice of the phenotype, by choice of candidate genes, or by the relatively little knowledge about the neurobiology of this disorder. We propose that choosing intermediate phenotypes that allow in vivo measurement of specific neuronal functions may be of great help in reducing several of the potential confounds intrinsic to clinical measurements. Functional neuroimaging is ideally suited to address several of these potential confounds, and it may represent a powerful strategy to investigate the relationship between behavior, brain function, genes, and individual variability in the response to treatment with antipsychotic drugs in schizophrenia. Preliminary evidence with potential susceptilibity genes such as COMT, DISC1, and GRM3 support these assumptions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
75Dialogues Clin Neurosci 2006 -1 8: 353-7
PMID17117617
TitleFunctional genomics in postmortem human brain: abnormalities in a DISC1 molecular pathway in schizophrenia.
AbstractThe disrupted in schizophrenia 1 (DISC1) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism (SNP) association studies and clinical data, suggesting that risk SNPs impact on hippocampal structure and function. We hypothesized that altered expression of DISC1 and/or its molecular partners (nuclear distribution element-like [NUDEL], fasciculation and elongation protein zeta-i [FEZ1], and lissencephaly 1 [LIS1]) may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and its binding partners in the hippocampus and dorsolateral prefrontal cortex of postmortem human brains of schizophrenic patients and controls. We found no difference in the expression of DISC1 mRNA in schizophrenia, and no association with previously identified risk SNPs. However, the expression of NUDEL, FEZ1, and LIS1 was significantly reduced in tissue from schizophrenic subjects, and the expression of each showed association with high-risk DISC1 polymorphisms. These data suggest involvement of genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
76Biol. Psychiatry 2006 Sep 60: 554-62
PMID16997000
TitleA single nucleotide polymorphism fine mapping study of chromosome 1q42.1 reveals the vulnerability genes for schizophrenia, GNPAT and DISC1: Association with impairment of sustained attention.
AbstractThe marker D1S251 of chromosome 1q42.1 showed significant association with schizophrenia in a Taiwanese sample. We used single nucleotide polymorphism (SNP) fine mapping to search for the vulnerability genes of schizophrenia.
We selected 120 SNPs covering 1 Mb around D1S251 from the public database. These selected SNPs were initially validated if allele frequency was >10%. Forty-seven validated SNPs were genotyped in 102 families with at least 2 siblings affected with schizophrenia.
Two SNP blocks showed significant association with schizophrenia. Block 1 (five-SNP), located between intron 2 and intron 13 of the glyceronephosphate O-acyltransferase (GNPAT) gene, showed the most significant associations using single-locus TDT (z = -2.07, p = .038, df = 1) and haplotype association analyses (z = -1.99, p = .046, df = 1). Block 2 (two-SNP), located between intron 4 and intron 5 of the disrupted-in-schizophrenia 1 (DISC1) gene, also showed the most significant results in both the single-locus (z = -3.22, p = .0013, df = 1) and haplotype association analyses (z = 3.35, p = .0008, df = 1). The association of the DISC1 gene with schizophrenia was mainly in the patient group with sustained attention deficits as assessed by the Continuous Performance Test.
Chromosome 1q42.1 harbors GNPAT and DISC1 as candidate genes for schizophrenia, and DISC1 is associated with sustained attention deficits.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
77Hum. Mol. Genet. 2006 Apr 15: 1245-58
PMID16510495
TitleExpression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs.
AbstractDISC1 has been identified as a schizophrenia susceptibility gene based on linkage and SNP association studies and clinical data suggesting that risk SNPs impact on hippocampal structure and function. In cell and animal models, C-terminus-truncated DISC1 disrupts intracellular transport, neural architecture and migration, perhaps because it fails to interact with binding partners involved in neuronal differentiation such as fasciculation and elongation protein zeta-1 (FEZ1), platelet-activating factor acetylhydrolase, isoform Ib, PAFAH1B1 or lissencephaly 1 protein (LIS1) and nuclear distribution element-like (NUDEL). We hypothesized that altered expression of DISC1 and/or its molecular partners may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and these selected binding partners as well as reelin, a protein in a related signaling pathway, in the hippocampus and dorsolateral prefrontal cortex of postmortem human brain patients with schizophrenia and controls. We found no difference in the expression of DISC1 or reelin mRNA in schizophrenia and no association with previously identified risk DISC1 SNPs. However, the expression of NUDEL, FEZ1 and LIS1 was each significantly reduced in the brain tissue from patients with schizophrenia and expression of each showed association with high-risk DISC1 polymorphisms. Although, many other DISC1 binding partners still need to be investigated, these data implicate genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
78J. Comp. Neurol. 2006 Jul 497: 436-50
PMID16736468
TitleDISC1 immunoreactivity at the light and ultrastructural level in the human neocortex.
AbstractDisrupted-In-schizophrenia 1 (DISC1) is one of two genes that straddle the chromosome 1 breakpoint of a translocation associated with an increased risk of schizophrenia. DISC1 has been identified in the brain of various mammalian species, but no previous immunocytochemical studies have been conducted in human neocortex. We examined DISC1 immunoreactivity in frontal and parietal cortex (BA 4, 9, 39, and 46) in normal human brain. At the light microscopic level, immunolabeling was prominent in the neuropil, in multiple populations of cells, and in the white matter. At the ultrastructural level, staining was prominent in structures associated with synaptic function. Immunolabeled axon terminals comprised 8% of all terminals and formed both asymmetric and symmetric synapses. Labeled axon terminals formed synapses with labeled spines and dendrites; in some, only the postsynaptic density (PSD) of the postsynaptic structure was labeled. The most common configuration, however, was an unlabeled axon terminal forming an asymmetric synapse with a spine that had immunoreactivity deposited on the PSD and throughout the spine. The presence of DISC1 in multiple types of synapses suggests the involvement of DISC1 in corticocortical as well as thalamocortical connections. Staining was also present in ribosomes, parts of the chromatin, in dendritic shafts, and on some microtubules. Labeling was absent from the Golgi apparatus and multivesicular bodies, which are associated with protein excretion. These anatomical localization data suggest that DISC1 participates in synaptic activity and microtubule function, and are consistent with the limited data on its adult function.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
79Hum. Mol. Genet. 2006 Oct 15: 3024-33
PMID16959794
TitleImpact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling.
AbstractDisrupted-in-schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and bipolar disorder. Although there are a number of patients with major depressive disorder (MDD) in the family members with the chromosome translocation, the possible association with MDD has not yet been studied. We therefore performed an association study of the DISC1 gene with MDD and schizophrenia. We found that Cys704 allele of the Ser704Cys single-nucleotide polymorphism (SNP) was associated with an increased risk of developing MDD (P=0.005, odds ratio=1.46) and stronger evidence for association in a multi-marker haplotype analysis containing this SNP (P=0.002). We also explored possible impact of Ser704Cys on brain morphology in healthy volunteers using MR imaging. We found a reduction in gray matter volume in cingulate cortex and a decreased fractional anisotropy in prefrontal white matter of individuals carrying the Cys704 allele compared with Ser/Ser704 subjects. In primary neuronal culture, knockdown of endogenous DISC1 protein by small interfering RNA resulted in the suppression of phosphorylation of ERK and Akt, whose signaling pathways are implicated in MDD. When effects of sDISC1 (Ser704) and cDISC1 (Cys704) proteins were examined separately, phosphorylation of ERK was greater in sDISC1 compared with cDISC1. A possible biological mechanism of MDD might be implicated by these convergent data that Cys704 DISC1 is associated with the lower biological activity on ERK signaling, reduced brain gray matter volume and an increased risk for MDD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
80Schizophr. Res. 2006 Sep 86: 1-14
PMID16842972
TitleSchizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability.
AbstractOver 130 genes have been associated with schizophrenia in genetic studies. None of these has reached a sufficient level of confidence to be accepted as a universal susceptibility gene and problems of replicability suggest that many may be false positives. Nevertheless, these genes can be grouped into distinct families related to glutamate transmission (in particular related to NMDA receptor function), the control of synaptic plasticity, dopaminergic transmission, oxidative stress, glutathione and quinone metabolism and oligodendrocyte viability. These families mirror the processes disrupted in the schizophrenic brain and certain gene families can be linked together to form a clearly defined signalling cascade involved in the phenomenon of NMDA receptor-dependent long-term potentiation and synaptic plasticity, that may be interconnected with oligodendrocyte and oxidative stress-related pathways. Many of the protein products of these genes interact with each other, forming complex integrated networks. Certain high-interest genes (for example DISC1, NRG1, COMT) may exert multiple effects on different areas of these pathways, while others exert more specific effects on certain branches. The convergence of a large number of genes on a definable signaling network raises the possibility of numerous interactions between gene candidates, and suggests that a targeted multigenic pathway approach would be useful in gene association studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
81Biochem. Soc. Trans. 2007 Nov 35: 1283-6
PMID17956330
TitleDissecting DISC1 function through protein-protein interactions.
AbstractDisrupted in schizophrenia 1 (DISC1) is emerging in the eyes of many as the most promising candidate of all the schizophrenia risk genes. This viewpoint is derived from the combination of genetic, clinical, imaging and rapidly advancing cell biology data around this gene. All of these areas have been reviewed extensively recently and this review will point you towards some of these excellent papers. My own personal view of the potential importance of DISC1 was echoed in a recent review which suggested that DISC1 may be a 'Rosetta Stone' for schizophrenia research [Ross, Margolis, Reading, Pletnikov and Coyle (2006) Neuron 52, 139-153]. Our own efforts to try to understand the function of DISC1 were through identification of its protein-binding partners. Through an extensive Y2H (yeast two-hybrid) and bioinformatics effort we generated the 'DISC1-Interactome', a comprehensive network of protein-protein interactions around DISC1. In two excellent industry-academia collaborations we focused on two main interacting partners: Ndel1 (nudE nuclear distribution gene E homologue-like 1), an enigmatic protein which may have diverse functions as both a cysteine protease and a key centrosomal structural protein; and PDE4B, a cAMP-specific phosphodiesterase. I will review the work around these two protein complexes in detail.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
82J. Physiol. (Lond.) 2007 Oct 584: 401-5
PMID17823207
TitleDisrupted in schizophrenia 1 and phosphodiesterase 4B: towards an understanding of psychiatric illness.
AbstractDisrupted in schizophrenia 1 (DISC1) is one of the most convincing genetic risk factors for major mental illness identified to date. DISC1 interacts directly with phosphodiesterase 4B (PDE4B), an independently identified risk factor for schizophrenia. DISC1-PDE4B complexes are therefore likely to be involved in molecular mechanisms underlying psychiatric illness. PDE4B hydrolyses cAMP and DISC1 may regulate cAMP signalling through modulating PDE4B activity. There is evidence that expression of both genes is altered in some psychiatric patients. Moreover, DISC1 missense mutations that give rise to phenotypes related to schizophrenia and depression in mice are located within binding sites for PDE4B. These mutations reduce the association between DISC1 and PDE4B, and one results in reduced brain PDE4B activity. Altered DISC1-PDE4B interaction may thus underlie the symptoms of some cases of schizophrenia and depression. Factors likely to influence this interaction include expression levels, binding site affinities and the DISC1 and PDE4 isoforms involved. DISC1 and PDE4 isoforms are targeted to specific subcellular locations which may contribute to the compartmentalization of cAMP signalling. Dysregulated cAMP signalling in specific cellular compartments may therefore be a predisposing factor for major mental illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
83Proc. Natl. Acad. Sci. U.S.A. 2007 Nov 104: 18280-5
PMID17984054
TitleSpecific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice.
AbstractDisrupted-in-schizophrenia 1 (DISC1) was initially discovered through a balanced translocation (1;11)(q42.1;q14.3) that results in loss of the C terminus of the DISC1 protein, a region that is thought to play an important role in brain development. Here, we use an inducible and reversible transgenic system to demonstrate that early postnatal, but not adult induction, of a C-terminal portion of DISC1 in mice results in a cluster of schizophrenia-related phenotypes, including reduced hippocampal dendritic complexity, depressive-like traits, abnormal spatial working memory, and reduced sociability. Accordingly, we report that individuals in a discordant twin sample with a DISC1 haplotype, associating with schizophrenia as well as working memory impairments and reduced gray matter density, were more likely to show deficits in sociability than those without the haplotype. Our findings demonstrate that alterations in DISC1 function during brain development contribute to schizophrenia pathogenesis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
84Novartis Found. Symp. 2007 -1 288: 246-55; discussion 255-9, 276-81
PMID18494263
TitleSchizophrenia susceptibility genes and their neurodevelopmental implications: focus on neuregulin 1.
AbstractOn the basis of epidemiological as well as neurobiological evidence, schizophrenia has been conceptualized as a neurodevelopmental disorder. It is also known to have a large heritable component and a complex genetic architecture. Many putative susceptibility genes have recently been identified, arising both from positional cloning and candidate gene approaches. The evidence is strong for neuregulin 1, dysbindin and DISC1, and moderate for several others. However, there are key unanswered questions. For example, concerning the molecular basis of genetic association, multiple, mostly non-coding, variants have been found within the genes, complicating discussion as to the strength and interpretation of the data. Second, there is speculation whether the genes converge on common pathways, notably glutamatergic synaptic transmission. Additional questions concern the emerging evidence for epistasis, the clinico-genetic correlates, and the extent to which the genes confer schizophrenia risk via their roles in neurodevelopment. Here, the genetic advances and their neurodevelopmental implications are summarised, with a particular focus on neuregulin 1.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
85Cell 2007 Sep 130: 981-3
PMID17889641
TitleDISC1 puts the brakes on neurogenesis.
AbstractThe gene DISC1 (Disrupted-in-schizophrenia 1) is a leading candidate gene for schizophrenia. In this issue, Duan et al. (2007) present evidence implicating DISC1 in the maturation and integration of newly generated neurons in the adult mouse hippocampus. Surprisingly, DISC1 appears to have opposite effects on neurogenesis during development and in adulthood.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
86Cell 2007 Sep 130: 1146-58
PMID17825401
TitleDisrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain.
AbstractAdult neurogenesis occurs throughout life in discrete regions of the adult mammalian brain. Little is known about the mechanism governing the sequential developmental process that leads to integration of new neurons from adult neural stem cells into the existing circuitry. Here, we investigated roles of Disrupted-In-schizophrenia 1 (DISC1), a schizophrenia susceptibility gene, in adult hippocampal neurogenesis. Unexpectedly, downregulation of DISC1 leads to accelerated neuronal integration, resulting in aberrant morphological development and mispositioning of new dentate granule cells in a cell-autonomous fashion. Functionally, newborn neurons with DISC1 knockdown exhibit enhanced excitability and accelerated dendritic development and synapse formation. Furthermore, DISC1 cooperates with its binding partner NDEL1 in regulating adult neurogenesis. Taken together, our study identifies DISC1 as a key regulator that orchestrates the tempo of functional neuronal integration in the adult brain and demonstrates essential roles of a susceptibility gene for major mental illness in neuronal development, including adult neurogenesis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
87Neurosci. Res. 2007 Jul 58: 234-44
PMID17418909
TitlePC12 cell model of inducible expression of mutant DISC1: new evidence for a dominant-negative mechanism of abnormal neuronal differentiation.
AbstractA balanced chromosomal translocation, segregating with mental illnesses in a large Scottish family, interrupts the disrupted-in-schizophrenia 1 (DISC1) gene, which would result in loss of DISC1 function via haploinsufficiency or dominant-negative effects (or possibly could cause gain-of-function effects) if a truncated protein is present. To evaluate the effects of a predicted protein, mutant DISC1, we generated stable PC12 cell clones with inducible expression of mutant or full-length human DISC1 (hDISC1). Our study presents new observations that the inhibitory effects of mutant hDISC1 on NGF-induced neurite outgrowth are dependent on the level and timing of expression of mutant DISC1 and the concentrations of NGF, and are associated with altered sub-cellular distribution of endogenous DISC1 and ATF4, and decreased protein levels of LIS1. Thus, inducible expression of DISC1 in PC12 cell clones is a valuable in vitro model for further studying the molecular mechanisms likely due to loss of function of DISC1 relevant to the pathogenesis of major mental illnesses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
88J. Neurosci. 2007 Jan 27: 4-14
PMID17202467
TitleDISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2.
AbstractDisrupted-in-schizophrenia-1 (DISC1) is a candidate gene for susceptibility of schizophrenia. In the accompanying paper (Taya et al., 2006), we report that DISC1 acts as a linker between Kinesin-1 and DISC1-interacting molecules, such as NudE-like, lissencephaly-1, and 14-3-3epsilon. Here we identified growth factor receptor bound protein 2 (Grb2) as a novel DISC1-interacting molecule. Grb2 acts as an adaptor molecule that links receptor tyrosine kinases and the Ras-extracellular signal-regulated kinase (ERK) pathway. DISC1 formed a ternary complex with Grb2 and kinesin heavy chain KIF5A of Kinesin-1. In cultured rat hippocampal neurons, both DISC1 and Grb2 partially colocalized at the distal part of axons. Knockdown of DISC1 or kinesin light chains of Kinesin-1 by RNA interference inhibited the accumulation of Grb2 from the distal part of axons. Knockdown of DISC1 also inhibited the neurotrophin-3 (NT-3)-induced phosphorylation of ERK-1/2 at the distal part of axons and inhibited NT-3-induced axon elongation. These results suggest that DISC1 is required for NT-3-induced axon elongation and ERK activation at the distal part of axons by recruiting Grb2 to axonal tips.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
89Neurotox Res 2007 Jan 11: 73-83
PMID17449450
TitleAre some genetic risk factors common to schizophrenia, bipolar disorder and depression? Evidence from DISC1, GRIK4 and NRG1.
AbstractDepression is common in patients with schizophrenia and it is well established from family studies that rates of depression are increased among relatives of probands with schizophrenia, making it likely that the phenotypes described under the categories of affective and non-affective psychoses share some genetic risk factors. Family linkage studies have identified several chromosomal regions likely to contain risk genes for schizophrenia and bipolar disorder, suggesting common susceptibility loci. Candidate gene association studies have provided further evidence to suggest that some genes including two of the most studied candidates, Disrupted in schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1) may be involved in both types of psychosis. We have recently identified another strong candidate for a role in both schizophrenia and affective disorders, GRIK4 a glutamate receptor mapped to chromosome 11q23 [Glutamate Receptor, Ionotropic, Kainate, type 4]. This gene is disrupted by a translocation breakpoint in a patient with schizophrenia, and case control studies show significant association of GRIK4 with both schizophrenia and bipolar disorder. Identifying genes implicated in the psychoses may eventually provide the basis for classification based on biology rather than symptoms, and suggest novel treatment strategies for these complex brain disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
90Proc. Natl. Acad. Sci. U.S.A. 2007 Sep 104: 14501-6
PMID17675407
TitleDominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans.
AbstractHere, we report generation and characterization of Disrupted-In-schizophrenia-1 (DISC1) genetically engineered mice as a potential model for major mental illnesses, such as schizophrenia. DISC1 is a promising genetic risk factor for major mental illnesses. In this transgenic model, a dominant-negative form of DISC1 (DN-DISC1) is expressed under the alphaCaMKII promoter. In vivo MRI of the DN-DISC1 mice detected enlarged lateral ventricles particularly on the left side, suggesting a link to the asymmetrical change in anatomy found in brains of patients with schizophrenia. Furthermore, selective reduction in the immunoreactivity of parvalbumin in the cortex, a marker for an interneuron deficit that may underlie cortical asynchrony, is observed in the DN-DISC1 mice. These results suggest that these transgenic mice may be used as a model for schizophrenia. DN-DISC1 mice also display several behavioral abnormalities, including hyperactivity, disturbance in sensorimotor gating and olfactory-associated behavior, and an anhedonia/depression-like deficit.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
91Neuron 2007 May 54: 387-402
PMID17481393
TitleBehavioral phenotypes of Disc1 missense mutations in mice.
AbstractTo support the role of DISC1 in human psychiatric disorders, we identified and analyzed two independently derived ENU-induced mutations in Exon 2 of mouse DISC1. Mice with mutation Q31L showed depressive-like behavior with deficits in the forced swim test and other measures that were reversed by the antidepressant bupropion, but not by rolipram, a phosphodiesterase-4 (PDE4) inhibitor. In contrast, L100P mutant mice exhibited schizophrenic-like behavior, with profound deficits in prepulse inhibition and latent inhibition that were reversed by antipsychotic treatment. Both mutant DISC1 proteins exhibited reduced binding to the known DISC1 binding partner PDE4B. Q31L mutants had lower PDE4B activity, consistent with their resistance to rolipram, suggesting decreased PDE4 activity as a contributory factor in depression. This study demonstrates that DISC1 missense mutations in mice give rise to phenotypes related to depression and schizophrenia, thus supporting the role of DISC1 in major mental illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
92Schizophr Bull 2007 Jan 33: 11-5
PMID17138582
TitleSchizophrenia in translation: disrupted in schizophrenia (DISC1): integrating clinical and basic findings.
AbstractThe disrupted in schizophrenia 1 (DISC1) gene has been linked to schizophrenia and other serious mental illnesses in multiple pedigrees. This article will review the neurobiology of DISC1 in normal developing and adult brain and the putative role of the mutant form in major mental illness, particularly schizophrenia. The initial genetic finding of an association between DISC1 and schizophrenia in a Scottish population has now been replicated in Finnish, American, Japanese, and Taiwanese populations. DISC1 is present throughout the brain of a variety of species during development and adulthood, including many of the brain regions known to be abnormal in schizophrenia, such as the prefrontal cortex, hippocampus, and thalamus. The functions of DISC1 in the developing brain include neuronal migration, neurite outgrowth, and neurite extension. In the adult, DISC1 has been identified in multiple populations of neurons and in structures associated with synaptic function, suggesting that one of its adult functions may be synaptic plasticity. DISC1 is associated with numerous cognitive functions that are abnormal in schizophrenia. Converging evidence from cell culture, mice mutants, postmortem brain, and genetics implicates mutant DISC1 in the pathophysiology of schizophrenia and other mental illnesses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
93Psychiatr. Genet. 2007 Jun 17: 129-33
PMID17417055
TitleThe PDE4B gene confers sex-specific protection against schizophrenia.
AbstractPhosphodiesterase 4B (PDE4B) is a candidate gene for schizophrenia and affective disorders through its disruption by a chromosomal translocation in an individual with schizophrenia, its inhibition by the antidepressant rolipram, and its physical interaction with another key candidate, Disrupted in schizophrenia (DISC1).
To determine the contribution made by PDE4B to the population risk of schizophrenia and bipolar disorder by carrying out a case-control association study.
Twenty-six tagging single nucleotide polymorphisms were selected across the PDE4B gene and genotyped in DNA samples from 386 schizophrenia cases, 368 bipolar disorder cases and 455 controls.
Single single nucleotide polymorphisms and a resulting haplotype conferred a protective effect against schizophrenia in the female population. The haplotype result remained significant after correction for multiple testing (P=0.012).
The observation that a PDE4B haplotype alters the genetic risk of schizophrenia in the Scottish population complements the known participation of this gene in biological processes associated with mental illness. Further studies are needed to replicate this finding and identify underlying sequence variants.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
94Curr. Opin. Neurobiol. 2007 Feb 17: 95-102
PMID17258902
TitleRole of DISC1 in neural development and schizophrenia.
AbstractHow can we hope to explain mechanistically the schizophrenic phenotype? Perhaps through the reductionist approach of genetics, which is beginning to yield biological clues. Growing evidence supports the view that the well-established genetic risk factor DISC1 plays an important role in schizophrenia biology by interacting with FEZ1 and NDEL1 during neurodevelopment and with the phosphodiesterase PDE4B in neuronal cell signalling. Thus, DISC1 and its pathways support the neurodevelopmental hypothesis of schizophrenia and provide a mechanistic explanation for the characteristic cognitive deficits. Genetic variants of DISC1 also predispose to related affective (mood) disorders. As a consequence, we can speculate on the mechanisms of DISC1 action and possible routes to treatment for these common, debilitating brain disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
95J Psychiatr Res 2007 Aug 41: 428-34
PMID16524593
TitleCase-control association study of Disrupted-in-Schizophrenia-1 (DISC1) gene and schizophrenia in the Chinese population.
AbstractDisrupted-in-schizophrenia-1 (DISC1) has first been identified as a candidate gene for schizophrenia through study of a Scottish family with a balanced (1; 11) (q42.1; q14.3) translocation. Lots of linkage and association studies supported DISC1 as a risk factor for schizophrenia. In this study, we genotyped three SNPs in DISC1 using a set of Han Chinese samples of 560 schizophrenics and 576 controls. No positive association was detected in the whole samples but analysis of allele frequencies in female samples showed weak association between SNP rs2295959 and the disease (chi(2)=6.188, P=0.0135, OR=0.728, 95% CI=0.567-0.935). Our results provide further evidence for sex difference for the effect of the gene on the aetiology of schizophrenia. Our findings also would encourage further studies, particularly family-based association studies with larger samples, to analyze the association between DISC1 and schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
96Cell. 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, schizophrenias
97Neurosci. Lett. 2007 May 417: 326-9
PMID17374448
TitleFailure to confirm the association between the FEZ1 gene and schizophrenia in a Japanese population.
AbstractFasciculation and elongation of protein zeta-1 (FEZ1) is a binding partner of Disrupted-In-schizophrenia 1 (DISC1). Because the DISC1 gene is shown to be a causative gene for psychosis in a Scottish family, the FEZ1 gene may well have importance in mental disease. A previous association study that analyzed polymorphisms of the FEZ1 gene in Japanese patients with schizophrenia and control subjects found significant association of the Asp123Glu polymorphism with schizophrenia. In the present study, we examined two polymorphic markers, rs559668 and rs597570 (Asp123Glu), in the FEZ1 gene to confirm the association in 1920 Japanese patients with schizophrenia and 1920 control subjects. The power to detect an association was more than 0.98. However, we did not detect genotypic associations of either of these two single nucleotide polymorphisms with schizophrenia (p=1 and 0.79, respectively). We concluded that the missense mutation Asp123Glu of the FEZ1 gene is unlikely to play a substantial role in the genetic susceptibility to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
98Biol. Psychiatry 2007 May 61: 1208-10
PMID17054920
TitleDisrupted in schizophrenia 1 genotype and positive symptoms in schizophrenia.
AbstractConverging evidence has demonstrated an association between the Disrupted in schizophrenia 1 (DISC1) gene and schizophrenia (SZ). Within the DISC1 gene, a single nucleotide polymorphism (SNP), Ser704Cys, has been associated with the structure and function of the hippocampus. Because positive symptoms in SZ have also been associated with hippocampal structure and function, we hypothesized that variation in a DISC1 haplotype containing Ser704Cys would be significantly associated with positive symptomatology in SZ.
We tested for an association between variation in a haplotype block within the DISC1 gene containing Ser704Cys and lifetime history of positive symptoms in 199 Caucasian patients with SZ.
We detected significant associations between a DISC1 haplotype containing Ser704Cys and Ser704Cys genotype and lifetime severity of delusions in SZ.
These data suggest that that the effect of DISC1 genetic variation might be associated with positive symptoms in patients with SZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
99Mol. 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, schizophrenias
100Neuron 2007 May 54: 387-402
PMID17481393
TitleBehavioral phenotypes of Disc1 missense mutations in mice.
AbstractTo support the role of DISC1 in human psychiatric disorders, we identified and analyzed two independently derived ENU-induced mutations in Exon 2 of mouse DISC1. Mice with mutation Q31L showed depressive-like behavior with deficits in the forced swim test and other measures that were reversed by the antidepressant bupropion, but not by rolipram, a phosphodiesterase-4 (PDE4) inhibitor. In contrast, L100P mutant mice exhibited schizophrenic-like behavior, with profound deficits in prepulse inhibition and latent inhibition that were reversed by antipsychotic treatment. Both mutant DISC1 proteins exhibited reduced binding to the known DISC1 binding partner PDE4B. Q31L mutants had lower PDE4B activity, consistent with their resistance to rolipram, suggesting decreased PDE4 activity as a contributory factor in depression. This study demonstrates that DISC1 missense mutations in mice give rise to phenotypes related to depression and schizophrenia, thus supporting the role of DISC1 in major mental illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
101Neuron 2007 May 54: 348-9
PMID17481386
TitleWhat is a schizophrenic mouse?
AbstractIn this issue of Neuron, Clapcote et al. examine mice containing missense mutations of the DISC1 gene, a locus associated with major mental illness in at least one large Scottish family. Genetic manipulation of mouse homologs of genes implicated in the etiology of psychiatric disorders is a promising avenue of research, but also one that is fraught with interpretative difficulties.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
102Schizophr 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, schizophrenias
103Curr. Opin. Neurobiol. 2007 Feb 17: 95-102
PMID17258902
TitleRole of DISC1 in neural development and schizophrenia.
AbstractHow can we hope to explain mechanistically the schizophrenic phenotype? Perhaps through the reductionist approach of genetics, which is beginning to yield biological clues. Growing evidence supports the view that the well-established genetic risk factor DISC1 plays an important role in schizophrenia biology by interacting with FEZ1 and NDEL1 during neurodevelopment and with the phosphodiesterase PDE4B in neuronal cell signalling. Thus, DISC1 and its pathways support the neurodevelopmental hypothesis of schizophrenia and provide a mechanistic explanation for the characteristic cognitive deficits. Genetic variants of DISC1 also predispose to related affective (mood) disorders. As a consequence, we can speculate on the mechanisms of DISC1 action and possible routes to treatment for these common, debilitating brain disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
104Neurosci. Lett. 2007 May 417: 316-21
PMID17346882
TitleAssociation analysis of ATF4 and ATF5, genes for interacting-proteins of DISC1, in bipolar disorder.
AbstractDisrupted in schizophrenia 1 (DISC1) and its molecular cascade are implicated in the pathophysiology of schizophrenia and bipolar disorder. As interacting-proteins with DISC1, Nudel, ATF4, ATF5, LIS1, alpha-tubulin, PDE4B, eIF3, FEZ1, Kendrin, MAP1A and MIPT3 were identified. We previously showed the down-regulation of ATF5 in the lymphoblastoid cells derived from affected co-twin of monozygotic twins discordant for bipolar disorder. We also suggested the contribution of endoplasmic reticulum stress response pathway to the illness, and ATF4 is one of major components in the pathway. Truncated mutant DISC1 reportedly cannot interact with ATF4 and ATF5. These findings suggest the role of these genes in the pathophysiology of bipolar disorder. In this study, we tested genetic association of ATF4 and ATF5 genes with bipolar disorder by a case-control study in Japanese population (438 patients and 532 controls) and transmission disequilibrium test in 237 trio samples from NIMH Genetics Initiative Pedigrees. We also performed gene expression analysis in lymphoblastoid cells. We did not find any significant association in both genetic study and expression analysis. By the exploratory haplotype analysis, nominal association of ATF4 with bipolar II patients was observed, but it was not significant after correction of multiple testing. Contribution of common variations of ATF4 and ATF5 to the pathophysiology of bipolar disorder may be minimal if any.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
105Psychiatry Clin. Neurosci. 2007 Feb 61: 3-19
PMID17239033
TitleMolecular genetics of bipolar disorder and depression.
AbstractIn this review, all papers relevant to the molecular genetics of bipolar disorder published from 2004 to the present (mid 2006) are reviewed, and major results on depression are summarized. Several candidate genes for schizophrenia may also be associated with bipolar disorder: G72, DISC1, NRG1, RGS4, NCAM1, DAO, GRM3, GRM4, GRIN2B, MLC1, SYNGR1, and SLC12A6. Of these, association with G72 may be most robust. However, G72 haplotypes and polymorphisms associated with bipolar disorder are not consistent with each other. The positional candidate approach showed an association between bipolar disorder and TRPM2 (21q22.3), GPR50 (Xq28), Citron (12q24), CHMP1.5 (18p11.2), GCHI (14q22-24), MLC1 (22q13), GABRA5 (15q11-q13), BCR (22q11), CUX2, FLJ32356 (12q23-q24), and NAPG (18p11). Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation. From gene expression analysis, PDLIM5, somatostatin, and the mtDNA 3243 mutation were found to be related to bipolar disorder. Whereas most previous positive findings were not supported by subsequent studies, DRD1 and IMPA2 have been implicated in follow-up studies. Several candidate genes in the circadian rhythm pathway, BmaL1, TIMELESS, and PERIOD3, are reported to be associated with bipolar disorder. Linkage studies show many new linkage loci. In depression, the previously reported positive finding of a gene-environmental interaction between HTTLPR (insertion/deletion polymorphism in the promoter of a serotonin transporter) and stress was not replicated. Although the role of the TPH2 mutation in depression had drawn attention previously, this has not been replicated either. Pharmacogenetic studies show a relationship between antidepressant response and HTR2A or FKBP5. New technologies for comprehensive genomic analysis have already been applied. HTTLPR and BDNF promoter polymorphisms are now found to be more complex than previously thought, and previous papers on these polymorphisms should be treated with caution. Finally, this report addresses some possible causes for the lack of replication in this field.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
106J Psychiatr Res 2007 Aug 41: 428-34
PMID16524593
TitleCase-control association study of Disrupted-in-Schizophrenia-1 (DISC1) gene and schizophrenia in the Chinese population.
AbstractDisrupted-in-schizophrenia-1 (DISC1) has first been identified as a candidate gene for schizophrenia through study of a Scottish family with a balanced (1; 11) (q42.1; q14.3) translocation. Lots of linkage and association studies supported DISC1 as a risk factor for schizophrenia. In this study, we genotyped three SNPs in DISC1 using a set of Han Chinese samples of 560 schizophrenics and 576 controls. No positive association was detected in the whole samples but analysis of allele frequencies in female samples showed weak association between SNP rs2295959 and the disease (chi(2)=6.188, P=0.0135, OR=0.728, 95% CI=0.567-0.935). Our results provide further evidence for sex difference for the effect of the gene on the aetiology of schizophrenia. Our findings also would encourage further studies, particularly family-based association studies with larger samples, to analyze the association between DISC1 and schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
107J. Neurosci. 2007 Aug 27: 9513-24
PMID17728464
TitleIsoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a genetic susceptibility factor for schizophrenia and related severe psychiatric conditions. DISC1 is a multifunctional scaffold protein that is able to interact with several proteins, including the independently identified schizophrenia risk factor phosphodiesterase-4B (PDE4B). Here we report that the 100 kDa full-length DISC1 isoform (fl-DISC1) can bind members of each of the four gene, cAMP-specific PDE4 family. Elevation of intracellular cAMP levels, so as to activate protein kinase A, caused the release of PDE4D3 and PDE4C2 isoforms from fl-DISC1 while not affecting binding of PDE4B1 and PDE4A5 isoforms. Using a peptide array strategy, we show that PDE4D3 binds fl-DISC1 through two regions found in common with PDE4B isoforms, the interaction of which is supplemented because of the presence of additional PDE4B-specific binding sites. We propose that the additional binding sites found in PDE4B1 underpin its resistance to release during cAMP elevation. We identify, for the first time, a functional distinction between the 100 kDa long DISC1 isoform and the short 71 kDa isoform. Thus, changes in the expression pattern of DISC1 and PDE4 isoforms offers a means to reprogram their interaction and to determine whether the PDE4 sequestered by DISC1 is released after cAMP elevation. The PDE4B-specific binding sites encompass point mutations in mouse DISC1 that confer phenotypes related to schizophrenia and depression and that affect binding to PDE4B. Thus, genetic variation in DISC1 and PDE4 that influence either isoform expression or docking site functioning may directly affect psychopathology.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
108J. Pharmacol. Exp. Ther. 2007 Aug 322: 600-9
PMID17519386
TitlePDE4B5, a novel, super-short, brain-specific cAMP phosphodiesterase-4 variant whose isoform-specifying N-terminal region is identical to that of cAMP phosphodiesterase-4D6 (PDE4D6).
AbstractThe cAMP-specific phosphodiesterase-4 (PDE4) gene family is the target of several potential selective therapeutic inhibitors. The four PDE4 genes generate several distinct protein-coding isoforms through the use of alternative promoters and 5'-coding exons. Using mouse transcripts, we identified a novel, super-short isoform of human PDE4B encoding a novel 5' terminus, which we label PDE4B5. The protein-coding region of the novel 5' exon is conserved across vertebrates, chicken, zebrafish, and fugu. Reverse-transcription-polymerase chain reaction (PCR) and quantitative (PCR) measurements show that this isoform is brain-specific. The novel protein is 58 +/- 2 kDa; it has cAMP hydrolyzing enzymatic activity and is inhibited by PDE4-selective inhibitors rolipram and cilomilast (Ariflo). Confocal and subcellular fractionation analyses show that it is distributed predominantly and unevenly within the cytosol. The 16 novel N-terminal residues of PDE4B5 are identical to the 16 N-terminal residues of the super-short isoform of PDE4D (PDE4D6), which is also brain-specific. PDE4B5 is able to bind the scaffold protein DISC1, whose gene has been linked to schizophrenia. Microarray expression profiling of the PDE4 gene family shows that specific PDE4 genes are enriched in muscle and blood fractions; however, only by monitoring the individual isoforms is the brain specificity of the super-short PDE4D and PDE4B isoforms revealed. Understanding the distinct tissue specificity of PDE4 isoforms will be important for understanding phosphodiesterase biology and opportunities for therapeutic intervention.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
109Cereb. Cortex 2007 Sep 17 Suppl 1: i6-15
PMID17434919
TitleCatecholamine and second messenger influences on prefrontal cortical networks of "representational knowledge": a rational bridge between genetics and the symptoms of mental illness.
AbstractBoth dopamine (DA) and norepinephrine (NE) have powerful, inverted U influences on prefrontal cortical (PFC) cognitive function. Optimal NE levels engage alpha2A-adrenoceptors and increase "signals" via inhibition of cAMP-HCN (cAMP-hyperpolarization-activated cyclic nucleotide-gated cation channel) signaling near preferred inputs, whereas optimal levels of DA D1 receptor stimulation decrease "noise" by increasing cAMP signaling near nonpreferred inputs. Excessive levels of catecholamine release during stress impair working memory 1) by very high levels of cAMP-HCN signaling diminishing preferred as well as nonpreferred inputs and 2) by high levels of NE engaging alpha1 stimulation of phosphotidyl inositol (PI) signaling that suppresses cell firing. Common mental illnesses are associated with extracellular changes in these pathways: Attention Deficit Hyperactivity Disorder is linked to genetic changes that reduce catecholamine transmission to suboptimal levels and is treated with agents that increase catecholamine transmission, whereas Post-Traumatic Stress Disorder (PTSD) is associated with amplified noradrenergic transmission that impairs PFC but strengthens amygdala function. PTSD is now treated with agents that block alpha1 or beta adrenoceptors. In contrast, the more severe mental illnesses, schizophrenia and bipolar disorder, are associated with genetic changes in molecules regulating intracellular signaling pathways activated by stress. Specifically, DISC1 inhibits cAMP signaling whereas regulator of G-protein signaling 4 inhibits PI signaling. Loss of function in these genes may render patients vulnerable to profound stress-induced PFC dysfunction including symptoms of thought disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
110Hum. Genet. 2007 Feb 120: 889-906
PMID17006672
TitleEvidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia.
AbstractCatechol-O-methyltransferase (COMT) regulates dopamine degradation and is located in a genomic region that is deleted in a syndrome associated with psychosis, making it a promising candidate gene for schizophrenia. COMT also has been shown to influence prefrontal cortex processing efficiency. Prefrontal processing dysfunction is a common finding in schizophrenia, and a background of inefficient processing may modulate the effect of other candidate genes. Using the NIMH sibling study (SS), a non-independent case-control set, and an independent German (G) case-control set, we performed conditional/unconditional logistic regression to test for epistasis between SNPs in COMT (rs2097603, Val158Met (rs4680), rs165599) and polymorphisms in other schizophrenia susceptibility genes. Evidence for interaction was evaluated using a likelihood ratio test (LRT) between nested models. SNPs in RGS4, G72, GRM3, and DISC1 showed evidence for significant statistical epistasis with COMT. A striking result was found in RGS4: three of five SNPs showed a significant increase in risk [LRT P-values: 90387 = 0.05 (SS); SNP4 = 0.02 (SS), 0.02 (G); SNP18 = 0.04 (SS), 0.008 (G)] in interaction with COMT; main effects for RGS4 SNPs were null. Significant results for SNP4 and SNP18 were also found in the German study. We were able to detect statistical interaction between COMT and polymorphisms in candidate genes for schizophrenia, many of which had no significant main effect. In addition, we were able to replicate other studies, including allelic directionality. The use of epistatic models may improve replication of psychiatric candidate gene studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
111Neurosci 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, schizophrenias
112Biol. 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, schizophrenias
113Proc. 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, schizophrenias
114Schizophr Bull 2007 Jul 33: 905-11
PMID17551090
TitleThe genetic deconstruction of psychosis.
AbstractPsychiatric research, including the search for predisposing genes, has tended to proceed under the assumptions that schizophrenia and bipolar disorder, as defined in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and International Statistical Classification of Diseases, 10th Revision, are discrete disease entities with distinct etiology and pathogenesis and that these disease entities can be identified by current "operational" diagnostic conventions. However, recent findings emerging from genetic studies show increasing evidence for an overlap in genetic susceptibility across the traditional binary classification of psychosis. Moreover, the emerging evidence suggests the possibility of relatively specific relationships between genotype and psychopathology. For example, variation in Disrupted in schizophrenia 1 (DISC1) and Neuregulin 1 (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 categorical approach. We can expect that, over the coming years, molecular genetics will catalyze a reappraisal of psychiatric nosology as well as contribute in a major way to our understanding of pathophysiology and to the development of improved treatments. However, our understanding of the brain mechanisms that link specific gene actions and products to the subjective experience of psychopathological symptoms is likely to be bridged by employing intermediate (or endo-) phenotypes in the domains such as cognition, neurophysiology, or neuroanatomy rather than relying upon clinical measures alone.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
115Aust N Z J Psychiatry 2007 Apr 41: 308-20
PMID17464717
TitleGene expression profiling in Brodmann's area 46 from subjects with schizophrenia.
AbstractTo identify altered gene expression in the dorsolateral prefrontal cortex obtained after death from subjects with schizophrenia.
Restriction fragment differential display (RFDD) was used to measure levels of mRNA in Brodmann area (BA) 46 from schizophrenia and control subjects. Findings on specific mRNA identified with RFDD were further investigated using real-time polymerase chain reaction (real-time PCR), PCR and western blotting.
Levels of mRNA for 63 of approximately 12,500 genes differed in BA 46 in schizophrenia. Subsequent real-time PCR has shown that mRNA for muscleblind protein 1 (MBNL1) and protocadherin 17 (PCDH17) are increased in BA 46 from subjects with schizophrenia of short, but not long, duration. Altered levels of mRNA for neither gene were present in BA 9 from subjects with schizophrenia or in either cortical area from subjects with bipolar 1 disorder. By contrast, both RFDD and real-time PCR failed to show altered expression of the schizophrenia candidate gene disrupted in schizophrenia 1 (DISC1) BA46 from any diagnostic cohort.
The present study has identified genes that are differentially expressed in BA 46 in schizophrenia. Initial studies have shown that there is a need for a careful validation of genes shown to be affected in schizophrenia using high-throughput technologies. In addition the present study has shown that gene expression may vary considerably depending on the duration of schizophrenia. This raises the hypothesis that changing gene expression may be underlying the change in symptom profile that occurs with disease progression in some subjects with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
116Mol. 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, schizophrenias
117Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Apr 144B: 266-70
PMID17286247
TitlePositive association of the Disrupted-in-Schizophrenia-1 gene (DISC1) with schizophrenia in the Chinese Han population.
AbstractDisrupted-in-schizophrenia-1 (DISC1) is located on 1q42.1, one of the most promising susceptibility loci in schizophrenia linkage studies. A non-synonymous genetic variation rs821616 (Ser704Cys) in DISC1, has recently been shown to be associated with schizophrenia in family-based study [Callicott et al. (2005); Proc Natl Acad Sci USA 102: 8627-8632]. In order to further confirm this issue, we examined four single nucleotide polymorphisms (SNPs) in a chromosomal region spanning 42 kb of this gene, namely rs821616, rs821597, rs4658971, and rs843979, in Chinese sample of 313 schizophrenia patients and 317 healthy controls. Our results showed that two SNPs had strong associations with schizophrenia (rs821616: Allele A > T, chi(2) = 7.8006, df = 1, P = 0.0052; Genotype, chi(2) = 7.7935, df = 2, P = 0.0203; rs821597: Allele A > G, chi(2) = 9.5404, df = 1, P = 0.0020; Genotype, chi(2) = 12.2780, df = 2, P = 0.0022). When haplotypes were constructed with two, three, and four markers, a number of haplotype combinations, especially those including rs821616 and rs821597, were significantly associated with schizophrenia. Furthermore, there was a strong evidence for association in a four-marker haplotype analysis (chi(2) = 7.686, df = 4, P = 0.005581, corrected P = 0.006199). Although the case-control and family-based association studies both suggest that DISC1 gene may play a role in genetic susceptibility to schizophrenia, the risk haplotypic combinations have subtle differences in the two studies. Our findings provide further evidence for DISC1 as a predisposing gene involved in schizophrenia in the Chinese Han Population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
118Hum. Mol. Genet. 2007 Oct 16: 2517-28
PMID17673452
TitleAssociation of distinct allelic haplotypes of DISC1 with psychotic and bipolar spectrum disorders and with underlying cognitive impairments.
AbstractBipolar disorder (BPD) and schizophrenia (SCZ) have at least a partially convergent aetiology and thus may share genetic susceptibility loci. Multiple lines of evidence emphasize the role of disrupted-in-schizophrenia-1 (DISC1) gene in psychotic disorders such as SCZ. We monitored the association of allelic variants of translin-associated factor X (TSNAX)/DISC1 gene cluster using 13 single-nucleotide polymorphisms (SNPs) in 723 members of 179 Finnish BPD families. Consistent with an earlier finding in Finnish SCZ families, the haplotype T-A of rs751229 and rs3738401 at the 5' end of DISC1 was over-transmitted to males with psychotic disorder (P = 0.008; for an extended haplotype P = 0.0007 with both genders). Haplotypes at the 3' end of DISC1 associated with bipolar spectrum disorder (P = 0.0002 for an under-transmitted haplotype T-T of rs821616 and rs1411771, for an extended haplotype P = 0.0001), as did a two-SNP risk haplotype at the 5' end of TSNAX (P = 0.007). The risk haplotype for psychotic disorder also associated to perseverations (P = 0.035; for rs751229 alone P = 0.0012), and a protective haplotype G-T-G with rs1655285 in addition to auditory attention (P = 0.0059). The 3' end variants associated with several cognitive traits, with the most robust signal for rs821616 and verbal fluency and rs980989 and psychomotor processing speed (P = 0.011 for both). These results support involvement of DISC1 in the genetic aetiology of BPD and suggest that its distinct variants contribute to variation in the dimensional features of psychotic and bipolar spectrum disorders. Finding of alternative associating haplotypes in the same set of BPD families gives evidence for allelic heterogeneity within DISC1, eventually leading to heterogeneity in the clinical outcome as well.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
119Mol. Psychiatry 2007 Apr 12: 398-407
PMID17389905
TitleA novel DISC1-interacting partner DISC1-Binding Zinc-finger protein: implication in the modulation of DISC1-dependent neurite outgrowth.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a (1;11) (q42.1;q14.3) translocation that segregates with major psychiatric disorders in a Scottish family. To investigate how DISC1 confers susceptibility to psychiatric disorders, we previously identified fasciculation and elongation protein zeta-1 and Kendrin as DISC1-interacting molecules in a yeast two-hybrid screen of a human brain complementary DNA library. Here, we have further identified a novel DISC1-interacting protein, termed DISC1-Binding Zinc-finger protein (DBZ), which has a predicted C(2)H(2)-type zinc-finger motif and coiled-coil domains. DBZ was co-immunoprecipitated with DISC1 in lysates of PC12 cells and rat brain tissue. The domain of DISC1 interacting with DBZ was close to the translocation breakpoint in the DISC1 gene. DBZ messenger RNA (mRNA) was expressed in human brains, but not in peripheral tissues. In situ hybridization revealed high expression of DBZ mRNA in the hippocampus, olfactory tubercle, cerebral cortex and striatum in rats. Because this pattern of localization was similar to that of the pituitary adenylate cyclase (PAC(1)) receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), which has recently been implicated in neuropsychological functions, we examined whether DISC1/DBZ interaction was involved in the PACAP signaling pathway. PACAP upregulated DISC1 expression and markedly reduced the association between DISC1 and DBZ in PC12 cells. A DISC1-binding domain of DBZ reduced the neurite length in PC12 cells after PACAP stimulation and in primary cultured hippocampal neurons. The present results provide some new molecular insights into the mechanisms of neuronal development and neuropsychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
120Gene Expr. Patterns 2007 Jun 7: 672-9
PMID17482883
TitleExpression profiles of ndel1a and ndel1b, two orthologs of the NudE-Like gene, in the zebrafish.
AbstractNudE-Like (NDEL1/NUDEL), through its interaction with LIS1 and DISC1, has been implicated in the etiology of neurological disorders such as lissencephaly and schizophrenia, respectively. Subsequently, a large portion of the research done on the function of NDEL1 has been specifically targeted to its role in brain development while ignoring its function in other developing and adult tissues. To begin a more global exploration of NDEL1's function, this study characterizes the developmental expression pattern of the NDEL1 orthologs in the zebrafish embryo. Our bioinformatic analyses identified two NDEL1 orthologs in the zebrafish, ndel1a and ndel1b. ndel1a is expressed predominantly in the anterior central nervous system (CNS), trigeminal ganglia, and eyes while ndel1b is expressed in the developing somites and, later, in the CNS. In addition to the spatial differences in their expression patterns, these genes are also individually regulated in their temporal expression. Both are expressed maternally but at later time-points there are subtle differences. ndel1a expression is lost between 6 and 12 hpf but then increases to a higher, near steady state, level from 72 to 120 hpf. ndel1b expression decreases from 3 to 36 hpf and subsequently increases from 36 to 120 hpf. The non-overlapping expression patterns of these two orthologs may indicate that they have split the functional role of the one NDEL1 gene present in mammalian species. The temporal and spatial regulation of these two orthologs will aid in the characterization of the multiple functions of this gene in both the developing and mature organism.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
121Neuropsychopharmacology 2007 Jan 32: 190-6
PMID16936715
TitleThe FEZ1 gene shows no association to schizophrenia in Caucasian or African American populations.
Abstractschizophrenia is a complex psychiatric disorder with both genetic and environmental components and is thought to be in part neurodevelopmental in origin. The DISC1 gene has been linked to schizophrenia in two independent Caucasian populations. The DISC1 protein interacts with a variety of proteins including FEZ1, the mammalian homolog of the Caenorhabditis elegans unc-76 protein, which is involved in axonal outgrowth. Variation at the FEZ1 gene has been associated with schizophrenia in a large Japanese cohort. In this study, nine SNP markers at the FEZ1 locus were genotyped in two populations. A North American Caucasian cohort of 212 healthy controls, 178 schizophrenics, 79 bipolar disorder, and 58 with schizoaffective disorder, and an African American cohort of 133 healthy controls, 162 schizophrenics, and 28 with schizoaffective disorder. No association to schizophrenia, bipolar disorder or schizoaffective disorder was found for any of the nine markers typed in these populations at the allelic or the genotypic level. Additionally no association was found in either population between specific haplotypes and any of the psychiatric disorders. Variation at the FEZ1 locus does not play a significant role in the etiology of schizophrenia, bipolar disorder or schizoaffective disorder in North American Caucasian or African American populations.Neuropsychopharmacology (2007) 32, 190-196. doi:10.1038/sj.npp.1301177; published online 16 August 2006.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
122J. Neurosci. 2007 Jan 27: 15-26
PMID17202468
TitleDISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1.
AbstractDisrupted-In-schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3epsilon. 14-3-3epsilon is involved in the proper localization of NUDEL and LIS1 in axons. Although the functional significance of this complex in neuronal development has been reported, the transport mechanism of the complex into axons and their functions in axon formation remain essentially unknown. Here we report that Kinesin-1, a motor protein of anterograde axonal transport, was identified as a novel DISC1-interacting molecule. DISC1 directly interacted with kinesin heavy chain of Kinesin-1. Kinesin-1 interacted with the NUDEL/LIS1/14-3-3epsilon complex through DISC1, and these molecules localized mainly at cell bodies and partially in the distal part of the axons. DISC1 partially colocalized with Kinesin family member 5A, NUDEL, LIS1, and 14-3-3epsilon in the growth cones. The knockdown of DISC1 by RNA interference or the dominant-negative form of DISC1 inhibited the accumulation of NUDEL, LIS1, and 14-3-3epsilon at the axons and axon elongation. The knockdown or the dominant-negative form of Kinesin-1 inhibited the accumulation of DISC1 at the axons and axon elongation. Furthermore, the knockdown of NUDEL or LIS1 inhibited axon elongation. Together, these results indicate that DISC1 regulates the localization of NUDEL/LIS1/14-3-3epsilon complex into the axons as a cargo receptor for axon elongation.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
123Hum. Mol. Genet. 2007 Mar 16: 453-62
PMID17185386
TitleFamilies with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1.
AbstractWe have previously reported a robust association between an allelic haplotype of 'Disrupted in schizophrenia 1' (DISC1) and schizophrenia in a nationwide collection of Finnish schizophrenia families. This specific DISC1 allele was later identified to associate with visual working memory, selectively in males. DISC1 association to schizophrenia has since been replicated in multiple independent study samples from different populations. In this study, we conditioned our sample of Finnish families for the presence of the Finnish tentative risk allele for DISC1 and re-analyzed our genome-wide scan data of 443 markers on the basis of this stratification. Two additional loci displayed an evidence of linkage (LOD > 3) and included a locus on 16p13, proximal to the gene encoding NDE1, which has been shown to biologically interact with DISC1. Although none of the observed linkages remained significant after multiple test correction through simulation, further analysis of NDE1 revealed an association between a tag-haplotype and schizophrenia (P = 0.00046) specific to females, which proved to be significant (P = 0.011) after multiple test correction. Our finding would support the concept that initial gene findings in multifactorial diseases will assist in the identification of other components of complex genetic etiology. Notably, this and other converging lines of evidence underline the importance of DISC1-related functional pathways in the etiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
124Cell. 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, schizophrenias
125Neuropsychopharmacology 2007 Jan 32: 190-6
PMID16936715
TitleThe FEZ1 gene shows no association to schizophrenia in Caucasian or African American populations.
Abstractschizophrenia is a complex psychiatric disorder with both genetic and environmental components and is thought to be in part neurodevelopmental in origin. The DISC1 gene has been linked to schizophrenia in two independent Caucasian populations. The DISC1 protein interacts with a variety of proteins including FEZ1, the mammalian homolog of the Caenorhabditis elegans unc-76 protein, which is involved in axonal outgrowth. Variation at the FEZ1 gene has been associated with schizophrenia in a large Japanese cohort. In this study, nine SNP markers at the FEZ1 locus were genotyped in two populations. A North American Caucasian cohort of 212 healthy controls, 178 schizophrenics, 79 bipolar disorder, and 58 with schizoaffective disorder, and an African American cohort of 133 healthy controls, 162 schizophrenics, and 28 with schizoaffective disorder. No association to schizophrenia, bipolar disorder or schizoaffective disorder was found for any of the nine markers typed in these populations at the allelic or the genotypic level. Additionally no association was found in either population between specific haplotypes and any of the psychiatric disorders. Variation at the FEZ1 locus does not play a significant role in the etiology of schizophrenia, bipolar disorder or schizoaffective disorder in North American Caucasian or African American populations.Neuropsychopharmacology (2007) 32, 190-196. doi:10.1038/sj.npp.1301177; published online 16 August 2006.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
126Mol. Psychiatry 2008 Apr 13: 361-3
PMID18347596
TitleDoes disrupted-in-schizophrenia (DISC1) generate fusion transcripts?
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
127Mol. Psychiatry 2008 Dec 13: 1138-48, 1069
PMID18762802
TitleNuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly.
AbstractDisrupted-in-schizophrenia-1 (DISC1) is one of major susceptibility factors for a wide range of mental illnesses, including schizophrenia, bipolar disorder, major depression and autism spectrum conditions. DISC1 is located in several subcellular domains, such as the centrosome and the nucleus, and interacts with various proteins, including NudE-like (NUDEL/NDEL1) and activating transcription factor 4 (ATF4)/CREB2. Nevertheless, a role for DISC1 in vivo remains to be elucidated. Therefore, we have generated a Drosophila model for examining normal functions of DISC1 in living organisms. DISC1 transgenic flies with preferential accumulation of exogenous human DISC1 in the nucleus display disturbance in sleep homeostasis, which has been reportedly associated with CREB signaling/CRE-mediated gene transcription. Thus, in mammalian cells, we characterized nuclear DISC1, and identified a subset of nuclear DISC1 that colocalizes with the promyelocytic leukemia (PML) bodies, a nuclear compartment for gene transcription. Furthermore, we identified three functional cis-elements that regulate the nuclear localization of DISC1. We also report that DISC1 interacts with ATF4/CREB2 and a corepressor N-CoR, modulating CRE-mediated gene transcription.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
128PLoS Genet. 2008 Mar 4: e1000044
PMID18369462
TitleAn essential role for DYF-11/MIP-T3 in assembling functional intraflagellar transport complexes.
AbstractMIP-T3 is a human protein found previously to associate with microtubules and the kinesin-interacting neuronal protein DISC1 (Disrupted-in-schizophrenia 1), but whose cellular function(s) remains unknown. Here we demonstrate that the C. elegans MIP-T3 ortholog DYF-11 is an intraflagellar transport (IFT) protein that plays a critical role in assembling functional kinesin motor-IFT particle complexes. We have cloned a loss of function dyf-11 mutant in which several key components of the IFT machinery, including Kinesin-II, as well as IFT subcomplex A and B proteins, fail to enter ciliary axonemes and/or mislocalize, resulting in compromised ciliary structures and sensory functions, and abnormal lipid accumulation. Analyses in different mutant backgrounds further suggest that DYF-11 functions as a novel component of IFT subcomplex B. Consistent with an evolutionarily conserved cilia-associated role, mammalian MIP-T3 localizes to basal bodies and cilia, and zebrafish mipt3 functions synergistically with the Bardet-Biedl syndrome protein Bbs4 to ensure proper gastrulation, a key cilium- and basal body-dependent developmental process. Our findings therefore implicate MIP-T3 in a previously unknown but critical role in cilium biogenesis and further highlight the emerging role of this organelle in vertebrate development.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
129Proc. Natl. Acad. Sci. U.S.A. 2008 May 105: 7076-81
PMID18458327
TitleA mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition.
AbstractDISC1 is a strong candidate susceptibility gene for schizophrenia, bipolar disorder, and depression. Using a mouse strain carrying an endogenous DISC1 orthologue engineered to model the putative effects of the disease-associated chromosomal translocation we demonstrate that impaired DISC1 function results in region-specific morphological alterations, including alterations in the organization of newly born and mature neurons of the dentate gyrus. Field recordings at CA3/CA1 synapses revealed a deficit in short-term plasticity. Using a battery of cognitive tests we found a selective impairment in working memory (WM), which may relate to deficits in WM and executive function observed in individuals with schizophrenia. Our results implicate malfunction of neural circuits within the hippocampus and medial prefrontal cortex and selective deficits in WM as contributing to the genetic risk conferred by this gene.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
130Proc. Natl. Acad. Sci. U.S.A. 2008 Sep 105: 14157-62
PMID18780780
TitleDevelopment of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain.
AbstractNew neurons are continuously generated in restricted regions of the adult mammalian brain. Although these adult-born neurons have been shown to receive synaptic inputs, little is known about their synaptic outputs. Using retrovirus-mediated birth-dating and labeling in combination with serial section electron microscopic reconstruction, we report that mossy fiber en passant boutons of adult-born dentate granule cells form initial synaptic contacts with CA3 pyramidal cells within 2 weeks after their birth and reach morphologic maturity within 8 weeks in the adult hippocampus. Knockdown of Disrupted-in-schizophrenia-1 (DISC1) in newborn granule cells leads to defects in axonal targeting and development of synaptic outputs in the adult brain. Together with previous reports of synaptic inputs, these results demonstrate that adult-born neurons are fully integrated into the existing neuronal circuitry. Our results also indicate a role for DISC1 in presynaptic development and may have implications for the etiology of schizophrenia and related mental disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
131Psychiatr. Genet. 2008 Dec 18: 282-8
PMID19018233
TitlePhosphodiesterase-4A expression is reduced in cerebella of patients with bipolar disorder.
AbstractThe cAMP-specific phosphodiesterase-4 (PDE4) gene family has four members (PDE4 A, B, C, and D) and is the target of several potential therapeutic inhibitors. Recently, PDE4A5 has been shown to bind with disrupted in schizophrenia 1 (DISC1), which has been identified as a risk factor for schizophrenia, bipolar disorder, and major depression. We sought to examine whether PDE4A5 expression was altered in cerebella of patients with schizophrenia, bipolar disorder, and major depression.
We measured protein levels of PDE4A isoforms in cerebella of patients with schizophrenia, bipolar disorder, and major depression versus matched controls using sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blotting.
We observed that specific isoforms of PDE4A were reduced in cerebella of patients with bipolar disorder, whereas there was no change in patients with schizophrenia or major depression.
Our results are the first to show that PDE4A expression is altered in patients with bipolar disorder and provide potential new therapeutic avenues for treatment of this disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
132Biochem. Biophys. Res. Commun. 2008 Dec 377: 1091-6
PMID18983980
TitleDISC1, PDE4B, and NDE1 at the centrosome and synapse.
AbstractDisrupted-In-schizophrenia 1 (DISC1) is a risk factor for schizophrenia and other major mental illnesses. Its protein binding partners include the Nuclear Distribution Factor E Homologs (NDE1 and NDEL1), LIS1, and phosphodiesterases 4B and 4D (PDE4B and PDE4D). We demonstrate that NDE1, NDEL1 and LIS1, together with their binding partner dynein, associate with DISC1, PDE4B and PDE4D within the cell, and provide evidence that this complex is present at the centrosome. LIS1 and NDEL1 have been previously suggested to be synaptic, and we now demonstrate localisation of DISC1, NDE1, and PDE4B at synapses in cultured neurons. NDE1 is phosphorylated by cAMP-dependant Protein Kinase A (PKA), whose activity is, in turn, regulated by the cAMP hydrolysis activity of phosphodiesterases, including PDE4. We propose that DISC1 acts as an assembly scaffold for all of these proteins and that the NDE1/NDEL1/LIS1/dynein complex is modulated by cAMP levels via PKA and PDE4.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
133Am. 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, schizophrenias
134J. Hum. Genet. 2008 -1 53: 914-9
PMID18685808
TitleMicroarray comparative genomic hybridization analysis of 59 patients with schizophrenia.
Abstractschizophrenia is a common psychiatric disorder with a strong genetic contribution. Disease-associated chromosomal abnormalities in this condition may provide important clues, such as DISC1. In this study, 59 schizophrenia patients were analyzed by microarray comparative genomic hybridization (CGH) using custom bacterial artificial chromosome (BAC) microarray (4,219 BACs with 0.7-Mb resolution). Chromosomal abnormalities were found in six patients (10%): 46,XY,der(13)t(12;13)(p12.1; p11).ish del(5)(p11p12); 46,XY, ish del(17)(p12p12); 46,XX.ish dup(11)(p13p13); and 46,X,idic(Y)(q11.2); and in two cases, mos 45,X/46XX. Autosomal abnormalities in three cases are likely to be pathogenic, and sex chromosome abnormalities in three follow previous findings. It is noteworthy that 10% of patients with schizophrenia have (sub)microscopic chromosomal abnormalities, indicating that genome-wide copy number survey should be considered in genetic studies of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
135J. Neurosci. 2008 Oct 28: 10893-904
PMID18945897
TitleSchizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1.
AbstractDisrupted-in-schizophrenia-1 (DISC1), identified by positional cloning of a balanced translocation (1;11) with the breakpoint in intron 8 of a large Scottish pedigree, is associated with a range of neuropsychiatric disorders including schizophrenia. To model this mutation in mice, we have generated DISC1(tr) transgenic mice expressing 2 copies of truncated DISC1 encoding the first 8 exons using a bacterial artificial chromosome (BAC). With this partial simulation of the human situation, we have discovered a range of phenotypes including a series of novel features not previously reported. DISC1(tr) transgenic mice display enlarged lateral ventricles, reduced cerebral cortex, partial agenesis of the corpus callosum, and thinning of layers II/III with reduced neural proliferation at midneurogenesis. Parvalbumin GABAergic neurons are reduced in the hippocampus and medial prefrontal cortex, and displaced in the dorsolateral frontal cortex. In culture, transgenic neurons grow fewer and shorter neurites. Behaviorally, transgenic mice exhibit increased immobility and reduced vocalization in depression-related tests, and impairment in conditioning of latent inhibition. These abnormalities in DISC1(tr) transgenic mice are consistent with findings in severe schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
136Hum. Mol. Genet. 2008 Oct 17: 3191-203
PMID18647754
TitleMice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants.
AbstractFEZ1 (fasciculation and elongation protein zeta 1), a mammalian ortholog of Caenorhabditis elegans UNC-76, interacts with DISC1 (disrupted in schizophrenia 1), a schizophrenia susceptibility gene product, and polymorphisms of human FEZ1 have been associated with schizophrenia. We have now investigated the role of FEZ1 in brain development and the pathogenesis of schizophrenia by generating mice that lack Fez1. Immunofluorescence staining revealed FEZ1 to be located predominantly in gamma-aminobutyric acid-containing interneurons. The Fez1(-/-) mice showed marked hyperactivity in a variety of behavioral tests as well as enhanced behavioral responses to the psychostimulants MK-801 and methamphetamine. In vivo microdialysis revealed that the methamphetamine-induced release of dopamine in the nucleus accumbens was exaggerated in the mutant mice, suggesting that enhanced mesolimbic dopaminergic transmission contributes to their hyperactivity phenotype. These observations implicate impairment of FEZ1 function in the pathogenesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
137J Psychiatr Res 2008 Nov 43: 7-12
PMID18329668
TitlePositive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the Japanese population.
AbstractThe phosphodiesterase 4B (PDE4B) gene is located at 1p31, a susceptibility region for schizophrenia (SZ). Moreover, PDE4B interacts with DISC1, which is a known genetic risk factor for SZ. Recently, it was reported that the PDE4B gene is associated with SZ in Caucasian and African American populations. In this study, case-controlled association analyses were performed in the Japanese population to determine if the PDE4B gene is implicated in SZ. Thirteen single nucleotide polymorphisms (SNPs) were analyzed in 444 schizophrenic patients and 452 control subjects. Three SNPs (rs2180335, rs910694 and rs472952) were significantly associated with SZ after applying multiple test correction (p=0.039, 0.004 and 0.028). In addition, a significant association was found between specific haplotypes (rs2180335 and rs910694) and SZ (permutation p=0.001). Our result suggests that variations at the PDE4B locus may play a significant role in the etiology of SZ in the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
138Eur. J. Neurosci. 2008 Nov 28: 2129-36
PMID19046394
TitleAssociation of the SerCys DISC1 polymorphism with human hippocampal formation gray matter and function during memory encoding.
AbstractA common nonsynonymous single nucleotide polymorphism leading to a serine-to-cysteine substitution at amino acid 704 (Ser(704)Cys) in the DISC1 protein sequence has been recently associated with schizophrenia and with specific hippocampal abnormalities. Here, we used multimodal neuroimaging to investigate in a large sample of healthy subjects the putative association of the Ser(704)Cys DISC1 polymorphism with in vivo brain phenotypes including hippocampal formation (HF) gray matter volume and function (as assessed with functional MRI) as well as HF functional coupling with the neural network engaged during encoding of recognition memory. Individuals homozygous for DISC1 Ser allele relative to carriers of the Cys allele showed greater gray matter volume in the HF. Further, Ser/Ser subjects exhibited greater engagement of the HF together with greater HF-dorsolateral prefrontal cortex functional coupling during memory encoding, in spite of similar behavioral performance. These findings consistently support the notion that Ser(704)Cys DISC1 polymorphism is physiologically relevant. Moreover, they support the hypothesis that genetic variation in DISC1 may affect the risk for schizophrenia by modifying hippocampal gray matter and function.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
139Curr Psychiatry Rep 2008 Apr 10: 140-7
PMID18474207
TitleDisrupted-in-Schizophrenia-1.
AbstractChromosomal abnormalities can be powerful tools to identify genes that influence disease risk. The study of a chromosome translocation that segregated with severe psychiatric illness in a large family led directly to the discovery of a gene disrupted by a chromosomal breakpoint. Disrupted-in-schizophrenia-1 (DISC1) is now an important candidate risk gene for schizophrenia and affective disorders. We review the work that led up to this discovery and the evidence that it is important in the wider population with schizophrenia and affective disorders. We also discuss the latest findings on the neuronal functions of the protein DISC1 encoded by the gene.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
140Mol. Cell. Neurosci. 2008 Feb 37: 187-95
PMID18055216
TitleHow has DISC1 enabled drug discovery?
AbstractGrowing genetic and clinical evidence has shown that disrupted-in-schizophrenia 1 (DISC1) is one of the most compelling risk genes for schizophrenia and other major mental disorders. The understanding of the role that DISC1 plays in neuronal development and cell signaling has been greatly enhanced by the identification of DISC1 binding partners, an appreciation of its expression during development and functional studies using RNA interference. But what is the impact of this explosion of data for psychiatric drug discovery? Though we are at a very early stage of our understanding of DISC1 biology, it is an important time to review what has already been achieved and to discuss its impact. DISC1 biology has enabled the identification of new therapeutic targets in the form of DISC1 binding partners and other molecules found within a large DISC1 interaction network, the so-called 'DISC1 interactome'. We will review the better characterized of these interactions and also emphasize the richness of potential targets in the more poorly studied areas of the interactome. Furthermore, DISC1 has encouraged the development of new animal models for psychiatric disorders, which is critical for the study of disease biology. Thus, DISC1 may have the potential to not only point us in the direction of novel drug targets but also provide more relevant animal models for compound testing.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
141Biochem. Biophys. Res. Commun. 2008 Dec 377: 1051-6
PMID18955030
TitleDISC1-kendrin interaction is involved in centrosomal microtubule network formation.
AbstractDisrupted-In-schizophrenia 1 (DISC1) was identified as a novel gene disrupted by a (1;11)(q42.1;q14.3) translocation segregating with schizophrenia, bipolar disorder and other major mental illnesses in a Scottish family. We previously identified 446-533 amino acids of DISC1 as the kendrin-binding region by means of a directed yeast two-hybrid interaction assay and showed that the DISC1-kendrin interaction is indispensable for the centrosomal localization of DISC1. In this study, to confirm the DISC1-kendrin interaction, we examined the interaction between deletion mutants of DISC1 and kendrin. Then, we demonstrated that the carboxy-terminus of DISC1 is indispensable for the interaction with kendrin. Furthermore, the immunocytochemistry revealed that the carboxy-terminus of DISC1 is also required for the centrosomal targeting of DISC1. Overexpression of the DISC1-binding region of kendrin or the DISC1 deletion mutant lacking the kendrin-binding region impairs the microtubule organization. These findings suggest that the DISC1-kendrin interaction plays a key role in the microtubule dynamics.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
142Brain Nerve 2008 Apr 60: 445-52
PMID18421986
Title[Neurodevelopmental disturbance in the pathogenesis of major mental disorders].
AbstractNeurodevelopmental disturbance may underlie the pathogenesis of major mental disorders, including autism and schizophrenia, based on evidence in epidemiology, clinical psychiatry, brain imaging, and neuropathology. This notion is further supported by the fact that many of genetic susceptibility factors for these disorders have key roles in neurodevelopment. Majority of these genetic factors, such as Neuroligins, SHANK3, Neureglin-1, Dysbindin, and Disrupted-in-schizophrenia-1 (DISC1) are associated with "synapse." Therefore, "synapse" is one of the most promising sites of convergence in regard to molecular pathways for these mental conditions. In this review, we will summarize the updates of schizophrenia and autism research, with an emphasis on neurodevelopmental disturbances.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
143Curr Opin Psychiatry 2008 May 21: 290-5
PMID18382230
TitleThe contribution of failing adult hippocampal neurogenesis to psychiatric disorders.
AbstractFailing adult neurogenesis is increasingly considered a factor in the pathogenesis and course of psychiatric disorders. The level of evidence in favor of such hypotheses varies, but disturbed cellular plasticity in the hippocampus may be a common aspect of several neuropsychiatric diseases.
This review covers the literature from mid-2006 to the end of 2007. We discuss studies and theoretical papers dealing with the contribution of adult neurogenesis to dementias and neurodegeneration, major depression, schizophrenia, and alcohol and drug abuse. Of these disorders, most progress has recently been made with schizophrenia for which, in contrast to the other conditions, suggestive genetic evidence exists (e.g. DISC1, Npas3).
Failing adult hippocampal neurogenesis may not explain major depression, addiction or schizophrenia, but contributes to the hippocampal aspects of the disease. We propose that the key to a more thorough understanding of this contribution will come from increased knowledge on the functional relevance of new neurons in the hippocampus and better clinical data relating to symptoms possibly related to such function. Research on the molecular basis of adult hippocampal neurogenesis may help to explain how hippocampal aspects of these disorders develop.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
144Cytogenet. Genome Res. 2008 -1 123: 27-35
PMID19287136
TitleCopy variations in schizophrenia and bipolar disorder.
AbstractThe analysis of copy number variations (CNVs) is an emerging tool for identifying genetic factors underlying complex traits. In this chapter I will review studies that have been carried out showing that CNVs play a role in the development of two such complex traits; schizophrenia (SZ) and bipolar disorder (BD). There are two aspects to consider regarding the role of copy variations in these conditions. One is gene discovery in which DNA from patients is analyzed for the purpose of identifying rare, patient-specific CNVs that may be informative to a larger population of affected individuals. The model for this concept is based on the emergence of DISC1 as a SZ candidate gene, which was discovered in a single informative family with a rare chromosomal translocation. Another aspect revolves around the idea that polymorphic CNVs found in the general population, many of which appear to disrupt previously identified SZ and BD candidate genes, contribute to disease pathogenesis. Here, gene-disrupting CNVs are viewed in the same manner as functional SNPs and analyzed for involvement in disease susceptibility using genetic association. Although the analysis of CNVs in patients with psychiatric disorders is in its infancy, informative new findings have already been made, suggesting that this is a very promising line of research.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
145Neurosci. Lett. 2008 Jan 430: 60-3
PMID17997036
TitleAssociation study of polymorphisms between DISC1 and schizophrenia in a Korean population.
AbstractTo further clarify schizophrenia (SCZ), disrupted in schizophrenia 1 (DISC1) is a promising candidate gene expressed predominantly within the hippocampus. Several lines of evidence suggest that DISC1 may be involved in susceptibility to SCZ. In this study, we investigated whether genetic polymorphisms in the coding region of DISC1 were associated with several SCZ clinical phenotypes in a Korean population. To examine any association between DISC1 and SCZ, we genotyped three clinical single nucleotide polymorphisms (SNPs) (rs3738401, R264Q; rs3738402, L465L; rs821616, S704C) in the coding region of the DISC1 gene using the Illumina Sentrix Array Matrix chip and direct sequencing in 303 patients with SCZ and 300 healthy controls. Our case-control analysis showed that none of these SNPs was associated with SCZ. In further endophenotype stratification, however, we found a significant association between rs821616 and the poor concentration subgroup of SCZ, determined using the Operational Criteria Checklist (codominant model, p=0.015). Our results suggest that DISC1 may be a susceptibility gene for poor concentration among Korean patients with SCZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
146Am 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, schizophrenias
147Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Oct 147B: 1089-100
PMID18384059
TitleAssociation analysis of schizophrenia on 18 genes involved in neuronal migration: MDGA1 as a new susceptibility gene.
AbstractSeveral lines of evidence support the theory of schizophrenia (SZ) being a neurodevelopmental disorder. The structural, cytoarchitectural and functional brain abnormalities reported in patients with SZ, might be due to aberrant neuronal migration, since the final position of neurons affects neuronal function, morphology, and formation of synaptic connections. We have investigated the putative association between SZ and gene variants engaged in the neuronal migration process, by performing an association study on 839 cases and 1,473 controls of Scandinavian origin. Using a gene-wide approach, tagSNPs in 18 candidate genes have been genotyped, with gene products involved in the neuron-to-glial cell adhesion, interactions with the DISC1 protein and/or rearrangements of the cytoskeleton. Of the 289 markers tested, 19 markers located in genes MDGA1, RELN, ITGA3, DLX1, SPARCL1, and ASTN1, attained nominal significant P-values (P < 0.05) in either a genotypic or allelic association test. All of these genes, except transcription factor DLX1, are involved in the adhesion between neurons and radial glial cells. Eight markers obtained nominal significance in both tests, and were located in intronic or 3'UTR regions of adhesion molecule MDGA1 and previously reported SZ candidate RELN. The most significant result was attained for MDGA1 SNP rs9462341 (unadjusted association results: genotypic P = 0.00095; allelic P = 0.010). Several haplotypes within MDGA1, RELN, ITGA3, and ENAH were nominally significant. Further studies in independent samples are needed, including upcoming genome wide association study results, but our data suggest that MDGA1 is a new SZ susceptibility gene, and that altered neuronal migration is involved in SZ pathology.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
148Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Sep 147B: 732-6
PMID18163433
TitleAssociations of ATF4 gene polymorphisms with schizophrenia in male patients.
AbstractActivating transcription factor 4 (ATF4) is considered as a positional candidate gene for schizophrenia due to its location at chromosome 22q13, a region linked to schizophrenia. Furthermore, as protein interaction partner of ATF4, disrupted in schizophrenia 1 (DISC1) and its signal pathway implicated in the pathophysiology of schizophrenia have been widely supported by a number of genetic and neurobiological studies. Our aim was to investigate whether ATF4 is associated with schizophrenia in case-control samples of Han Chinese subjects consisting of 352 schizophrenia patients and 357 healthy controls. We detected 18 single nucleotide polymorphisms (SNPs) in ATF4 locus, two of which were analyzed, including one insertion at the putative core promoter region (rs17001266, -/C) and one nonsynonymous variant in exon 1 (rs4894, C/A, Pro22Gln). Allele distributions of two SNPs showed significant associations with schizophrenia in male subjects (respectively, rs17001266: P = 0.021, OR = 1.58, 95% CI = 1.07-2.33; rs4894: P = 0.004, OR = 1.78, 95% CI = 1.19-2.67), but not in female subjects as well as the entire population. Two haplotypes CC and -A constructed of rs17001266-rs4894 also revealed significant associations with schizophrenia in male group (global P = 0.0097). These findings support that ATF4 gene may be involved in susceptibility to schizophrenia with sex-dependent effect in the Chinese Han population and suggest that further functional assays are needed to verify their relevance to the pathogenesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
149Arch. Gen. Psychiatry 2008 Sep 65: 996-1006
PMID18762586
TitleRecruitment of PCM1 to the centrosome by the cooperative action of DISC1 and BBS4: a candidate for psychiatric illnesses.
AbstractA role for the centrosome has been suggested in the pathology of major mental illnesses, especially schizophrenia (SZ).
To show that pericentriolar material 1 protein (PCM1) forms a complex at the centrosome with disrupted-in-schizophrenia 1 (DISC1) and Bardet-Biedl syndrome 4 protein (BBS4), which provides a crucial pathway for cortical development associated with the pathology of SZ. To identify mutations in the PCM1 gene in an SZ population.
Interaction of DISC1, PCM1, and BBS proteins was assessed by immunofluorescent staining and coimmunoprecipitation. Effects of PCM1, DISC1, and BBS on centrosomal functions and corticogenesis in vivo were tested by RNA interference. The PCM1 gene was examined by sequencing 39 exons and flanking splice sites.
Probands and controls were from the collection of one of us (A.E.P.).
Thirty-two probands with SZ from families that had excess allele sharing among affected individuals at 8p22 and 219 white controls.
Protein interaction and recruitment at the centrosome in cells; neuronal migration in the cerebral cortex; and variant discovery in PCM1 in patients with SZ.
PCM1 forms a complex with DISC1 and BBS4 through discrete binding domains in each protein. DISC1 and BBS4 are required for targeting PCM1 and other cargo proteins, such as ninein, to the centrosome in a synergistic manner. In the developing cerebral cortex, suppression of PCM1 leads to neuronal migration defects, which are phenocopied by the suppression of either DISC1 or BBS4 and are exacerbated by the concomitant suppression of both. Furthermore, a nonsense mutation that segregates with SZ spectrum psychosis was found in 1 family.
Our data further support for the role of centrosomal proteins in cortical development and suggest that perturbation of centrosomal function contributes to the development of mental diseases, including SZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
150Gene Expr. Patterns 2008 Sep 8: 494-501
PMID18620078
TitleImmunohistochemical analysis of Disc1 expression in the developing and adult hippocampus.
AbstractIn recent years, Disrupted-In-schizophrenia 1 (DISC1) has emerged as one of the most promising candidate genes whose disruption confers an increased risk for schizophrenia. Cell biology studies have implicated DISC1 in key neurodevelopmental processes including neurite outgrowth and neuronal migration. In situ hybridization analysis has revealed that DISC1 is expressed in the hypothalamus, olfactory bulbs, the developing cerebral cortex and the hippocampus. The hippocampus is of particular interest because abnormalities in hippocampal volume and function have been consistently reported in schizophrenics. Moreover, DISC1 mutations have been associated with abnormal activation of the hippocampus in humans. Given the involvement of the hippocampus in the pathophysiology of schizophrenia, there is an intriguing possibility that disruption of DISC1 may increase schizophrenia susceptibility by altering the normal development and function of the hippocampus. In order to contribute to our understanding of DISC1's role in the hippocampus, we have performed a detailed analysis of the DISC1 expression pattern in the mouse hippocampus throughout development. We report that DISC1 is expressed throughout the hippocampus during embryonic development, with expression becoming increasingly specialized in Ammon's horn and dentate gyrus granule cells within the first postnatal week. This expression pattern remains consistent into adulthood, with a noted decrease in DISC1 expression in the adult CA1. DISC1 is also expressed in proliferating cells in the adult subgranular zone, as well as in a subset of GABAergic interneurons. Our results are the first report of a detailed immunohistochemical analysis of the ontogeny of DISC1 expression within the hippocampus.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
151Learn. Mem. 2008 Aug 15: 551-64
PMID18685145
TitleMolecular mechanisms of stress-induced prefrontal cortical impairment: implications for mental illness.
AbstractThe symptoms of mental illness often involve weakened regulation of thought, emotion, and behavior by the prefrontal cortex. Exposure to stress exacerbates symptoms of mental illness and causes marked prefrontal cortical dysfunction. Studies in animals have revealed the intracellular signaling pathways activated by stress exposure that induce profound prefrontal cortical impairment: Excessive dopamine stimulation of D1 receptors impairs prefrontal function via cAMP intracellular signaling, leading to disconnection of prefrontal networks, while excessive norepinephrine stimulation of alpha1 receptors impairs prefrontal function via phosphatidylinositol-protein kinase C intracellular signaling. Genetic studies indicate that the genes disrupted in serious mental illness (bipolar disorder and schizophrenia) often encode for the intracellular proteins that serve as brakes on the intracellular stress pathways. For example, disrupted in schizophrenia 1 (DISC1) normally regulates cAMP levels, while regulator of G protein signaling 4 (RGS4) and diacylglycerol kinase (DGKH)-the molecule most associated with bipolar disorder- normally serve to inhibit phosphatidylinositol-protein kinase C intracellular signaling. Patients with mutations resulting in loss of adequate function of these genes likely have weaker endogenous regulation of these stress pathways. This may account for the vulnerability to stress and the severe loss of PFC regulation of behavior, thought, and affect in these illnesses. This review highlights the signaling pathways onto which genetic vulnerability and stress converge to impair PFC function and induce debilitating symptoms such as thought disorder, disinhibition, and impaired working memory.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
152Mol. Psychiatry 2008 Jan 13: 36-64
PMID17912248
TitleThe DISC locus in psychiatric illness.
AbstractThe DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-schizophrenia-1 (DISC1) and Disrupted-in-schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
153Arch. 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, schizophrenias
154Hum. Mol. Genet. 2008 Oct 17: 3212-22
PMID18658164
TitleIdentification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia.
Abstractschizophrenia is a complex mental disorder with a fairly high degree of heritability. Although the causes of schizophrenia remain unclear, it is now widely accepted that it is a neurodevelopmental and neurodegenerative disorder involving disconnectivity and disorder of the synapses. Disrupted-in-schizophrenia 1 (DISC1) is a promising candidate susceptibility gene involved in neurodevelopment, including maturation of the cerebral cortex. To identify other susceptibility genes for schizophrenia, we screened for DISC1-interacting molecules [NudE-like (NUDEL), Lissencephaly-1 (LIS1), 14-3-3epsilon (YWHAE), growth factor receptor bound protein 2 (GRB2) and Kinesin family 5A of Kinesen1 (KIF5A)], assessing a total of 25 tagging single-nucleotide polymorphisms (SNPs) in a Japanese population. We identified a YWHAE SNP (rs28365859) that showed a highly significant difference between case and control samples, with higher minor allele frequencies in controls (P(allele) = 1.01 x 10(-5) and P(genotype) = 4.08 x 10(-5) in 1429 cases and 1728 controls). Both messenger RNA transcription and protein expression of 14-3-3epsilon were also increased in the lymphocytes of healthy control subjects harboring heterozygous and homozygous minor alleles compared with homozygous major allele subjects. To further investigate a potential role for YWHAE in schizophrenia, we studied Ywhae(+/-) mice in which the level of 14-3-3epsilon protein is reduced to 50% of that in wild-type littermates. These mice displayed weak defects in working memory in the eight-arm radial maze and moderately enhanced anxiety-like behavior in the elevated plus-maze. Our results suggest that YWHAE is a possible susceptibility gene that functions protectively in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
155Mol. Psychiatry 2008 Feb 13: 173-86, 115
PMID17848917
TitleInducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia.
AbstractA strong candidate gene for schizophrenia and major mental disorders, disrupted-in-schizophrenia 1 (DISC1) was first described in a large Scottish family in which a balanced chromosomal translocation segregates with schizophrenia and other psychiatric illnesses. The translocation mutation may result in loss of DISC1 function via haploinsufficiency or dominant-negative effects of a predicted mutant DISC1 truncated protein product. DISC1 has been implicated in neurodevelopment, including maturation of the cerebral cortex. To evaluate the neuronal and behavioral effects of mutant DISC1, the Tet-off system under the regulation of the CAMKII promoter was used to generate transgenic mice with inducible expression of mutant human DISC1 (hDISC1) limited to forebrain regions, including cerebral cortex, hippocampus and striatum. Expression of mutant hDISC1 was not associated with gross neurodevelopmental abnormalities, but led to a mild enlargement of the lateral ventricles and attenuation of neurite outgrowth in primary cortical neurons. These morphological changes were associated with decreased protein levels of endogenous mouse DISC1, LIS1 and SNAP-25. Compared to their sex-matched littermate controls, mutant hDISC1 transgenic male mice exhibited spontaneous hyperactivity in the open field and alterations in social interaction, and transgenic female mice showed deficient spatial memory. The results show that the neuronal and behavioral effects of mutant hDISC1 are consistent with a dominant-negative mechanism, and are similar to some features of schizophrenia. The present mouse model may facilitate the study of aspects of the pathogenesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
156Aust N Z J Psychiatry 2008 Aug 42: 662-77
PMID18622774
TitleDual constraints on synapse formation and regression in schizophrenia: neuregulin, neuroligin, dysbindin, DISC1, MuSK and agrin.
AbstractDuring adolescence there is a loss of approximately 30% of the synapses formed in the cortex during childhood. Comprehensive studies of the visual cortex show that this loss of synapses does not occur as a consequence of less appropriate projections being eliminated in favour of more appropriate ones. Rather it seems that synapses with low efficacy for transmission are eliminated in favour of those with higher efficacy. The loss of low-efficacy synapses is known, on theoretical grounds, to enhance the function of neural networks, but large synapse losses lead to failure of network function. In the dorsolateral prefrontal cortex (DLPC) of those suffering from schizophrenia the number of synapses is relatively very low, approximately 60% lower than that observed in normal childhood. It is not known if this is due to an additional loss over that during normal adolescence or whether it results from a failure to form a normal complement of synapses during childhood. The first study of synapse loss in the mammalian nervous system was made on the neuromuscular junction at Sydney University in 1974. Since then this junction has provided principal insights into the molecular basis of synapse formation and regression, so providing a paradigm for investigations of these phenomena in the DLPC. For example the molecules muscle-specific receptor tyrosine kinase (MuSK), agrin and neuregulin have been identified and their critical roles in the formation and maintenance of synapses elucidated. Loss of function of MuSK or agrin leads to failure of neuromuscular synapse formation as well as a loss of approximately 30% of excitatory synapses in the cortex. Similar synapse loss occurs on failure of neuregulin in vitro and of neuroligin in vivo. It is suggested that three important questions need to be answered: first, over what development period are the synapse numbers in DLPC of subjects with schizophrenia lower than normal; second, what are the relative importance of MuSK/agrin, neuregulin/ErB and neurexin/neuroligin in synapse formation and regression in the DLPC; and third, to what extent have these molecules gone awry in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
157Novartis Found. Symp. 2008 -1 289: 208-16; discussion 216-21, 238-40
PMID18497105
TitleWhat can we learn from the disrupted in schizophrenia 1 interactome: lessons for target identification and disease biology?
AbstractEmerging genetic and biological data strongly supports Disrupted in schizophrenia 1 (DISC1) as a schizophrenia risk gene of great significance for not only understanding the underlying causes of schizophrenia and related disorders but potentially to open up new avenues of treatment. DISC1 appeared to be a very enigmatic protein upon the initial disclosure of its protein sequence. Though it contained some well-characterized protein domains, they did not reveal anything about possible function. Recently, the identification of its binding partners has revealed an incredible diversity of potential cellular and physiological functions. In an attempt to capture this information we set out to generate a comprehensive network of protein-protein interactions (PPIs) around DISC1. This was achieved by utilizing iterative yeast-two hybrid screens, combined with detailed pathway and functional analysis. This so-called 'DISC1 interactome' contains many novel PPIs and has provided a molecular framework to explore the function of DISC1. Interrogation of the interactome has shown DISC1 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. Furthermore, potential novel therapeutic targets have also emerged as we have characterized in detail the interactions with the phosphodiesterase PDE4B in collaboration with the Porteous and Houslay labs, and with Ndel1-EOPA with Hayashi and colleagues. Many components of the interactome are themselves now being shown to be schizophrenia risk genes, or to interact with other risk genes, emphasising the power of protein interaction studies for revealing the underlying biology of a disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
158Biochem. Biophys. Res. Commun. 2008 Mar 367: 700-6
PMID18164685
TitleIdentification of high risk DISC1 structural variants with a 2% attributable risk for schizophrenia.
AbstractThe causes of schizophrenia remain elusive. In a large Scottish pedigree, a balanced translocation t(1;11) (q42.1;q14.3) disrupting the DISC1 and DISC2 genes segregates with major mental illness, including schizophrenia and unipolar depression. A frame-shift carboxyl-terminal deletion was reported in DISC1 in an American family, but subsequently found in two controls. A few common structural variants have been associated with less than a 2-fold increased risk for schizophrenia, but replication has not been uniform. No large scale case-control mutation study has been performed. We have analyzed the regions of likely functional significance in the DISC1 gene in 288 patients with schizophrenia and 288 controls (5 megabases of genomic sequence analyzed). Six patients with schizophrenia were heterozygous for ultra-rare missense variants not found in the 288 controls (p=0.015) and shown to be ultra-rare by their absence in a pool of 10,000 control alleles. We conclude that ultra-rare structural variants in DISC1 are associated with an attributable risk of about 2% for schizophrenia. In addition, we confirm that two common structural variants (Q264R and S704C) elevate the risk for schizophrenia slightly (odds ratio 1.3, 95% CI: 1.0-1.7). DISC1 illustrates how common/moderate risk alleles suggested by the HapMap project might be followed up by resequencing to identify genes with high risk, low frequency alleles of clinical relevance.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
159Schizophr. Res. 2008 Dec 106: 237-41
PMID18818052
TitleAssociation between a disrupted-in-schizophrenia 1 (DISC1) single nucleotide polymorphism and schizophrenia in a combined Scandinavian case-control sample.
AbstractDisrupted-in-schizophrenia-1 (DISC1), located on chromosome 1q42.1, is linked to rare familial schizophrenia in a large Scottish family. The chromosomal translocation that segregates with the disease results in a truncated protein that impairs neurite outgrowth and proper development of the cerebral cortex, suggesting that lost DISC1 function may underlie neurodevelopmental dysfunction in schizophrenia. DISC1 has been associated with schizophrenia in multiple populations, but there is little evidence of convergence across populations. In the present case-control study three Scandinavian samples of 837 individuals affected with schizophrenia and 1473 controls, were used in an attempt to replicate previously reported associations between single nucleotide polymorphisms (SNPs) in DISC1 and schizophrenia. No SNP with allele frequency above 10% was significantly associated with the disease after correction for multiple testing. However, the minor allele of rs3737597 (frequency 2%) in the 3'-untranslated region (UTR), previously identified as a risk allele in Finnish families, was significantly and consistently associated with the disorder across the three samples, (p-value corrected for multiple testing was 0.002). Our results suggest that a relatively uncommon DISC1 mutation, which increases the susceptibility for schizophrenia may be segregating in the Scandinavian population, and support the view that common DISC1 SNP alleles are unlikely to account for a substantial proportion of the genetic risk of the disease across populations of European descent.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
160Biol. Psychiatry 2008 Apr 63: 678-85
PMID17884020
TitleGene and expression analyses reveal enhanced expression of pericentrin 2 (PCNT2) in bipolar disorder.
AbstractDISC1 has been suggested as a causative gene for psychoses in a large Scottish kindred. PCNT2 has recently been identified as an interacting partner of DISC1. In this study, we investigated the role of PCNT2 in bipolar disorder, by gene expression analysis and genetic association study.
By TaqMan real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), we examined the messenger RNA (mRNA) levels of PCNT2 in the postmortem prefrontal cortex of bipolar disorder (n = 34), schizophrenia (n = 31), and control subjects (n = 32), obtained from Stanley Array Collection. We also compared the mRNA levels of PCNT2 in the peripheral blood lymphocytes of bipolar disorder (n = 21), schizophrenia (n = 21), depression (n = 33), and control subjects (n = 57). For the association study, 23 single nucleotide polymorphisms (SNPs) were analyzed in 285 bipolar disorder patients and 287 age-and gender-matched control subjects, all of Japanese origin. The genotypes were determined by TaqMan assay.
Significantly higher expression of PCNT2 was observed in the brain samples of bipolar group, compared with the control (p = .001) and schizophrenia (p = .018) groups. In the peripheral blood lymphocytes also, a significantly higher expression of PCNT2 was observed in the bipolar group, compared with the control subjects (p = .043). However, none of the SNPs analyzed in our study showed a significant association with bipolar disorder; a weak tendency toward association was observed for two intronic SNPs.
Our findings suggest that elevated levels of PCNT2 might be implicated in the pathophysiology of bipolar disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
161Am. 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, schizophrenias
162Am. 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, schizophrenias
163Hum. Mol. Genet. 2008 Aug 17: 2462-73
PMID18469341
TitleElucidating the relationship between DISC1, NDEL1 and NDE1 and the risk for schizophrenia: evidence of epistasis and competitive binding.
AbstractDISC1 influences susceptibility to psychiatric disease and related phenotypes. Intact functions of DISC1 and its binding partners, NDEL1 and NDE1, are critical to neurodevelopmental processes aberrant in schizophrenia (SZ). Despite evidence of an NDEL1-DISC1 protein interaction, there have been no investigations of the NDEL1 gene or the relationship between NDEL1 and DISC1 in SZ. We genotyped six NDEL1 single-nucleotide polymorphisms (SNPs) in 275 Caucasian SZ patients and 200 controls and tested for association and interaction between the functional SNP Ser704Cys in DISC1 and NDEL1. We also evaluated the relationship between NDE1 and DISC1 genotype and SZ. Finally, in a series of in vitro assays, we determined the binding profiles of NDEL1 and NDE1, in relation to DISC1 Ser704Cys. We observed a single haplotype block within NDEL1; the majority of variation was captured by NDEL1 rs1391768. We observed a significant interaction between rs1391768 and DISC1 Ser704Cys, with the effect of NDEL1 on SZ evident only against the background of DISC1 Ser704 homozygosity. Secondary analyses revealed no direct relationship between NDE1 genotype and SZ; however, there was an opposite pattern of risk for NDE1 genotype when conditioned on DISC1 Ser704Cys, with NDE1 rs3784859 imparting a significant effect but only in the context of a Cys-carrying background. In addition, we report opposing binding patterns of NDEL1 and NDE1 to Ser704 versus Cys704, at the same DISC1 binding domain. These data suggest that NDEL1 significantly influences risk for SZ via an interaction with DISC1. We propose a model where NDEL1 and NDE1 compete for binding with DISC1.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
164J. Neurosci. 2008 Apr 28: 3839-45
PMID18400883
TitleInsolubility of disrupted-in-schizophrenia 1 disrupts oligomer-dependent interactions with nuclear distribution element 1 and is associated with sporadic mental disease.
AbstractDisrupted-in-schizophrenia 1 (DISC1) and other genes have been identified recently as potential molecular players in chronic psychiatric diseases such as affective disorders and schizophrenia. A molecular mechanism of how these genes may be linked to the majority of sporadic cases of these diseases remains unclear. The chronic nature and irreversibility of clinical symptoms in a subgroup of these diseases prompted us to investigate whether proteins corresponding to candidate genes displayed subtle features of protein aggregation. Here, we show that in postmortem brain samples of a distinct group of patients with phenotypes of affective disorders or schizophrenia, but not healthy controls, significant fractions of DISC1 could be identified as cold Sarkosyl-insoluble protein aggregates. A loss-of-function phenotype could be demonstrated for insoluble DISC1 through abolished binding to a key DISC1 ligand, nuclear distribution element 1 (NDEL1): in human neuroblastoma cells, DISC1 formed expression-dependent, detergent-resistant aggregates that failed to interact with endogenous NDEL1. Recombinant (r) NDEL1 expressed in Escherichia coli selectively bound an octamer of an rDISC1 fragment but not dimers or high molecular weight multimers, suggesting an oligomerization optimum for molecular interactions of DISC1 with NDEL1. For DISC1-related sporadic psychiatric disease, we propose a mechanism whereby impaired cellular control over self-association of DISC1 leads to excessive multimerization and subsequent formation of detergent-resistant aggregates, culminating in loss of ligand binding, here exemplified by NDEL1. We conclude that the absence of oligomer-dependent ligand interactions of DISC1 can be associated with sporadic mental disease of mixed phenotypes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
165Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Oct 147B: 1065-9
PMID18270998
TitleDISC1 mRNA expression is not influenced by common Cis-acting regulatory polymorphisms or imprinting.
AbstractThe hypothesis that genetic variation in Disrupted in schizophrenia 1 (DISC1) influences risk of schizophrenia and other major psychiatric disorders is supported by a growing body of genetic association data and plausible functional biology. Risk of psychiatric disorder is not attributable to non-synonymous changes that alter the protein coding sequence of DISC1, although certain such variants possibly contribute to risk haplotypes. Thus, it is widely hypothesized that the risk variants at DISC1 influence its expression. As a complicating factor, it has also been recently proposed that DISC1 is subject to imprinting, a hypothesis that would profoundly influence the interpretation of current genetic studies. We have tested these two main hypotheses using allelic expression analysis. Of 148 human brain mRNA samples, 65 were informative for analysis. However, only a single sample showed evidence for unequal expression of paternal and maternal transcripts. Analysis of the proximal promoter region in that subject revealed the presence of a previously unknown duplication of the 22 nucleotides -168 to -147 relative to the transcription start site. However, the altered expression in that subject did not appear to be explained by this insertion. Our data robustly demonstrate that DISC1 is not imprinted in the adult human brain, and strongly suggest that reports of genetic association between DISC1 and psychiatric disorder are not explicable by sequence changes that alter mRNA abundance.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
166Biol Psychol 2008 Sep 79: 103-10
PMID18078707
TitleDISC1 is associated with prefrontal cortical gray matter and positive symptoms in schizophrenia.
AbstractDISC1 is considered a susceptibility gene for schizophrenia and schizoaffective disorder, but little is known regarding the potential mechanisms through which it may confer increased risk. Given that DISC1 plays a role in cerebral cortex development, polymorphisms in this gene may have relevance for neurobiological models of schizophrenia that have implicated cortical deficits in its pathophysiology.
We investigated whether the DISC1 leu607phe polymorphism was associated with prefrontal gray matter volumes using magnetic resonance imaging in a cohort of patients with schizophrenia (N=19) and healthy volunteers (N=25) and positive and negative symptoms in 200 patients with schizophrenia.
Among patients and healthy volunteers, phe carriers (N=11) had significantly less gray matter in the superior frontal gyrus and anterior cingulate gyrus compared to leu/leu homozygotes (N=33). Further, among patients left superior frontal gyrus gray matter volume was significantly negatively correlated with severity of hallucinations. In addition, patients who were phe carriers (N=144) had significantly greater severity of positive symptoms (hallucinations) compared to patients who were leu/leu homozygotes (N=56).
These findings implicate DISC1 in variation of prefrontal cortical volume and positive symptoms, thus providing a potential mechanism through which DISC1 may confer increased risk for schizophrenia or schizoaffective disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
167J Psychiatr Res 2008 Nov 43: 7-12
PMID18329668
TitlePositive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the Japanese population.
AbstractThe phosphodiesterase 4B (PDE4B) gene is located at 1p31, a susceptibility region for schizophrenia (SZ). Moreover, PDE4B interacts with DISC1, which is a known genetic risk factor for SZ. Recently, it was reported that the PDE4B gene is associated with SZ in Caucasian and African American populations. In this study, case-controlled association analyses were performed in the Japanese population to determine if the PDE4B gene is implicated in SZ. Thirteen single nucleotide polymorphisms (SNPs) were analyzed in 444 schizophrenic patients and 452 control subjects. Three SNPs (rs2180335, rs910694 and rs472952) were significantly associated with SZ after applying multiple test correction (p=0.039, 0.004 and 0.028). In addition, a significant association was found between specific haplotypes (rs2180335 and rs910694) and SZ (permutation p=0.001). Our result suggests that variations at the PDE4B locus may play a significant role in the etiology of SZ in the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
168Mol. Psychiatry 2008 Feb 13: 187-96
PMID17579608
TitleAssociation of DISC1 with autism and Asperger syndrome.
AbstractThe DISC1 gene at 1q42 has generated considerable interest in various psychiatric diseases, since a balanced translocation interrupting the gene was found to cosegregate with schizophrenia and related mental illnesses in a large Scottish pedigree. To date, linkage and association findings to this locus have been replicated in several study samples ascertained for psychotic disorders. However, the biological function of DISC1 in neuronal development would suggest a potential role for this gene also in other, early onset neuropsychiatric disorders. Here we have addressed the allelic diversity of the DISC1, DISC2 and TRAX genes, clustered in 1q42, in Finnish families ascertained for infantile autism (97 families, n(affected)=138) and Asperger syndrome (29 families, n(affected)=143). We established association between autism and a DISC1 intragenic microsatellite (D1S2709; P=0.004). In addition, evidence for association to Asperger syndrome was observed with an intragenic single nucleotide polymorphism (SNP) of DISC1 (rs1322784; P=0.0058), as well as with a three-SNP haplotype (P=0.0013) overlapping the HEP3 haplotype, that was previously observed to associate with schizophrenia in Finnish families. The strongest associations were obtained with broad diagnostic categories for both disorders and with affected males only, in agreement with the previous sex-dependent effects reported for DISC1. These results would further support the involvement of DISC1 gene also in the etiopathogenesis of early onset neuropsychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
169Gene Expr. Patterns 2008 Sep 8: 494-501
PMID18620078
TitleImmunohistochemical analysis of Disc1 expression in the developing and adult hippocampus.
AbstractIn recent years, Disrupted-In-schizophrenia 1 (DISC1) has emerged as one of the most promising candidate genes whose disruption confers an increased risk for schizophrenia. Cell biology studies have implicated DISC1 in key neurodevelopmental processes including neurite outgrowth and neuronal migration. In situ hybridization analysis has revealed that DISC1 is expressed in the hypothalamus, olfactory bulbs, the developing cerebral cortex and the hippocampus. The hippocampus is of particular interest because abnormalities in hippocampal volume and function have been consistently reported in schizophrenics. Moreover, DISC1 mutations have been associated with abnormal activation of the hippocampus in humans. Given the involvement of the hippocampus in the pathophysiology of schizophrenia, there is an intriguing possibility that disruption of DISC1 may increase schizophrenia susceptibility by altering the normal development and function of the hippocampus. In order to contribute to our understanding of DISC1's role in the hippocampus, we have performed a detailed analysis of the DISC1 expression pattern in the mouse hippocampus throughout development. We report that DISC1 is expressed throughout the hippocampus during embryonic development, with expression becoming increasingly specialized in Ammon's horn and dentate gyrus granule cells within the first postnatal week. This expression pattern remains consistent into adulthood, with a noted decrease in DISC1 expression in the adult CA1. DISC1 is also expressed in proliferating cells in the adult subgranular zone, as well as in a subset of GABAergic interneurons. Our results are the first report of a detailed immunohistochemical analysis of the ontogeny of DISC1 expression within the hippocampus.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
170Novartis Found. Symp. 2008 -1 289: 208-16; discussion 216-21, 238-40
PMID18497105
TitleWhat can we learn from the disrupted in schizophrenia 1 interactome: lessons for target identification and disease biology?
AbstractEmerging genetic and biological data strongly supports Disrupted in schizophrenia 1 (DISC1) as a schizophrenia risk gene of great significance for not only understanding the underlying causes of schizophrenia and related disorders but potentially to open up new avenues of treatment. DISC1 appeared to be a very enigmatic protein upon the initial disclosure of its protein sequence. Though it contained some well-characterized protein domains, they did not reveal anything about possible function. Recently, the identification of its binding partners has revealed an incredible diversity of potential cellular and physiological functions. In an attempt to capture this information we set out to generate a comprehensive network of protein-protein interactions (PPIs) around DISC1. This was achieved by utilizing iterative yeast-two hybrid screens, combined with detailed pathway and functional analysis. This so-called 'DISC1 interactome' contains many novel PPIs and has provided a molecular framework to explore the function of DISC1. Interrogation of the interactome has shown DISC1 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. Furthermore, potential novel therapeutic targets have also emerged as we have characterized in detail the interactions with the phosphodiesterase PDE4B in collaboration with the Porteous and Houslay labs, and with Ndel1-EOPA with Hayashi and colleagues. Many components of the interactome are themselves now being shown to be schizophrenia risk genes, or to interact with other risk genes, emphasising the power of protein interaction studies for revealing the underlying biology of a disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
171Neuron 2009 Sep 63: 761-73
PMID19778506
TitleDISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212.
AbstractDisrupted-in-schizophrenia 1 (DISC1), a susceptibility gene for major mental illnesses, regulates multiple aspects of embryonic and adult neurogenesis. Here, we show that DISC1 suppression in newborn neurons of the adult hippocampus leads to overactivated signaling of AKT, another schizophrenia susceptibility gene. Mechanistically, DISC1 directly interacts with KIAA1212, an AKT binding partner that enhances AKT signaling in the absence of DISC1, and DISC1 binding to KIAA1212 prevents AKT activation in vitro. Functionally, multiple genetic manipulations to enhance AKT signaling in adult-born neurons in vivo exhibit similar defects as DISC1 suppression in neuronal development that can be rescued by pharmacological inhibition of mammalian target of rapamycin (mTOR), an AKT downstream effector. Our study identifies the AKT-mTOR signaling pathway as a critical DISC1 target in regulating neuronal development and provides a framework for understanding how multiple susceptibility genes may functionally converge onto a common pathway in contributing to the etiology of certain psychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
172Pharmacogenomics 2009 Dec 10: 1967-78
PMID19958095
TitleRole of the PACAP-PAC1-DISC1 and PACAP-PAC1-stathmin1 systems in schizophrenia and bipolar disorder: novel treatment mechanisms?
AbstractTwo pituitary adenylate cyclase-activating polypeptide (PACAP)-signaling pathways linked to schizophrenia were reviewed. One pathway regulates the association between disrupted-in-schizophrenia 1 (DISC1) and DISC1-binding zinc-finger protein via PACAP, and the other inhibits stathmin1 expression via PACAP. PACAP reduces the association of the binding between DISC1 (a potential susceptibility gene for major psychiatric disease) and DISC1-binding zinc-finger protein (which binds to DISC1 near the translocation site) to induce neurite outgrowth. In addition, an association between SNPs of the PACAP or PAC1 genes and schizophrenia has been reported. On the other hand, expression of stathmin1, which induces abnormal axonal arborization, is upregulated in PACAP-knock out mice and the brains of patients with schizophrenia. Thus it is likely that, in the schizophrenic brain, the neural development depending on these two systems has been disturbed. The possibility that the regulation of these two systems could lead to new treatments for schizophrenia is also discussed.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
173Neuron 2009 Sep 63: 774-87
PMID19778507
TitleRoles of disrupted-in-schizophrenia 1-interacting protein girdin in postnatal development of the dentate gyrus.
AbstractDisrupted-In-schizophrenia 1 (DISC1), a susceptibility gene for major psychiatric disorders, regulates neuronal migration and differentiation during mammalian brain development. Although roles for DISC1 in postnatal neurogenesis in the dentate gyrus (DG) have recently emerged, it is not known how DISC1 and its interacting proteins govern the migration, positioning, and differentiation of dentate granule cells (DGCs). Here, we report that DISC1 interacts with the actin-binding protein girdin to regulate axonal development. DGCs in girdin-deficient neonatal mice exhibit deficits in axonal sprouting in the cornu ammonis 3 region of the hippocampus. Girdin deficiency, RNA interference-mediated knockdown, and inhibition of the DISC1/girdin interaction lead to overextended migration and mispositioning of the DGCs resulting in profound cytoarchitectural disorganization of the DG. These findings identify girdin as an intrinsic factor in postnatal development of the DG and provide insights into the critical role of the DISC1/girdin interaction in postnatal neurogenesis in the DG.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
174J. Neurosci. 2009 Oct 29: 12768-75
PMID19828788
TitleUnderstanding the role of DISC1 in psychiatric disease and during normal development.
AbstractThe biology of schizophrenia is complex with multiple hypotheses (dopamine, glutamate, neurodevelopmental) well supported to underlie the disease. Pathways centered on the risk factor "disrupted in schizophrenia 1" (DISC1) may be able to explain and unite these disparate hypotheses and will be the topic of this mini-symposium preview. Nearly a decade after its original identification at the center of a translocation breakpoint in a large Scottish family that was associated with major psychiatric disease, we are starting to obtain credible insights into its function and role in disease etiology. This preview will highlight a number of exciting areas of current DISC1 research that are revealing roles for DISC1 during normal brain development and also in the disease state. Together these different threads will provide a timely and exciting overview of the DISC1 field and its potential in furthering our understanding of psychiatric diseases and in developing new therapies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
175Curr. 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, schizophrenias
176Prog. Brain Res. 2009 -1 179: 75-86
PMID20302820
TitleGene models of schizophrenia: DISC1 mouse models.
AbstractDisrupted in schizophrenia-1 (DISC1) is one of the most likely susceptibility genes for schizophrenia (SZ). DISC1 is being established as a hub protein with various functions in the pre- and postnatal development of the nervous system. Since generation of a knockout (KO) mouse has proved challenging, various alternative approaches have been taken. Seven DISC1 mouse models have been described to date. All of them display neuroanatomical and behavioral abnormalities relevant to SZ, although most of them have not been fully characterized yet, requiring further analysis. NRG1 and ErbB4, also highly promising susceptibility genes for SZ, share many features with DISC1. They are involved in various aspects of pre- and postnatal neurodevelopment. The NRG1 and ErbB4 mouse models also display neuroanatomical and behavioral abnormalities similar to the DISC1 mouse models. In the future, four main directions need further study. First, further characterization of the seven DISC1 mouse models, especially in light of basic research findings. Second, more extensive employment of the inducible models. Third, generation of a DISC1 KO. Fourth, combination of the DISC1 mouse models with other risk factors: crossing with other genetic models such as NRG1/ErbB4 mutants and exposure to environmental risk factors.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
177Curr Opin Psychiatry 2009 Mar 22: 154-60
PMID19553869
TitleRecent advances in postmortem pathology and neurochemistry in schizophrenia.
AbstractThis is a review examining recent data from the study of the postmortem central nervous system (CNS) of patients with schizophrenia.
Studies on the human CNS transcriptome suggest changes in pro-inflammatory pathways and myelination in schizophrenia, whereas changes in the proteome suggest that pathways involved in energy and metabolism may be particularly stressed. There appear to be complex changes in the expression of proposed candidate genes for schizophrenia such as NRG1, DISC1, RGS4 and DTNB1, and there are continued reports of alterations in central gamma-aminobutyric acidergic, dopaminergic, glutamatergic and cholinergic pathways in patients with the disorder. Data on epigenetic mechanisms and transcriptome regulation suggest that at least some changes in gene expression may be due to changes in levels of gene promoter methylation or microRNAs in the CNS of patients with schizophrenia.
Postmortem CNS studies have begun to unravel changes in the epigenetic regulation of gene expression that may be central to how gene-environment interactions contribute to the onset of schizophrenia. In addition, a recent study indicates that it is possible to use biomarkers to segregate the syndrome of schizophrenia into more biologically homogeneous populations, which should decrease the biological complexity observed within that group within the schizophrenia syndrome.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
178Biochem. Soc. Trans. 2009 Feb 37: 308-12
PMID19143653
TitleMutant models for genes associated with schizophrenia.
Abstractschizophrenia is a highly complex and heritable psychiatric disorder in which multiple genes and environmental factors interact to cause the schizophrenia phenotype. A new generation of molecular studies has yielded numerous candidate genes with a putative role in risk for schizophrenia, whereas other genes regulate putative pathophysiological mechanisms. Mutant mice having either deletion (knockout) or insertion (knockin/transgenesis) of schizophrenia risk genes now allow the functional role of these genes to be investigated. In the present mini-review, we outline the advantages and limitations of various approaches to phenotypic assessment of mutant mouse models, including ethologically based methods. Thereafter, we consider recent findings, with a particular focus on, first, dopaminergic and glutamatergic pathophysiological models and, secondly, putative roles for DISC1 (disrupted in schizophrenia 1) and NRG1 (neuregulin 1) as susceptibility genes for schizophrenia. Finally, we identify current challenges associated with the use of genetic mutant models and highlight their potential value for exploring gene-gene and gene-environment interactions in relation to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
179J Psychiatry Neurosci 2009 May 34: 195-8
PMID19448849
TitlePositive association of the pericentrin (PCNT) gene with major depressive disorder in the Japanese population.
AbstractPericentrin (PCNT) interacts with disruption-in-schizophrenia 1 (DISC1), a known genetic risk factor for schizophrenia, bipolar disorder and major depressive disorder (MDD). We sought to determine whether the PCNT gene is implicated in MDD.
We performed case-control association analyses in the Japanese population. We analyzed 9 single nucleotide polymorphisms (SNPs) in 173 patients with MDD and 348 healthy controls.
We found a significant allelic association between 3 SNPs (rs3788265, rs2073376 and rs2073380) of the PCNT gene and MDD (p = 0.006, 0.005 and 0.021, respectively). After correction for multiple testing, 2 SNPs (rs3788265 and rs2073376) retained significant allelic associations with MDD. In addition, we found a significant association between the 2 marker haplotypes (r3788265 and rs2073376) and MDD (permutation p = 0.011).
Our sample was small and comprised only Japanese participants. In addition, owing to the late onset of MDD, it is possible that the disorder will develop in at least some participants in our control group. Finally, we did not show how SNPs of the PCNT gene alter its function.
Our results suggest that genetic variations in the PCNT gene may play a significant role in the etiology of MDD in the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
180Schizophr. Res. 2009 Oct 114: 39-49
PMID19632097
TitleGenetic association and post-mortem brain mRNA analysis of DISC1 and related genes in schizophrenia.
AbstractConvergent evidence from genetic linkage, genetic association and biological studies implicates the Disrupted in schizophrenia 1 (DISC1) gene in the etiology and pathophysiology of schizophrenia. We conducted genetic association studies in matched case-control and family sample sets (N=117 families; N=210 case-control pairs), testing polymorphisms across DISC1 and DISC1 interacting genes: LIS1, NUDEL, FEZ1 and PDE4B. We found that DISC1 variants, particularly in the exon 9/intron 9/intron 10 region of the gene, may be associated with risk for schizophrenia in our sample population. There was no strong evidence for association with LIS1, NUDEL, FEZ1 and PDE4B. Gene-gene interaction analyses and mRNA quantification in post-mortem brains from schizophrenia patients and control subjects did not reveal significant differences.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
181PLoS ONE 2009 -1 4: e4906
PMID19300510
TitleThe DISC1 pathway modulates expression of neurodevelopmental, synaptogenic and sensory perception genes.
AbstractGenetic and biological evidence supports a role for DISC1 across a spectrum of major mental illnesses, including schizophrenia and bipolar disorder. There is evidence for genetic interplay between variants in DISC1 and in biologically interacting loci in psychiatric illness. DISC1 also associates with normal variance in behavioral and brain imaging phenotypes.
Here, we analyze public domain datasets and demonstrate correlations between variants in the DISC1 pathway genes and levels of gene expression. Genetic variants of DISC1, NDE1, PDE4B and PDE4D regulate the expression of cytoskeletal, synaptogenic, neurodevelopmental and sensory perception proteins. Interestingly, these regulated genes include existing targets for drug development in depression and psychosis.
Our systematic analysis provides further evidence for the relevance of the DISC1 pathway to major mental illness, identifies additional potential targets for therapeutic intervention and establishes a general strategy to mine public datasets for insights into disease pathways.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
182Rev Neurosci 2009 -1 20: 321-30
PMID20397618
TitleDISCopathies: brain disorders related to DISC1 dysfunction.
AbstractDuring the last decade, disrupted-in-schizophrenia 1 (DISC1) has emerged as a protein involved in the pathogenesis of chronic mental diseases such as schizophrenia, or recurrent affective disorders. Its multiple functions include regulating corticogenesis, synapse integrity and adult neurogenesis, indicating a key role in the hard-wiring and the maintenance of communicative abilities of the brain. From its cellular functions, the DISC1 protein is a 'molecular facilitator', which interacts with a quartenary complex including NDEL1, NDE1, LIS1, as well as the signaling molecules, GSK-3beta, PDE4B, and others. DISC1 oligomerizes, can form misassembled dysfunctional multimers as well as disease-associated insoluble protein complexes which qualify these diseases as protein conformational disorders. Disease categories ultimately serve the goal of defining pathophysiological conditions amenable to similar and efficient (pharmaco) therapies. Here, it is proposed to classify brain disorders related to dysfunctional DISC1 protein as one disease entity, that is, as DISCopathies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
183Development 2009 Aug 136: 2623-32
PMID19570850
TitleDisc1 regulates foxd3 and sox10 expression, affecting neural crest migration and differentiation.
AbstractThis work reports the characterization and functional analysis of disrupted in schizophrenia 1 (DISC1), a well-documented schizophrenia-susceptibility gene, in zebrafish cranial neural crest (CNC). Our data demonstrated that DISC1 was expressed in zebrafish CNC cells. Loss of DISC1 resulted in persistent CNC cell medial migration, dorsal to the developing neural epithelium, and hindered migration away from the region dorsal to the neural rod. General CNC cell motility was not affected by DISC1 knockdown, however, as the speed of CNC cells was indistinguishable from that of wild-type counterparts. We determined that the failure of CNC cells to migrate away from the neural rod correlated with the enhanced expression of two transcription factors, foxd3 and sox10. These transcription factors have many functions in CNC cells, including the maintenance of precursor pools, timing of migration onset, and the induction of cell differentiation. Our work, in conjunction with previous studies, suggests that the perpetuation of expression of these factors affects several aspects of CNC cell development, leading to a loss of craniofacial cartilage and an expansion of peripheral cranial glia. Based on our data, we propose a model in which DISC1 functions in the transcriptional repression of foxd3 and sox10, thus mediating CNC cell migration and differentiation.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
184Biol. 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, schizophrenias
185J. Formos. Med. Assoc. 2009 Jul 108: 587-91
PMID19586833
TitleConstruction of balanced translocation t(1;11)(q42.1;q14.3) probe and screening application in genomic samples in Taiwan.
AbstractThe disrupted-in-schizophrenia 1 (DISC1) gene is a candidate gene in schizophrenia. The balanced t(1;11)(q42.1;q14.3) translocation with a breakpoint between exons 8 and 9 of DISC1 has been found to be co-segregated with psychosis in a Scottish family. To examine whether the t(1;11)(q42.1;q14.3) translocation exists in Taiwanese samples, we constructed a plasmid probe that carried the two DNA fragments of chromosome 1 (738 bp) and chromosome 11 (719 bp) that covered the breakpoint. This probe was validated using a derived DNA gift from the translocation carrier of the Scottish family. We screened genomic DNA samples from 619 subjects (507 cases and 112 controls). None of the subjects showed the designed polymerase chain reaction (PCR) product detected by the probe. We concluded that the significant association between schizophrenia and the DISC1 gene in the Taiwanese sample was not caused by balance translocation, but rather by polymorphic variations of the gene to be detected.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
186Prog. Brain Res. 2009 -1 179: 107-15
PMID20302823
TitleModeling schizophrenia in flies.
Abstractschizophrenia is a debilitating mental illness that affects 1% of the population worldwide. Although its molecular etiology remains unclear, recent advances in human psychiatric genetics have identified a large number of candidate genetic risk factors involved in schizophrenia. Modeling the disease in genetically tractable animals is thus a challenging but increasingly important task. In this review, I discuss the potential problems and perspectives associated with modeling schizophrenia in fruit flies, and briefly review the recent studies analyzing the molecular and cellular functions of Disrupted-In-schizophrenia-1 (DISC1) in transgenic flies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
187Neurosci. Lett. 2009 May 455: 134-9
PMID19368862
TitleDecreased levels of disrupted-in-schizophrenia 1 (DISC1) are associated with expansion of the dentate granule cell layer in normal and kindled rats.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a candidate gene involved in the pathogenesis of schizophrenia. DISC1 expression is particularly abundant in the adult dentate gyrus, in which decreased levels lead to aberrant growth, impaired migration, and accelerated integration of adult generated neurons. Because seizures can also result in similar changes, we tested the hypothesis that DISC1 expression may be altered in an animal model of epilepsy. We found that extended amygdala kindling (i.e., 99-electrical stimulations) significantly decreased DISC1 labeling in the dentate granule cell layer and subgranular zone. Extended kindling also led to an increase in the number of ectopic granule cells in the hilus. In addition, although the width of the granule cell layer was not generally affected by kindling, decreased levels of DISC1 in the subgranular zone and granule cell layer were associated with an expansion of the upper blade and crest of the dentate gyrus in both normal and kindled rats. These novel findings suggest that seizure activity affects DISC1 signaling in the dentate gyrus and that DISC1 expression may regulate the cytoarchitectural organization of the granule cell layer.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
188Cell 2009 Mar 136: 1017-31
PMID19303846
TitleDisrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling.
AbstractThe Disrupted in schizophrenia 1 (DISC1) gene is disrupted by a balanced chromosomal translocation (1; 11) (q42; q14.3) in a Scottish family with a high incidence of major depression, schizophrenia, and bipolar disorder. Subsequent studies provided indications that DISC1 plays a role in brain development. Here, we demonstrate that suppression of DISC1 expression reduces neural progenitor proliferation, leading to premature cell cycle exit and differentiation. Several lines of evidence suggest that DISC1 mediates this function by regulating GSK3beta. First, DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin. Importantly, expression of stabilized beta-catenin overrides the impairment of progenitor proliferation caused by DISC1 loss of function. Furthermore, GSK3 inhibitors normalize progenitor proliferation and behavioral defects caused by DISC1 loss of function. Together, these results implicate DISC1 in GSK3beta/beta-catenin signaling pathways and provide a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
189Cell 2009 Mar 136: 990-2
PMID19303839
TitleDISC1 partners with GSK3beta in neurogenesis.
AbstractThe protein DISC1, encoded by a gene implicated in schizophrenia susceptibility, regulates the development of postmitotic neurons. Mao et al. (2009) now report that DISC1 also regulates the proliferation of embryonic and adult neural progenitor cells through the GSK3beta/beta-catenin pathway, providing new insights into how susceptibility genes may contribute to the etiology of psychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
190Neurosci. Lett. 2009 Jan 449: 228-33
PMID19000741
TitleNDE1 and NDEL1: multimerisation, alternate splicing and DISC1 interaction.
AbstractNuclear Distribution Factor E Homolog 1 (NDE1) and NDE-Like 1 (NDEL1) are highly homologous mammalian proteins. However, whereas NDEL1 is well studied, there is remarkably little known about NDE1. We demonstrate the presence of multiple isoforms of both NDE1 and NDEL1 in the brain, showing that NDE1 binds directly to multiple isoforms of Disrupted in schizophrenia 1 (DISC1), and to itself. We also show that NDE1 can complex with NDEL1. Together these results predict a high degree of complexity of DISC1-mediated regulation of neuronal activity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
191Proc. Natl. Acad. Sci. U.S.A. 2009 Sep 106: 15873-8
PMID19805229
TitleDISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms.
AbstractDisrupted-In-schizophrenia-1 (DISC1) is a promising susceptibility gene for major mental illness, but the mechanism of the clinical association is unknown. We searched for DISC1 transcripts in adult and fetal human brain and tested whether their expression is altered in patients with schizophrenia and is associated with genetic variation in DISC1. Many alternatively spliced transcripts were identified, including groups lacking exon 3 (Delta3), exons 7 and 8 (Delta7Delta8), an exon 3 insertion variant (extra short variant-1, Esv1), and intergenic splicing between TSNAX and DISC1. Isoforms Delta7Delta8, Esv1, and Delta3, which encode truncated DISC1 proteins, were expressed more abundantly during fetal development than during postnatal ages, and their expression was higher in the hippocampus of patients with schizophrenia. schizophrenia risk-associated polymorphisms [non-synonymous SNPs rs821616 (Cys704Ser) and rs6675281 (Leu607Phe), and rs821597] were associated with the expression of Delta3 and Delta7Delta8. Moreover, the same allele at rs6675281, which predicted higher expression of these transcripts in the hippocampus, was associated with higher expression of DISC1Delta7Delta8 in lymphoblasts in an independent sample. Our results implicate a molecular mechanism of genetic risk associated with DISC1 involving specific alterations in gene processing.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
192Schizophr 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, schizophrenias
193Acta 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, schizophrenias
194Neuroscience 2009 Nov 164: 331-43
PMID19358880
TitleThe genetics of bipolar disorder.
AbstractBipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. Linkage studies have implicated several chromosomal regions as harboring relevant genes, but results have been inconsistent. It is now widely accepted that the genetic liability to bipolar disorder reflects the action of many genes of individually small effect, a scenario for which linkage studies are poorly suited. Thus, association studies, which are more powerful for the detection of modest effect loci, have become the focus of gene-finding research. A large number of candidate genes, including biological candidates derived from hypotheses about the pathogenesis of the disorder and positional candidates derived from linkage and cytogenetic studies, have been evaluated. Several of these genes have been associated with the disorder in independent studies (including BDNF, DAOA, DISC1, GRIK4, SLC6A4, and TPH2), but none has been established. The clinical heterogeneity of bipolar disorder and its phenotypic and genetic overlap with other disorders (especially schizophrenia, schizoaffective disorder, and major depressive disorder) have raised questions about the optimal phenotype definition for genetic studies. Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
195Pharmacol. Ther. 2009 Jan 121: 115-22
PMID19046988
TitleAltered growth factor signaling pathways as the basis of aberrant stem cell maturation in schizophrenia.
AbstractIn recent years evidence has accumulated that the activity of the signaling cascades of Neuregulin-1, Wnt, TGF-beta, BDNF-p75 and DISC1 is different between control subjects and patients with schizophrenia. These pathways are involved in embryonic and adult neurogenesis and neuronal maturation. A review of the clinical data indicates that in schizophrenia the Wnt pathway is most likely hypoactive, whereas the Nrg1-ErbB4, the TGF-beta- and the BDNF-p75-pathways are hyperactive. Haplo-insuffiency of the DISC1 gene is currently the best established schizophrenia risk factor. Preclinical experiments indicate that suppression of DISC1 signaling leads to accelerated dendrite development in neuronal stem cells, accelerated migration and aberrant integration into the neuronal network. Other preclinical experiments show that increasing NRG1-, BDNF- and TGF-beta signaling and decreasing Wnt signaling, also promotes adult neuronal differentiation and migration. Thus deviations in these pathways detected in schizophrenia could contribute to premature neuronal differentiation, accelerated migration and inappropriate insertion into the neuronal network. Initial clinical findings are confirmatory: neuronal stem cells isolated from nasal biopsies from schizophrenia patients display signs of accelerated development, whilst increased erosion of telomeres and bone age provide further support for accelerated cell maturation in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
196Hum. Mol. Genet. 2009 Sep 18: 3286-97
PMID19502360
TitleDisc1 regulates granule cell migration in the developing hippocampus.
Abstractschizophrenia is a severely debilitating psychiatric disease that is hypothesized to have its roots in neurodevelopment. Although the precise neuropathology underlying schizophrenia has remained elusive, there are consistent reports of abnormalities in several brain areas. Chief among these is the hippocampus, an area which has displayed both structural and functional abnormalities in many schizophrenic patients. In order to better understand how disruption of hippocampal development may contribute to the etiology of psychiatric disease, we investigated the function of a highly promising schizophrenia susceptibility gene, DISC1 (Disrupted-In-schizophrenia 1), in the development of the hippocampus. DISC1 is strongly expressed in the hippocampus from its early development through adulthood and has been implicated in hippocampal structure and function in human studies. However, its precise role in the development of the hippocampus is not yet known. Here, we show that in utero electroporation of DISC1 shRNA into the developing mouse hippocampus hinders the migration of dentate gyrus granule cells. Intriguingly, DISC1 knockdown does not affect the migration of CA1 pyramidal neurons, suggesting that DISC1's role in regulating neuronal migration is spatially restricted within the hippocampus. These findings support the idea that DISC1 abnormalities that contribute to the onset of schizophrenia may do so through their influences on hippocampal development.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
197Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Jun 150B: 527-34
PMID18785206
TitleGene expression and association analyses of the phosphodiesterase 4B (PDE4B) gene in major depressive disorder in the Japanese population.
AbstractThe phosphodiesterase 4B (PDE4B) interacts with disrupted-in-schizophrenia 1 (DISC1), which is a known genetic risk factor for schizophrenia, bipolar disorder and major depressive disorder (MDD). PDE4B is also important in the regulation of cAMP signaling, a second messenger implicated in learning, memory, and mood. In this study, we determined mRNA expression levels of the PDE4B gene in the peripheral blood leukocytes of patients with MDD and control subjects (n = 33, each). Next we performed two-stage case-controlled association analyses (first set; case = 174, controls = 348; second set; case = 481, controls = 812) in the Japanese population to determine if the PDE4B gene is implicated in MDD. In the leukocytes, a significantly higher expression of the PDE4B mRNA was observed in the drug-nave MDD patients compared with control subjects (P < 0.0001) and the expression of the MDD patients significantly decreased after antidepressant treatment (P = 0.030). In the association analysis, we observed significant allelic associations of four SNPs (the most significant, rs472952; P = 0.002) and a significant haplotypic association (permutation P = 0.019) between the PDE4B gene and MDD in the first-set samples. However, we could not confirm these significant associations in the following independent second-set of samples. Our results suggest that the PDE4B gene itself does not link to MDD but the elevated mRNA levels of PDE4B might be implicated in the pathophysiology of MDD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
198J. 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, schizophrenias
199Trends Neurosci. 2009 Sep 32: 485-95
PMID19712980
TitleNeurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1.
Abstractschizophrenia (SZ) is primarily an adult psychiatric disorder in which disturbances caused by susceptibility genes and environmental insults during early neurodevelopment initiate neurophysiological changes over a long time course, culminating in the onset of full-blown disease nearly two decades later. Aberrant postnatal brain maturation is an essential mechanism underlying the disease. Currently, symptoms of SZ are treated with anti-psychotic medications that have variable efficacy and severe side effects. There has been much interest in the prodromal phase and the possibility of preventing SZ by interfering with the aberrant postnatal brain maturation associated with this disorder. Thus, it is crucial to understand the mechanisms that underlie the long-term progression to full disease manifestation to identify the best targets and approaches towards this goal. We believe that studies of certain SZ genetic susceptibility factors with neurodevelopmental implications will be key tools in this task. Accumulating evidence suggests that neuregulin-1 (NRG1) and disrupted-in-schizophrenia-1 (DISC1) are probably functionally convergent and play key roles in brain development. We provide an update on the role of these emerging concepts in understanding the complex time course of SZ from early neurodevelopmental disturbances to later onset and suggest ways of testing these in the future.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
200Hum. Mol. Genet. 2009 Feb 18: 391-404
PMID18996920
TitleDisrupted-in-schizophrenia 1 and neuregulin 1 are required for the specification of oligodendrocytes and neurones in the zebrafish brain.
Abstractschizophrenia may arise from subtle abnormalities in brain development due to alterations in the functions of candidate susceptibility genes such as Disrupted-in-schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1). To provide novel insights into the functions of DISC1 in brain development, we mapped the expression of zebrafish DISC1 and set out to characterize its role in early embryonic development using morpholino antisense methods. These studies revealed a critical requirement for DISC1 in oligodendrocyte development by promoting specification of olig2-positive cells in the hindbrain and other brain regions. Since NRG1 has well-documented roles in myelination, we also analyzed the roles of nrg1 and ErbB signalling in zebrafish brain development and we observed strikingly similar defects to those seen in DISC1 morphant embryos. In addition to their effects on oligodendrocyte development, knock-down of DISC1 or nrg1 caused near total loss of olig2-positive cerebellar neurones, but caused no apparent loss of spinal motor neurones. These findings suggest that DISC1 and nrg1 function in common or related pathways controlling development of oligodendrocytes and neurones from olig2-expressing precursor cells. Like DISC1 and NRG1, OLIG2 and ERBB4 are promising candidate susceptibility genes for schizophrenia. Hence our findings in the zebrafish embryo suggest that hitherto unappreciated neurodevelopmental connections may exist between key human schizophrenia susceptibility genes. These connections could be investigated in DISC1 and Nrg1 mouse models and in genetically defined groups of patients in order to determine whether they are relevant to the pathobiology of schizophrenia. GenBank accession number for Danio rerio DISC1: EU273350.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
201Nihon Shinkei Seishin Yakurigaku Zasshi 2009 Apr 29: 47-53
PMID19562941
Title[Development of animal models for schizophrenia based on clinical evidence: expectation for psychiatrists].
Abstractschizophrenic patients show positive symptoms, negative symptoms and cognitive dysfunction. In humans, phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, reproduces the schizophrenia-like psychosis including positive symptoms, negative symptoms and cognitive dysfunction. Ketamine, another non-competitive NMDA receptor antagonist, also reproduces a schizophrenia-like psychosis in healthy volunteers, and exaggerates the psychosis in schizophrenic patients. It has been hypothesized that insufficient glutamate neurotransmission is involved in the pathophysiology of schizophrenia. Therefore, attempts have been made to develop animal models of schizophrenia by using NMDA receptor antagonists such as PCP, ketamine and dizocilpine. In addition to pharmacological approaches, genetic approaches have been adopted to develop animal models of schizophrenia. The disrupted in schizophrenia 1 (DISC1) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism (SNP) association studies and clinical data, demonstrating that risk SNPs impact on the hippocampal structure and function in clinical and functional roles of DISC1 are analyzed in many kinds of transgenic mice developed. In this review, we focused on PCP and DISC1 transgenic animal models of schizophrenia and summarized recent evidence from several investigators. The basic researchers would need to collaborate with clinical psychiatrists to develop appropriate animal models for schizophrenia based on clinical evidence.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
202Biol. Psychiatry 2009 Jun 65: 1055-62
PMID19251251
TitleAssociation between genes of Disrupted in schizophrenia 1 (DISC1) interactors and schizophrenia supports the role of the DISC1 pathway in the etiology of major mental illnesses.
AbstractDisrupted in schizophrenia 1 (DISC1) is currently one of the most interesting candidate genes for major mental illness, having been demonstrated to associate with schizophrenia, bipolar disorder, major depression, autism, and Asperger's syndrome. We have previously reported a DISC1 haplotype, HEP3, and an NDE1 spanning tag haplotype to associate to schizophrenia in Finnish schizophrenia families. Because both DISC1 and NDE1 display association in our study sample, we hypothesized that other genes interacting with DISC1 might also have a role in the etiology of schizophrenia.
We selected 11 additional genes encoding components of the "DISC1 pathway" and studied these in our study sample of 476 families including 1857 genotyped individuals. We performed single nucleotide polymorphism (SNP) and haplotype association analyses in two independent sets of families. For markers and haplotypes found to be consistently associated in both sets, the overall significance was tested with the combined set of families.
We identified three SNPs to be associated with schizophrenia in PDE4D (rs1120303, p = .021), PDE4B (rs7412571, p = .018), and NDEL1 (rs17806986, p = .0038). Greater significance was observed with allelic haplotypes of PDE4D (p = .00084), PDE4B (p = .0022 and p = .029), and NDEL1 (p = .0027) that increased or decreased schizophrenia susceptibility.
Our findings with other converging lines of evidence support the underlying importance of DISC1-related molecular pathways in the etiology of schizophrenia and other major mental illnesses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
203Mol. Psychiatry 2009 Sep 14: 865-73
PMID18317464
TitleDISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder.
AbstractDisrupted in schizophrenia 1 (DISC1) has been associated with risk of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism and Asperger syndrome, but apart from in the original translocation family, true causal variants have yet to be confirmed. Here we report a harmonized association study for DISC1 in European cohorts of schizophrenia and bipolar disorder. We identify regions of significant association, demonstrate allele frequency heterogeneity and provide preliminary evidence for modifying interplay between variants. Whereas no associations survived permutation analysis in the combined data set, significant corrected associations were observed for bipolar disorder at rs1538979 in the Finnish cohorts (uncorrected P=0.00020; corrected P=0.016; odds ratio=2.73+/-95% confidence interval (CI) 1.42-5.27) and at rs821577 in the London cohort (uncorrected P=0.00070; corrected P=0.040; odds ratio=1.64+/-95% CI 1.23-2.19). The rs821577 single nucleotide polymorphism (SNP) showed evidence for increased risk within the combined European cohorts (odds ratio=1.27+/-95% CI 1.07-1.51), even though significant corrected association was not detected (uncorrected P=0.0058; corrected P=0.28). After conditioning the European data set on the two risk alleles, reanalysis revealed a third significant SNP association (uncorrected P=0.00050; corrected P=0.025). This SNP showed evidence for interplay, either increasing or decreasing risk, dependent upon the presence or absence of rs1538979 or rs821577. These findings provide further support for the role of DISC1 in psychiatric illness and demonstrate the presence of locus heterogeneity, with the effect that clinically relevant genetic variants may go undetected by standard analysis of combined cohorts.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
204Biochemistry 2009 Aug 48: 7746-55
PMID19583211
TitleOligomer assembly of the C-terminal DISC1 domain (640-854) is controlled by self-association motifs and disease-associated polymorphism S704C.
AbstractGenetic studies have established a role of disrupted-in-schizophrenia-1 (DISC1) in chronic mental diseases (CMD). Limited experimental data are available on the domain structure of the DISC1 protein although multiple interaction partners are known including a self-association domain within the middle part of DISC1 (residues 403-504). The DISC1 C-terminal domain is deleted in the original Scottish pedigree where DISC1 harbors two coiled-coil domains and disease-associated polymorphisms at 607 and 704, as well as the important nuclear distribution element-like 1 (NDEL1) binding site at residues 802-839. Here, we performed mutagenesis studies of the C-terminal domain of the DISC1 protein (residues 640-854) and analyzed the expressed constructs by biochemical and biophysical methods. We identified novel DISC1 self-association motifs and the necessity of their concerted action for orderly assembly: the region 765-854 comprising a coiled-coil domain is a dimerization domain and the region 668-747 an oligomerization domain; dimerization was found to be a prerequisite for orderly assembly of oligomers. Consistent with this, disease-associated polymorphism C704 displayed a slightly higher oligomerization propensity. The heterogeneity of DISC1 multimers in vitro was confirmed with a monoclonal antibody binding exclusively to HMW multimers. We also identified C-terminal DISC1 fragments in human brains, suggesting that C-terminal fragments could carry out DISC1-dependent functions. When the DISC1 C-terminal domain was transiently expressed in cells, it assembled into a range of soluble and insoluble multimers with distinct fractions selectively binding NDEL1, indicating functionality. Our results suggest that assembly of the C-terminal domain is controlled by distinct domains including the disease-associated polymorphism 704 and is functional in vivo.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
205Arch. Gen. Psychiatry 2009 Feb 66: 134-41
PMID19188535
TitleAssociation of variants in DISC1 with psychosis-related traits in a large population cohort.
AbstractThere is an abundance of data from human genetic studies and animal models that implies a role for the disrupted in schizophrenia 1 gene (DISC1) in the etiology of schizophrenia and other major mental illnesses.
To study the effect of previously identified risk alleles of DISC1 on quantitative intermediate phenotypes for psychosis in an unselected population.
We examined 41 single-nucleotide polymorphisms within DISC1 and performed tests of association with 4 quantitative phenotypes.
Academic research.
Individuals from an unselected birth cohort in Finland. Originally, everyone born in the catchment area in 1966 (N = 12 058) was included in the study. Of these, 4651 (38.6%) attended the 31-year follow-up and could be included in the study.
Scores on 4 psychometric instruments selected to function as proxies for positive and negative aspects of psychotic disorders, including the Perceptual Aberration Scale, Revised Social Anhedonia Scale, Revised Physical Anhedonia Scale, and Schizoidia Scale by Golden and Meehl.
Carriers of the minor allele of marker rs821577 had significantly higher scores on social anhedonia (P < .001). The minor allele of marker rs821633 was strongly associated with lower scores on social anhedonia when analyzed dependent on the absence of the minor alleles of markers rs1538979 and rs821577 (P < .001).
Variants in DISC1 affect the level of social anhedonia, a cardinal symptom of schizophrenia in the general population. DISC1 might be more central to human psychological functioning than previously thought, as it seems to affect the degree to which people enjoy social interactions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
206Hum. Mol. Genet. 2009 Jul 18: 2719-27
PMID19414483
TitleThe DISC locus and schizophrenia: evidence from an association study in a central European sample and from a meta-analysis across different European populations.
AbstractAssociation studies, as well as the initial translocation family study, identified the gene Disrupted-In-schizophrenia-1 (DISC1) as a risk factor for schizophrenia. DISC1 encodes a multifunctional scaffold protein involved in neurodevelopmental processes implicated in the etiology of schizophrenia. The present study explores the contribution of the DISC locus to schizophrenia using three different approaches: (i) systematic association mapping aimed at detecting DISC risk variants in a schizophrenia sample from a central European population (556 SNPs, n = 1621 individuals). In this homogenous sample, a circumscribed DISC1 interval in intron 9 was significantly associated with schizophrenia in females (P = 4 x 10(-5)) and contributed most strongly to early-onset cases (P = 9 x 10(-5)). The odds ratios (ORs) were in the range of 1.46-1.88. (ii) The same sample was used to test for the locus-specific SNP-SNP interaction most recently associated with schizophrenia. Our results confirm the SNP interplay effect between rs1538979 and rs821633 that significantly conferred disease risk in male patients with schizophrenia (P = 0.016, OR 1.57). (iii) In order to detect additional schizophrenia variants, a meta-analysis was performed using nine schizophrenia samples from different European populations (50 SNPs, n = 10 064 individuals maximum, n = 3694 minimum). We found evidence for a common schizophrenia risk interval within DISC1 intron 4-6 (P = 0.002, OR 1.27). The findings point to a complex association between schizophrenia and DISC, including the presence of different risk loci and SNP interplay effects. Furthermore, our phenotype-genotype results--including the consideration of sex-specific effects--highlight the value of homogenous samples in mapping risk genes for schizophrenia in general, and at the DISC locus in particular.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
207Psychiatry Res 2009 May 172: 128-35
PMID19304459
TitleThe Disrupted-in-Schizophrenia-1 Ser704Cys polymorphism and brain morphology in schizophrenia.
AbstractThe Disrupted-in-schizophrenia-1 (DISC1) polymorphism is a strong candidate for a schizophrenia-susceptibility gene as it is widely expressed in cortical and limbic regions, but the effect of its genotype variation on brain morphology in schizophrenia is not well known. This study examined the association between the DISC1 Ser704Cys polymorphism and volumetric measurements for a broad range of fronto-parietal, temporal, and limbic-paralimbic regions using magnetic resonance imaging in a Japanese sample of 33 schizophrenia patients and 29 healthy comparison subjects. The Cys carriers had significantly larger volumes of the medial superior frontal gyrus and short insular cortex than the Ser homozygotes only for healthy comparison subjects. The Cys carriers tended to have a smaller supramarginal gyrus than the Ser homozygotes in schizophrenia patients, but not in healthy comparison subjects. The right medial superior frontal gyrus volume was significantly correlated with daily dosage of antipsychotic medication in Ser homozygote schizophrenia patients. These different genotype effects of the DISC1 Ser704Cys polymorphism on the brain morphology in schizophrenia patients and healthy comparison subjects suggest that variation in the DISC1 gene might be, at least partly, involved in the neurobiology of schizophrenia. Our findings also suggest that the DISC1 genotype variation might have some relevance to the medication effect on brain morphology in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
208Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Oct 150B: 967-76
PMID19191256
TitleAssociation studies and gene expression analyses of the DISC1-interacting molecules, pericentrin 2 (PCNT2) and DISC1-binding zinc finger protein (DBZ), with schizophrenia and with bipolar disorder.
AbstractDisrupted-in-schizophrenia 1 (DISC1) and its molecular cascade have been implicated in the pathophysiology of major psychoses. Previously, we identified pericentrin 2 (PCNT2) and DISC1-binding zinc finger protein (DBZ) as binding partners of DISC1; further, we observed elevated expression of PCNT2 in the postmortem brains and in the lymphocytes of bipolar disorder patients, compared to controls. Here, we examined the association of PCNT2 with schizophrenia in a case-control study of Japanese cohorts. We also examined the association of DBZ with schizophrenia and with bipolar disorder, and compared the mRNA levels of DBZ in the postmortem brains of schizophrenia, bipolar and control samples. DNA from 180 schizophrenia patients 201 controls were used for the association study of PCNT2 and DBZ with schizophrenia. Association of DBZ with bipolar disorder was examined in DNA from 238 bipolar patients and 240 age- and gender-matched controls. We observed significant allelic and genotypic associations of the PCNT2 SNPs, rs2249057, rs2268524, and rs2073380 (Ser/Arg) with schizophrenia; the association of rs2249057 (P = 0.002) withstand multiple testing correction. Several two SNP- and three SNP-haplotypes showed significant associations; the associations of haplotypes involving rs2249057 withstand multiple testing correction. No associations were observed for DBZ with schizophrenia or with bipolar disorder; further, there was no significant difference between the DBZ mRNA levels of control, schizophrenia and bipolar postmortem brains. We suggest a possible role of PCNT2 in the pathogenesis of schizophrenia. Abnormalities of PCNT2, the centrosomal protein essential for microtubule organization, may be suggested to lead to neurodevelopmental abnormalities.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
209Pharmacogenomics 2009 Dec 10: 1967-78
PMID19958095
TitleRole of the PACAP-PAC1-DISC1 and PACAP-PAC1-stathmin1 systems in schizophrenia and bipolar disorder: novel treatment mechanisms?
AbstractTwo pituitary adenylate cyclase-activating polypeptide (PACAP)-signaling pathways linked to schizophrenia were reviewed. One pathway regulates the association between disrupted-in-schizophrenia 1 (DISC1) and DISC1-binding zinc-finger protein via PACAP, and the other inhibits stathmin1 expression via PACAP. PACAP reduces the association of the binding between DISC1 (a potential susceptibility gene for major psychiatric disease) and DISC1-binding zinc-finger protein (which binds to DISC1 near the translocation site) to induce neurite outgrowth. In addition, an association between SNPs of the PACAP or PAC1 genes and schizophrenia has been reported. On the other hand, expression of stathmin1, which induces abnormal axonal arborization, is upregulated in PACAP-knock out mice and the brains of patients with schizophrenia. Thus it is likely that, in the schizophrenic brain, the neural development depending on these two systems has been disturbed. The possibility that the regulation of these two systems could lead to new treatments for schizophrenia is also discussed.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
210Acta 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, schizophrenias
211Hum. Mol. Genet. 2009 Sep 18: 3286-97
PMID19502360
TitleDisc1 regulates granule cell migration in the developing hippocampus.
Abstractschizophrenia is a severely debilitating psychiatric disease that is hypothesized to have its roots in neurodevelopment. Although the precise neuropathology underlying schizophrenia has remained elusive, there are consistent reports of abnormalities in several brain areas. Chief among these is the hippocampus, an area which has displayed both structural and functional abnormalities in many schizophrenic patients. In order to better understand how disruption of hippocampal development may contribute to the etiology of psychiatric disease, we investigated the function of a highly promising schizophrenia susceptibility gene, DISC1 (Disrupted-In-schizophrenia 1), in the development of the hippocampus. DISC1 is strongly expressed in the hippocampus from its early development through adulthood and has been implicated in hippocampal structure and function in human studies. However, its precise role in the development of the hippocampus is not yet known. Here, we show that in utero electroporation of DISC1 shRNA into the developing mouse hippocampus hinders the migration of dentate gyrus granule cells. Intriguingly, DISC1 knockdown does not affect the migration of CA1 pyramidal neurons, suggesting that DISC1's role in regulating neuronal migration is spatially restricted within the hippocampus. These findings support the idea that DISC1 abnormalities that contribute to the onset of schizophrenia may do so through their influences on hippocampal development.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
212Nihon Shinkei Seishin Yakurigaku Zasshi 2009 Apr 29: 47-53
PMID19562941
Title[Development of animal models for schizophrenia based on clinical evidence: expectation for psychiatrists].
Abstractschizophrenic patients show positive symptoms, negative symptoms and cognitive dysfunction. In humans, phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, reproduces the schizophrenia-like psychosis including positive symptoms, negative symptoms and cognitive dysfunction. Ketamine, another non-competitive NMDA receptor antagonist, also reproduces a schizophrenia-like psychosis in healthy volunteers, and exaggerates the psychosis in schizophrenic patients. It has been hypothesized that insufficient glutamate neurotransmission is involved in the pathophysiology of schizophrenia. Therefore, attempts have been made to develop animal models of schizophrenia by using NMDA receptor antagonists such as PCP, ketamine and dizocilpine. In addition to pharmacological approaches, genetic approaches have been adopted to develop animal models of schizophrenia. The disrupted in schizophrenia 1 (DISC1) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism (SNP) association studies and clinical data, demonstrating that risk SNPs impact on the hippocampal structure and function in clinical and functional roles of DISC1 are analyzed in many kinds of transgenic mice developed. In this review, we focused on PCP and DISC1 transgenic animal models of schizophrenia and summarized recent evidence from several investigators. The basic researchers would need to collaborate with clinical psychiatrists to develop appropriate animal models for schizophrenia based on clinical evidence.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
213Curr Top Behav Neurosci 2010 -1 4: 629-56
PMID21312416
TitleMolecules, signaling, and schizophrenia.
Abstractschizophrenia is one of the most common psychiatric disorders, but despite some progress in identifying the genetic factors implicated in its development, the molecular mechanisms underlying its etiology and pathogenesis remain poorly understood. However, accumulating evidence suggests that regardless of the underlying genetic complexity, the mechanisms of the disease may impact a small number of common signaling pathways. In this review, we discuss the evidence for a role of schizophrenia susceptibility genes in intracellular signaling cascades by focusing on three prominent candidate genes: AKT, PPP3CC (calcineurin), and DISC1. We describe the regulation of a number of signaling cascades by AKT and calcineurin through protein phosphorylation and dephosphorylation, and the recently uncovered functions of DISC1 in cAMP and GSK3beta signaling. In addition, we present independent evidence for the involvement of their downstream signaling pathways in schizophrenia. Finally, we discuss evidence supporting an impact of these susceptibility genes on common intracellular signaling pathways and the convergence of their effects on neuronal processes implicated in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
214Neuron 2010 Jul 67: 33-48
PMID20624590
TitleDixdc1 is a critical regulator of DISC1 and embryonic cortical development.
AbstractThe psychiatric illness risk gene Disrupted in schizophrenia-1 (DISC1) plays an important role in brain development; however, it is unclear how DISC1 is regulated during cortical development. Here, we report that DISC1 is regulated during embryonic neural progenitor proliferation and neuronal migration through an interaction with DIX domain containing-1 (Dixdc1), the third mammalian gene discovered to contain a Disheveled-Axin (DIX) domain. We determined that Dixdc1 functionally interacts with DISC1 to regulate neural progenitor proliferation by co-modulating Wnt-GSK3beta/beta-catenin signaling. However, DISC1 and Dixdc1 do not regulate migration via this pathway. During neuronal migration, we discovered that phosphorylation of Dixdc1 by cyclin-dependent kinase 5 (Cdk5) facilitates its interaction with the DISC1-binding partner Ndel1. Furthermore, Dixdc1 phosphorylation and its interaction with DISC1/Ndel1 in vivo is required for neuronal migration. Together, these data reveal that Dixdc1 integrates DISC1 into Wnt-GSK3beta/beta-catenin-dependent and -independent signaling pathways during cortical development and further delineate how DISC1 contributes to neuropsychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
215Brain Res. 2010 Aug 1348: 114-9
PMID20561508
TitleDisruption of thermal nociceptive behaviour in mice mutant for the schizophrenia-associated genes NRG1, COMT and DISC1.
AbstractAbnormalities in pain perception, especially altered warmth and heat pain sensitivity, have been reported in schizophrenia. Therefore, genes associated with schizophrenia, including neuregulin-1 (NRG1), catechol-O-methyltranferase (COMT) and disrupted-in-schizophrenia-1 (DISC1), may play a role in modulating the physiological and psychological effects of pain stimuli in such patients. Thermal pain sensitivity was assessed in NRG1, COMT and DISC1 mutant mice, and the anti-nociceptive effects of acute Delta(9)-tetrahydrocannabinol (THC) were compared in NRG1 and COMT mutants. At baseline, deletion of NRG1 and DISC1 each reduced thermal pain sensitivity, while deletion of COMT increased pain sensitivity. Neither NRG1 nor COMT deletion altered the anti-nociceptive effects of acute systemic THC (8.0mg/kg). These results indicate a differential contribution of NRG1 and DISC1 vis--vis COMT to the processing of thermal nociceptive stimuli and extend their phenotypic relationship to psychotic illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
216Trends Pharmacol. Sci. 2010 Aug 31: 381-90
PMID20579747
TitleSignaling pathways in schizophrenia: emerging targets and therapeutic strategies.
AbstractDopamine D(2) receptor antagonism is a unifying property of all antipsychotic drugs in use for schizophrenia. While often effective at ameliorating psychosis, these drugs are largely ineffective at treating negative and cognitive symptoms. Increasing attention is being focused on the complex genetics of the illness and the signaling pathways implicated in its pathophysiology. We review targeted approaches for pharmacotherapy involving the glutamatergic, GABAergic and cholinergic pathways. We also describe several of the major genetic findings that identify signaling pathways representing potential targets for novel pharmacological intervention. These include genes in the 22q11 locus, DISC1, Neuregulin 1/ErbB4, and components of the Akt/GSK-3 pathway.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
217Clin. Genet. 2010 Apr 77: 389-94
PMID20002455
TitleDISC1 duplication in two brothers with autism and mild mental retardation.
AbstractWe describe the identification and delineation of an inherited 2.07 Mb microduplication in 1q42.2 in two brothers with autism and mild mental retardation. Since this duplication was not present in 1577 Belgian persons, we consider this as an extremely rare variant which has the potential to provide further insight into the genetics of autism. The duplication contains seven genes including the DISC1 gene, an interesting candidate gene that has been associated to schizophrenia, bipolar disorder, autism and Asperger syndrome. In this report we describe additional analyses undertaken to investigate the causal relationship of the duplication to the autism phenotype. We conclude that the 1q42.2 microduplication probably confers susceptibility to autism in the current family. This study is a typical illustration of the difficult interpretation of causality of a very rare variant in neuropsychiatric disease and the challenge of genetic counselling in a particular family.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
218J. Biol. Chem. 2010 Dec 285: 40554-61
PMID20956536
TitleCAMDI, a novel disrupted in schizophrenia 1 (DISC1)-binding protein, is required for radial migration.
AbstractCentrosomes play a crucial role in the directed migration of developing neurons. However, the underlying mechanism is poorly understood. This study has identified a novel disrupted in schizophrenia 1 (DISC1)-interacting protein, named CAMDI after coiled-coil protein associated with myosin II and DISC1, which translocates to the centrosome in a DISC1-dependent manner. Knockdown of CAMDI by shRNA revealed severely impaired radial migration with disoriented centrosomes. A yeast two-hybrid screen identified myosin II as a binding protein of CAMDI. CAMDI interacts preferentially with phosphomyosin II and induces an accumulation of phosphomyosin II at the centrosome in a DISC1-dependent manner. Interestingly, one single nucleotide polymorphism of the CAMDI gene (R828W) is identified, and its gene product was found to reduce the binding ability to phosphomyosin II. Furthermore, mice with overexpression of R828W in neurons exhibit an impaired radial migration. Our findings indicate that CAMDI is required for radial migration probably through DISC1 and myosin II-mediated centrosome positioning during neuronal development.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
219Genes Brain Behav. 2010 Oct 9: 777-89
PMID20618446
TitleEnhanced dopamine function in DISC1-L100P mutant mice: implications for schizophrenia.
AbstractSignificant advances have been made in understanding the role of disrupted-in-schizophrenia-1 (DISC1) in the brain and accumulating findings suggest the possible implication of DISC1 in the regulation of dopamine (DA) function. A mutation in the second exon of DISC1 at L100P leads to the development of schizophrenia-related behavior in mutant mice (DISC1-L100P). We investigated here the role of DA in the expression of schizophrenia-related endophenotypes in the DISC1-L100P genetic mouse model. The mutated DISC1 resulted in facilitation of the psychostimulant effect of amphetamine in DISC1-L100P mutant mice assessed in the open field and prepulse inhibition (PPI) tests. Biochemical studies detected a 2.1-fold increase in the proportion of striatal D receptors without significant changes in DA release in vivo in the striatum of DISC1-L100P mutants in response to the low dose of amphetamine. The D(2) receptor antagonist haloperidol reversed the hyperactivity, PPI and latent inhibition (LI) deficits and blocked the psychostimulant effect of amphetamine in DISC1-L100P mutants. Taken together, our findings show the role of DISC1 in D(2) -related pathophysiological mechanism of schizophrenia, linking DISC1 with well-established DA hypothesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
220Mol. Psychiatry 2010 Aug 15: 778, 798-809
PMID20479754
TitleDISC1 regulates cell-cell adhesion, cell-matrix adhesion and neurite outgrowth.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a promising susceptibility gene for major mental illness. Recent studies have implicated DISC1 in key neurodevelopmental processes, including neurite outgrowth, neuronal migration and proliferation. Here, we report that DISC1 regulates cell-cell and cell-matrix adhesion and neurite outgrowth. DISC1 overexpression increased expression of the adherence junction protein N-cadherin and enhanced cell-cell adhesion. The increased N-cadherin accumulated in the areas of cell-cell contact. DISC1 overexpression also enhanced cell-matrix adhesion by inducing expression of beta1-integrin protein. In the presence of nerve growth factor (NGF), DISC1 overexpression increased beta1-integrin expression at the cell membrane and growth cone. NGF-induced neurite extension was enhanced by DISC1, and anti-beta1-integrin antibody reduced the neurite outgrowth of DISC1-overexpressing cells to the control level. Furthermore, DISC1 also regulated N-cadherin and beta1-integrin expression at the cell membrane in primary neurons. We conclude that DISC1 regulates cell-cell adhesion and cell-matrix adhesion by regulating the expression of adhesion molecules.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
221Neuromolecular Med. 2010 Sep 12: 243-7
PMID19937158
TitleAssociation study between the pericentrin (PCNT) gene and schizophrenia.
AbstractDisrupted-in-schizophrenia 1 (DISC1), a known genetic risk factor for schizophrenia (SZ) and major depressive disorder (MDD), interacts with several proteins and some of them are reported to be genetically associated with SZ. Pericentrin (PCNT) also interacts with DISC1 and recently single-nucleotide polymorphisms (SNPs) within the PCNT gene have been found to show significant associations with SZ and MDD. In this study, case-controlled association analysis was performed to determine if the PCNT gene is implicated in SZ. Nine SNPs were analyzed in 1,477 individuals (726 patients with SZ and 751 healthy controls). No significant difference was observed between the controls and the patients in allelic frequencies or genotypic distributions of eight SNPs. Although allelic distribution of rs11702684 was different between the two groups (P = 0.042), the difference did not reach statistical significance after permutation correction for multiple comparisons. In the haplotypic analysis, we could not find any significant association in our subjects, either. This gene may not play a major role independently in the etiology of SZ in the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
222Nat. Neurosci. 2010 Mar 13: 327-32
PMID20139976
TitleDisrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1.
AbstractSynaptic spines are dynamic structures that regulate neuronal responsiveness and plasticity. We examined the role of the schizophrenia risk factor DISC1 in the maintenance of spine morphology and function. We found that DISC1 anchored Kalirin-7 (Kal-7), regulating access of Kal-7 to Rac1 and controlling the duration and intensity of Rac1 activation in response to NMDA receptor activation in both cortical cultures and rat brain in vivo. These results explain why Rac1 and its activator (Kal-7) serve as important mediators of spine enlargement and why constitutive Rac1 activation decreases spine size. This mechanism likely underlies disturbances in glutamatergic neurotransmission that have been frequently reported in schizophrenia that can lead to alteration of dendritic spines with consequential major pathological changes in brain function. Furthermore, the concept of a signalosome involving disease-associated factors, such as DISC1 and glutamate, may well contribute to the multifactorial and polygenetic characteristics of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
223Nihon Shinkei Seishin Yakurigaku Zasshi 2010 Jun 30: 149-52
PMID20666147
Title[Current perspective on the pathogenesis of schizophrenia from the viewpoint of risk factors such as DISC1 (corrected)].
AbstractThe onset of schizophrenia symptoms typically occurs in young adulthood. It most commonly manifests as hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking. schizophrenia is often accompanied by social or occupational dysfunction. Recent genetic studies revealed several probable susceptibility genes for schizophrenia such as Neuregulin1, Dysbindin and Disrupted-in-schizophrenia-1 (DISC1). DISC1 was originally identified as the sole gene that associated with a high inheritance of schizophrenia and other psychiatric illnesses in a large Scottish family. We here review the recent advance in understanding of pathophysiological functions of DISC1. [corrected]
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
224Nat. Rev. Neurosci. 2010 Aug 11: 539-51
PMID20648061
TitleGSK3 signalling in neural development.
AbstractRecent evidence suggests that glycogen synthase kinase 3 (GSK3) proteins and their upstream and downstream regulators have key roles in many fundamental processes during neurodevelopment. Disruption of GSK3 signalling adversely affects brain development and is associated with several neurodevelopmental disorders. Here, we discuss the mechanisms by which GSK3 activity is regulated in the nervous system and provide an overview of the recent advances in the understanding of how GSK3 signalling controls neurogenesis, neuronal polarization and axon growth during brain development. These recent advances suggest that GSK3 is a crucial node that mediates various cellular processes that are controlled by multiple signalling molecules--for example, disrupted in schizophrenia 1 (DISC1), partitioning defective homologue 3 (PAR3), PAR6 and Wnt proteins--that regulate neurodevelopment.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
225Dev. Cell 2010 Jul 19: 7-8
PMID20643344
TitleSwitching DISC1 function in neurogenesis: Dixdc1 selects DISC1 binding partners.
AbstractThe schizophrenia-associated protein DISC1 regulates several steps in neurogenesis. In a recent study published in Neuron, Singh et al. showed how DISC1 and its interacting partner Dixdc1 regulate cell proliferation and cell migration in different manners during embryonic neurogenesis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
226PLoS ONE 2010 -1 5: e10902
PMID20531939
TitleDISC1 regulates primary cilia that display specific dopamine receptors.
AbstractMutations in the DISC1 gene are strongly associated with major psychiatric syndromes such as schizophrenia. DISC1 encodes a cytoplasmic protein with many potential interaction partners, but its cellular functions remain poorly understood. We identified a role of DISC1 in the cell biology of primary cilia that display disease-relevant dopamine receptors.
A GFP-tagged DISC1 construct expressed in NIH3T3 cells and rat striatal neurons localized near the base of primary cilia. RNAi-mediated knockdown of endogenous DISC1 resulted in a marked reduction in the number of cells expressing a primary cilium. FLAG-tagged versions of the cloned human D1, D2 and D5 dopamine receptors concentrated highly on the ciliary surface, and this reflects a specific targeting mechanism specific because D3 and D4 receptors localized to the plasma membrane but were not concentrated on cilia.
These results identify a role of DISC1 in regulating the formation and/or maintenance of primary cilia, and establish subtype-specific targeting of dopamine receptors to the ciliary surface. Our findings provide new insight to receptor cell biology and suggest a relationship between DISC1 and neural dopamine signaling.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
227Eur Neuropsychopharmacol 2010 May 20: 281-7
PMID20207112
TitleDoes subtle disturbance of neuronal migration contribute to schizophrenia and other neurodevelopmental disorders? Potential genetic mechanisms with possible treatment implications.
AbstractPathways associated with genes that regulate neuronal migration by influencing the function of microtubules in the developing fetal brain may be interfered with as part of the "first-hit" of schizophrenia. In the fully-developed brain, these same pathways that impact microtubule function mediate at least some aspects of experience-dependent plasticity, which may also be impaired in schizophrenia. Whereas severe presentations of "lissencephaly" are associated with mutations and deletions of DISC1, LIS1 and the gene for the very low-density lipoprotein receptor, genetic variations of these loci are good candidate schizophrenia genes. Importantly, in the fully-developed brain, there is a possibility that at least some of the consequences of these disturbed genetic pathways that adversely affect microtubule function may be "bypassed" or mitigated.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
228Neuron 2010 Feb 65: 480-9
PMID20188653
TitleKnockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits.
AbstractAdult brain function and behavior are influenced by neuronal network formation during development. Genetic susceptibility factors for adult psychiatric illnesses, such as Neuregulin-1 and Disrupted-in-schizophrenia-1 (DISC1), influence adult high brain functions, including cognition and information processing. These factors have roles during neurodevelopment and are likely to cooperate, forming pathways or "signalosomes." Here we report the potential to generate an animal model via in utero gene transfer in order to address an important question of how nonlethal deficits in early development may affect postnatal brain maturation and high brain functions in adulthood, which are impaired in various psychiatric illnesses such as schizophrenia. We show that transient knockdown of DISC1 in the pre- and perinatal stages, specifically in a lineage of pyramidal neurons mainly in the prefrontal cortex, leads to selective abnormalities in postnatal mesocortical dopaminergic maturation and behavioral abnormalities associated with disturbed cortical neurocircuitry after puberty.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
229Neuron 2010 Feb 65: 437-9
PMID20188647
TitleNow you see it, now you don't--closing in on allostasis and developmental basis of psychiatric disorders.
AbstractThe mode through which early insults in brain development result in the onset of psychiatric disorders years after impact become a little less mysterious with the report by Niwa et al. that a transient reduction of the schizophrenia risk gene DISC1 can alter prefrontal cortex neurochemistry, architecture, and function.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
230J. Neurosci. 2010 Aug 30: 10431-40
PMID20685985
TitleBiochemical and functional interaction of disrupted-in-schizophrenia 1 and amyloid precursor protein regulates neuronal migration during mammalian cortical development.
AbstractAlthough clinically distinct, schizophrenia and Alzheimer's disease are common and devastating disorders that profoundly impair cognitive function. For Alzheimer's disease, key mechanistic insights have emerged from genetic studies that identified causative mutations in amyloid precursor protein (APP) and presenilin. Several genes have been associated with schizophrenia and other major psychoses, and understanding their normal functions will help elucidate the underlying causes of these disorders. One such gene is disrupted-in-schizophrenia 1 (DISC1). DISC1 and APP have been implicated separately in cortical development, with each having roles in both neuronal migration and neurite outgrowth. Here, we report a previously unrecognized biochemical and functional interaction between DISC1 and APP. Using in utero electroporation in the living rat brain, we show that DISC1 acts downstream of APP and Disabled-1 to regulate cortical precursor cell migration. Specifically, overexpression of DISC1 rescues the migration defect caused by a loss of APP expression. Moreover, knockdown of APP in cultured embryonic neurons results in altered subcellular localization of DISC1. Using transfected cells and normal brain tissue, we show that APP and DISC1 coimmunoprecipitate and that the intracellular domain of APP interacts with the N-terminal domain of DISC1. Based on these findings, we hypothesize that the APP cytoplasmic region transiently interacts with DISC1 to help regulate the translocation of DISC1 to the centrosome, where it plays a key role in controlling neuronal migration during cortical development.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
231Biochem. J. 2010 Apr 427: 69-78
PMID20141511
TitleBioinformatic and experimental survey of 14-3-3-binding sites.
AbstractMore than 200 phosphorylated 14-3-3-binding sites in the literature were analysed to define 14-3-3 specificities, identify relevant protein kinases, and give insights into how cellular 14-3-3/phosphoprotein networks work. Mode I RXX(pS/pT)XP motifs dominate, although the +2 proline residue occurs in less than half, and LX(R/K)SX(pS/pT)XP is prominent in plant 14-3-3-binding sites. Proline at +1 is rarely reported, and such motifs did not stand up to experimental reanalysis of human Ndel1. Instead, we discovered that 14-3-3 interacts with two residues that are phosphorylated by basophilic kinases and located in the DISC1 (disrupted-in-schizophrenia 1)-interacting region of Ndel1 that is implicated in cognitive disorders. These data conform with the general findings that there are different subtypes of 14-3-3-binding sites that overlap with the specificities of different basophilic AGC (protein kinase A/protein kinase G/protein kinase C family) and CaMK (Ca2+/calmodulin-dependent protein kinase) protein kinases, and a 14-3-3 dimer often engages with two tandem phosphorylated sites, which is a configuration with special signalling, mechanical and evolutionary properties. Thus 14-3-3 dimers can be digital logic gates that integrate more than one input to generate an action, and coincidence detectors when the two binding sites are phosphorylated by different protein kinases. Paired sites are generally located within disordered regions and/or straddle either side of functional domains, indicating how 14-3-3 dimers modulate the conformations and/or interactions of their targets. Finally, 14-3-3 proteins bind to members of several multi-protein families. Two 14-3-3-binding sites are conserved across the class IIa histone deacetylases, whereas other protein families display differential regulation by 14-3-3s. We speculate that 14-3-3 dimers may have contributed to the evolution of such families, tailoring regulatory inputs to different physiological demands.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
232Proc. Natl. Acad. Sci. U.S.A. 2010 Mar 107: 5622-7
PMID20212127
TitleDisrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade.
AbstractNeuregulin-1 (NRG1) and Disrupted-in-schizophrenia-1 (DISC1) are promising susceptibility factors for schizophrenia. Both are multifunctional proteins with roles in a variety of neurodevelopmental processes, including progenitor cell proliferation, migration, and differentiation. Here, we provide evidence linking these factors together in a single pathway, which is mediated by ErbB receptors and PI3K/Akt. We show that signaling by NRG1 and NRG2, but not NRG3, increase expression of an isoform of DISC1 in vitro. Receptors ErbB2 and ErbB3, but not ErbB4, are responsible for transducing this effect, and PI3K/Akt signaling is also required. In NRG1 knockout mice, this DISC1 isoform is selectively reduced during neurodevelopment. Furthermore, a similar decrease in DISC1 expression is seen in beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) knockout mice, in which NRG1/Akt signaling is reportedly impaired. In contrast to neuronal DISC1 that was reported and characterized, expression of DISC1 in other types of cells in the brain has not been addressed. Here we demonstrate that DISC1, like NRG and ErbB proteins, is expressed in neurons, astrocytes, oligodendrocytes, microglia, and radial progenitors. These findings may connect NRG1, ErbBs, Akt, and DISC1 in a common pathway, which may regulate neurodevelopment and contribute to susceptibility to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
233Brain Struct Funct 2010 Jun 214: 495-517
PMID20512377
TitleThe von Economo neurons in frontoinsular and anterior cingulate cortex in great apes and humans.
AbstractThe von Economo neurons (VENs) are large bipolar neurons located in frontoinsular (FI) and anterior cingulate cortex in great apes and humans, but not other primates. We performed stereological counts of the VENs in FI and LA (limbic anterior, a component of anterior cingulate cortex) in great apes and in humans. The VENs are more numerous in humans than in apes, although one gorilla approached the lower end of the human range. We also examined the ontological development of the VENs in FI and LA in humans. The VENs first appear in small numbers in the 36th week post-conception, are rare at birth, and increase in number during the first 8 months after birth. There are significantly more VENs in the right hemisphere than in the left in FI and LA in postnatal brains of apes and humans. This asymmetry in VEN numbers may be related to asymmetries in the autonomic nervous system. The activity of the inferior anterior insula, which contains FI, is related to physiological changes in the body, decision-making, error recognition, and awareness. The VENs appear to be projection neurons, although their targets are unknown. We made a preliminary study of the connections of FI cortex based on diffusion tensor imaging in the brain of a gorilla. The VEN-containing regions connect to the frontal pole as well as to other parts of frontal and insular cortex, the septum, and the amygdala. It is likely that the VENs in FI are projecting to some or all of these structures and relaying information related to autonomic control, decision-making, or awareness. The VENs selectively express the bombesin peptides neuromedin B (NMB) and gastrin releasing peptide (GRP) which are also expressed in another population of closely related neurons, the fork cells. NMB and GRP signal satiety. The genes for NMB and GRP are expressed selectively in small populations of neurons in the insular cortex in mice. These populations may be related to the VEN and fork cells and may be involved in the regulation of appetite. The loss of these cells may be related to the loss of satiety signaling in patients with frontotemporal dementia who have damage to FI. The VENs and fork cells may be morphological specializations of an ancient population of neurons involved in the control of appetite present in the insular cortex in all mammals. We found that the protein encoded by the gene DISC1 (disrupted in schizophrenia) is preferentially expressed by the VENs. DISC1 has undergone rapid evolutionary change in the line leading to humans, and since it suppresses dendritic branching it may be involved in the distinctive VEN morphology.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
234Neuroimage 2010 Nov 53: 1016-22
PMID19913623
TitleAdditive effect of NRG1 and DISC1 genes on lateral ventricle enlargement in first episode schizophrenia.
AbstractNeuregulin 1 (NRG1) and Disrupted-in-schizophrenia (DISC1) genes, which are candidate genes for schizophrenia, are implicated in brain development. We have previously reported an association between the T allele of the rs6994992 SNP within NRG1 gene and lateral ventricle (LV) enlargement in first-episode schizophrenia patients. Moreover, transgenic mice with mutant DISC1 have also been reported as showing LV enlargement. In this study, we examined the possible interactive effects of NRG1 and DISC1 on brain volumes in a sample of first-episode schizophrenia patients. Ninety-one patients experiencing their first episode of schizophrenia underwent genotyping of three SNPs within DISC1 and structural brain MRI. These results were combined with our previously reported genotypes on three SNPs within NRG1. The T/T genotype of rs2793092 SNP in DISC1 was significantly associated with increased LV volume. However, taking into account the rs6994992 SNP in the NRG1 gene, which was also associated with LV volume in a previous study, the DISC1 SNP only predicted LV enlargement among those patients carrying the T allele in the NRG1 SNP. Those patients with the "at risk" allelic combinations in both genes had LV volumes which were 48% greater than those with none of the allelic combinations. Our findings suggest that NRG1 and DISC1 genes may be associated with brain abnormalities in schizophrenia through their influence on related pathways of brain development.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
235Mol. Psychiatry 2010 Aug 15: 844-9
PMID19255581
TitleAssociation of DISC1 and TSNAX genes and affective disorders in the depression case-control (DeCC) and bipolar affective case-control (BACCS) studies.
AbstractThe gene known as Disrupted-in-schizophrenia-1, DISC1, was originally discovered in a large family, in which it also co-segregated with bipolar affective disorder (BD) and with major depressive disorder (MDD). The TSNAX (Translin-associated factor X) gene, located immediately upstream of DISC1, has also been suggested as a candidate gene in relation to psychiatric illness, as one transcript resulting from intergenic splicing encodes a novel TSNAX-DISC1 fusion protein. We explored the TSNAX-DISC1 gene region for an association with BD and MDD in a sample of 1984 patients (1469 MDD, 515 BD) and 1376 ethnically matched controls. Eight single nucleotide polymorphisms (SNPs) within the TSNAX-DISC1 region (rs766288, rs3738401, rs2492367, rs6675281, rs12133766, rs1000731, rs7546310 and rs821597) were investigated using the SNPlex Genotyping System. We found a significant allelic and genotypic association of the TSNAX-DISC1 gene region with BD, whereas a haplotypic association was found for both BD and MDD. Therefore, our results suggest an association between the TSNAX-DISC1 region and both forms of affective disorders, and support the hypothesis that a portion of the genotypic overlap between schizophrenia and affective disorders is attributable to this gene.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
236Biol. Psychiatry 2010 Dec 68: 1172-81
PMID21130225
TitlePrenatal interaction of mutant DISC1 and immune activation produces adult psychopathology.
AbstractGene-environment interactions (GEI) are involved in the pathogenesis of mental diseases. We evaluated interaction between mutant human disrupted-in-schizophrenia 1 (mhDISC1) and maternal immune activation implicated in schizophrenia and mood disorders.
Pregnant mice were treated with saline or polyinosinic:polycytidylic acid at gestation day 9. Levels of inflammatory cytokines were measured in fetal and adult brains; expression of mhDISC1, endogenous DISC1, lissencephaly type 1, nuclear distribution protein nudE-like 1, glycoprotein 130, growth factor receptor-bound protein 2, and glycogen synthase kinase-3beta were assessed in cortical samples of newborn mice. Tissue content of monoamines, volumetric brain abnormalities, dendritic spine density in the hippocampus, and various domains of the mouse behavior repertoire were evaluated in adult male mice.
Prenatal interaction produced anxiety, depression-like responses, and altered social behavior that were accompanied by decreased reactivity of the hypothalamic-pituitary-adrenal axis, attenuated serotonin neurotransmission in the hippocampus, reduced enlargement of lateral ventricles, decreased volumes of amygdala and periaqueductal gray matter and density of spines on dendrites of granule cells of the hippocampus. Prenatal interaction modulated secretion of inflammatory cytokines in fetal brains, levels of mhDISC1, endogenous mouse DISC1, and glycogen synthase kinase-3beta. The behavioral effects of GEI were observed only if mhDISC1 was expressed throughout the life span.
Prenatal immune activation interacted with mhDISC1 to produce the neurobehavioral phenotypes that were not seen in untreated mhDISC1 mice and that resemble aspects of major mental illnesses. Our DISC1 mouse model is a valuable system to study GEI relevant to mental illnesses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
237Biochem. Biophys. Res. Commun. 2010 Oct 400: 631-7
PMID20807500
TitleMigration defects by DISC1 knockdown in C57BL/6, 129X1/SvJ, and ICR strains via in utero gene transfer and virus-mediated RNAi.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a promising genetic risk factor for major mental disorders. Many groups repeatedly reported a role for DISC1 in brain development in various strains of mice and rats by using RNA interference (RNAi) approach. Nonetheless, due to the complexity of its molecular disposition, such as many splice variants and a spontaneous deletion in a coding exon of the DISC1 gene in some mouse strains, there have been debates on the interpretation on these published data. Thus, in this study, we address this question by DISC1 knockdown via short-hairpin RNAs (shRNAs) against several distinct target sequences with more than one delivery methodologies into several mouse strains, including C57BL/6, ICR, and 129X1/SvJ. Here, we show that DISC1 knockdown by in utero electroporation of shRNA against exons 2, 6, and 10 consistently results in neuronal migration defects in the developing cerebral cortex, which are successfully rescued by co-expression of full-length DISC1. Furthermore, lentivirus-mediated shRNA also led to migration defects, which is consistent with two other methodologies already published, such as plasmid-mediated and retrovirus-mediated ones. The previous study by Song's group also reported that, in the adult hippocampus, the phenotype elicited by DISC1 knockdown with shRNA targeting exon 2 was consistently seen in both C57BL/6 and 129S6 mice. Taken together, we propose that some of DISC1 isoforms that are feasible to be knocked down by shRNAs to exon 2, 6, and 10 of the DISC1 gene play a key role for neuronal migration commonly in various mouse strains and rats.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
238Behav. Brain Res. 2010 Jan 206: 32-7
PMID19716847
TitleCombined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood.
AbstractGene-environment interaction may play a role in the etiology of schizophrenia. Transgenic mice expressing dominant-negative DISC1 (DN-DISC1 mice) show some histological and behavioral endophenotypes relevant to schizophrenia. Viral infection during neurodevelopment provides a major environmental risk for schizophrenia. Neonatal injection of polyriboinosinic-polyribocytidylic acid (polyI:C), which mimics innate immune responses elicited by viral infection, leads to schizophrenia-like behavioral alteration in mice after puberty. To study how gene-environmental interaction during neurodevelopment results in phenotypic changes in adulthood, we treated DN-DISC1 mice or wild-type littermates with injection of polyI:C during the neonatal stage, according to the published method, respectively, and the behavioral and histological phenotypes were examined in adulthood. We demonstrated that neonatal polyI:C treatment in DN-DISC1 mice resulted in the deficits of short-term, object recognition, and hippocampus-dependent fear memories after puberty, although polyI:C treatment by itself had smaller influences on wild-type mice. Furthermore, polyI:C-treated DN-DISC1 mice exhibited signs of impairment of social recognition and interaction, and augmented susceptibility to MK-801-induced hyperactivity as compared with vehicle-treated wild-type mice. Of most importance, additive effects of polyI:C and DN-DISC1 were observed by a marked decrease in parvalbumin-positive interneurons in the medial prefrontal cortex. These results suggest that combined effect of neonatal polyI:C treatment and DN-DISC1 affects some behavioral and histological phenotypes in adulthood.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
239Hum. Genet. 2010 Apr 127: 441-52
PMID20084519
TitleEvidence of statistical epistasis between DISC1, CIT and NDEL1 impacting risk for schizophrenia: biological validation with functional neuroimaging.
AbstractThe etiology of schizophrenia likely involves genetic interactions. DISC1, a promising candidate susceptibility gene, encodes a protein which interacts with many other proteins, including CIT, NDEL1, NDE1, FEZ1 and PAFAH1B1, some of which also have been associated with psychosis. We tested for epistasis between these genes in a schizophrenia case-control study using machine learning algorithms (MLAs: random forest, generalized boosted regression andMonteCarlo logic regression). Convergence of MLAs revealed a subset of seven SNPs that were subjected to 2-SNP interaction modeling using likelihood ratio tests for nested unconditional logistic regression models. Of the 7C2 = 21 interactions, four were significant at the ? = 0.05 level: DISC1 rs1411771-CIT rs10744743 OR = 3.07 (1.37, 6.98) p = 0.007; CIT rs3847960-CIT rs203332 OR = 2.90 (1.45, 5.79) p = 0.003; CIT rs3847960-CIT rs440299 OR = 2.16 (1.04, 4.46) p = 0.038; one survived Bonferroni correction (NDEL1 rs4791707-CIT rs10744743 OR = 4.44 (2.22, 8.88) p = 0.00013). Three of four interactions were validated via functional magnetic resonance imaging (fMRI) in an independent sample of healthy controls; risk associated alleles at both SNPs predicted prefrontal cortical inefficiency during the N-back task, a schizophrenia-linked intermediate biological phenotype: rs3847960-rs440299; rs1411771-rs10744743, rs4791707-rs10744743 (SPM5 p < 0.05, corrected), although we were unable to statistically replicate the interactions in other clinical samples. Interestingly, the CIT SNPs are proximal to exons that encode theDISC1 interaction domain. In addition, the 3' UTR DISC1 rs1411771 is predicted to be an exonic splicing enhancer and the NDEL1 SNP is ~3,000 bp from the exon encoding the region of NDEL1 that interacts with the DISC1 protein, giving a plausible biological basis for epistasis signals validated by fMRI.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
240Hum. Mol. Genet. 2010 Jun 19: 2487-96
PMID20360304
TitleThe DISC1 Ser704Cys substitution affects centrosomal localization of its binding partner PCM1 in glia in human brain.
AbstractDisrupted-in-schizophrenia 1 (DISC1) has been genetically associated with schizophrenia, and with brain phenotypes including grey matter volume and working memory performance. However, the molecular and cellular basis for these associations remains to be elucidated. One potential mechanism may be via an altered interaction of DISC1 with its binding partners. In this context, we previously demonstrated that one DISC1 variant, Leu607Phe, influenced the extent of centrosomal localization of pericentriolar material 1 (PCM1) in SH-SY5Y cells. The current study extends this work to human brain, and includes another DISC1 coding variant, Ser704Cys. Using immunohistochemistry, we first characterized the distribution of PCM1 in human superior temporal gyrus (STG). PCM1 immunoreactivity was localized to the centrosome in glia, but not in neurons, which showed widespread immunoreactivity. We quantified centrosomal PCM1 immunoreactivity in STG glia of 81 controls and 67 subjects with schizophrenia, genotyped for the two polymorphisms. Centrosomal PCM1 immunoreactive area was smaller in Cys704 carriers than in Ser704 homozygotes, with a similar trend in Phe607 homozygotes compared with Leu607 carriers, replicating the finding in SH-SY5Y cells. No differences were seen between controls and subjects with schizophrenia. These findings confirm in vivo that DISC1 coding variants modulate centrosomal PCM1 localization, highlight a role for DISC1 in glial function and provide a possible cellular mechanism contributing to the association of these DISC1 variants with psychiatric phenotypes. Whether this influence of DISC1 genotype extends to other centrosomal proteins and DISC1 binding partners remains to be determined.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
241Neurosci. Lett. 2010 Dec 486: 136-40
PMID20850505
TitleIdentification of high risk DISC1 protein structural variants in patients with bipolar spectrum disorder.
AbstractIn a large Scottish pedigree, a balanced translocation t (1;11)(q42.1;q14.3) disrupting the DISC1 and DISC2 genes segregates with major mental illness, including schizophrenia and depression. A frame-shift carboxyl-terminal deletion was reported in DISC1 in an American family with schizophrenia, but subsequently found in two controls. Herein, we test one hypothesis utilizing a large scale case-control mutation analysis: uncommon DISC1 variants are associated with high risk for bipolar spectrum disorder. We have analyzed the regions of likely functional significance in the DISC1 gene in 504 patients with bipolar spectrum disorder and 576 ethnically similar controls. Five patients were heterozygous for ultra-rare protein structural variants not found in the 576 controls (p=0.02, one-sided Fisher's exact test) and shown to be ultra-rare by their absence in a pool of 10,000 control alleles. In our sample, ultra-rare (private) protein structural variants in DISC1 are associated with an estimated attributable risk of about 0.5% in bipolar spectrum disorder. These data are consistent with: (i) the high frequency of depression in the large Scottish family with a translocation disrupting DISC1; (ii) linkage disequilibrium analysis demonstrating haplotypes associated with relatively small increases in risk for bipolar disorder (<3-fold odds ratio). The data illustrate how low/moderate risk haplotypes that might be found by the HapMap project can be followed up by resequencing to identify protein structural variants with high risk, low frequency and of potential clinical utility.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
242Neuromolecular Med. 2010 Mar 12: 78-85
PMID19760522
TitleTranslin-associated factor X gene (TSNAX) may be associated with female major depressive disorder in the Japanese population.
AbstractSeveral investigations have reported that the translin-associated factor X gene (TSNAX)/disrupted-in-schizophrenia-1 gene (DISC1) was associated with major psychiatric disorders including schizophrenia, bipolar disorder (BP), and major depressive disorder (MDD). TSNAX is located immediately upstream of DISC1, and has been shown to undergo intergenic splicing with DISC1. It thus may also be influenced by translocation. To our knowledge, there are no reported gene-based association analyses between TSNAX and mood disorders in the Japanese population. We conducted a case-control study of Japanese samples (158 bipolar patients, 314 major depressive disorder patients, and 811 controls) with three tagging SNPs in TSNAX, selected using HapMap database. In addition, we performed an association analysis between TSNAX and the efficacy of fluvoxamine treatment in 120 Japanese patients with MDD. The MDD patients in this study had scores of 12 or higher on the 17 items of the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D). We defined a clinical response as a decrease of more than 50% in baseline SIGH-D within 8 weeks, and clinical remission as an SIGH-D score of less than 7 at 8 weeks. We found an association between rs766288 in TSNAX and female MDD in the allele/genotype analysis. However, we did not find any association between TSNAX and BP or the fluvoxamine therapeutic response in MDD in the allele/genotype analysis or haplotype analysis. Our results suggest that rs766288 in TSNAX may play a role in the pathophysiology of female MDD in the Japanese population. A replication study using larger samples may be required for conclusive results, since our sample size was small.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
243Proc. Natl. Acad. Sci. U.S.A. 2010 Oct 107: 17785-90
PMID20880836
TitleDisrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin.
AbstractDisrupted-in-schizophrenia 1 (DISC1) has emerged as a schizophrenia-susceptibility gene affecting various neuronal functions. In this study, we characterized Mitofilin, a mitochondrial inner membrane protein, as a mediator of the mitochondrial function of DISC1. A fraction of DISC1 was localized to the inside of mitochondria and directly interacts with Mitofilin. A reduction in DISC1 function induced mitochondrial dysfunction, evidenced by decreased mitochondrial NADH dehydrogenase activities, reduced cellular ATP contents, and perturbed mitochondrial Ca(2+) dynamics. In addition, deficiencies in DISC1 and Mitofilin induced a reduction in mitochondrial monoamine oxidase-A activity. The mitochondrial dysfunctions evoked by the deficiency of DISC1 were partially phenocopied by an overexpression of truncated DISC1 that is associated with schizophrenia in human. DISC1 deficiencies induced the ubiquitination of Mitofilin, suggesting that DISC1 is critical for the stability of Mitofilin. Finally, the mitochondrial dysfunction induced by DISC1 deficiency was partially reversed by coexpression of Mitofilin, confirming a functional link between DISC1 and Mitofilin for the normal mitochondrial function. According to these results, we propose that DISC1 plays essential roles for mitochondrial function in collaboration with a mitochondrial interacting partner, Mitofilin.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
244Psychiatr. Genet. 2010 Dec 20: 298-303
PMID20505556
TitleAssociation of DISC1 gene with schizophrenia in families from two distinct French and Algerian populations.
AbstractThe Disrupted-in-schizophrenia-1 (DISC1) gene is a promising genetic risk factor for major mental illnesses, especially schizophrenia. Several variants encompassing the DISC1 gene have been associated with schizophrenia and specific clinical features. Negative results were nevertheless observed, stratification biases, heterogeneity of the analyzed samples and low statistical power being potentially involved.
We analyzed four single nucleotide polymorphisms (SNPs), including three non-synonymous SNPs, of DISC1 in two independent samples of trios, from France and Algeria, using family-based association tests to elude statistical limits.
In 114 French schizophrenia trios, the C allele of non-synonymous rs6675281/Leu607Phe/C1872T was significantly over-transmitted [odds ratio (OR)=2.3, 95% confidence interval (CI)=1.1-4.4]. This same SNP was also more frequently transmitted in the 100 Algerian schizophrenia trios (OR=2.6, 95% CI=0.9-7.3). In the combined 214 trios, a significant over-transmission of the C allele of rs6675281 to the affected probands was observed (P=0.002), even after correction for multiple testing (P corrected=0.01 OR=2.4 and 95% CI=1.3-4.2). Assessing if a dimension of schizophrenia could be more specifically involved, we found that patients with the C allele had a significantly higher Scale for the Assessment of Negative Symptoms total score (P=0.0002).
The analysis adds convergent evidence in favor of a significant role of the DISC1 gene as a risk factor for schizophrenia, as present in two different samples, in family trios rather than with a case--control approach, and even when multiple tests are controlled for. We could further potentially attribute this effect to the negative dimension of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
245Life Sci. 2010 May 86: 722-5
PMID20227423
TitleA functional polymorphism in the disrupted-in schizophrenia 1 gene is associated with chronic fatigue syndrome.
AbstractDisrupted-in schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and major depressive disorder (MDD). Patients with chronic fatigue syndrome (CFS) report having continuous severe fatigue and many overlapping symptoms with MDD; however, the mechanism and effective treatment of CFS are still unclear. We focused on the overlapping symptoms between CFS and MDD and performed an association study of the functional single-nucleotide polymorphism (SNP) in the DISC1 gene with CFS.
Venous blood was drawn from CFS patients and controls and genomic DNA was extracted from the whole blood according to standard procedures. Ser704Cys DISC1 SNP was genotyped using the TaqMan 5'-exonuclease allelic discrimination assay.
We found that the Cys704 allele of Ser704Cys SNP was associated with an increased risk of CFS development compared with the Ser704 allele.
DISC1 Ser704Cys might be a functional variant that affects one of the mechanisms implicated in the biology of CFS. Some patients with CFS showed a phenotype similar to that of patients with MDD, but further studies are needed to clarify the biological mechanism, because this study is of a rather preliminary nature. Despite the variety of patients with CFS, DISC1 Ser704Cys has an association with CFS, which may also suggest that DISC1 plays a central role in the induction of various psychiatric diseases.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
246Psychol Med 2010 Apr 40: 529-40
PMID19818200
TitleWhat have the genomics ever done for the psychoses?
AbstractDespite the substantial heritability of the psychoses and their genuine public health burden, the applicability of the genomic approach in psychiatry has been strongly questioned or prematurely dismissed.
selective review of the recent literature on molecular genetic and genomic approaches to the psychoses including the early output from genome-wide association studies and the genomic analysis of DNA structural variation.
Susceptibility variants at strong candidate genes have been identified including neuregulin, dysbindin, DISC1 and neurexin 1. Rare but highly penetrant copy number variants and new mutations affecting genes involved in neurodevelopment, cell signalling and synaptic function have been described showing some overlapping genetic architecture with other developmental disorders including autism. The de-novo mutations described offer an explanation for the familial sporadic divide and the persistence of schizophrenia in the population. The functional effects of risk variants at the level of cognition and connectivity has been described and recently, ZNF804A has been identified, and the MHC re-identified as risk loci, and it has been shown that at least a third of the variation in liability is due to multiple common risk variants of small effect with a substantial shared genetic liability between schizophrenia and bipolar affective disorder.
The genomics have done much for the psychoses to date and more is anticipated.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
247Mol. Psychiatry 2010 Jun 15: 615-28
PMID19048012
TitleA threonine to isoleucine missense mutation in the pericentriolar material 1 gene is strongly associated with schizophrenia.
AbstractMarkers at the pericentriolar material 1 gene (PCM1) have shown genetic association with schizophrenia in both a University College London (UCL) and a USA-based case-control sample. In this paper we report a statistically significant replication of the PCM1 association in a large Scottish case-control sample from Aberdeen. Resequencing of the genomic DNA from research volunteers who had inherited haplotypes associated with schizophrenia showed a threonine to isoleucine missense mutation in exon 24 which was likely to change the structure and function of PCM1 (rs370429). This mutation was found only as a heterozygote in 98 schizophrenic research subjects and controls out of 2246 case and control research subjects. Among the 98 carriers of rs370429, 67 were affected with schizophrenia. The same alleles and haplotypes were associated with schizophrenia in both the London and Aberdeen samples. Another potential aetiological base pair change in PCM1 was rs445422, which altered a splice site signal. A further mutation, rs208747, was shown by electrophoretic mobility shift assays to create or destroy a promoter transcription factor site. Five further non-synonymous changes in exons were also found. Genotyping of the new variants discovered in the UCL case-control sample strengthened the evidence for allelic and haplotypic association (P=0.02-0.0002). Given the number and identity of the haplotypes associated with schizophrenia, further aetiological base pair changes must exist within and around the PCM1 gene. PCM1 protein has been shown to interact directly with the disrupted-in-schizophrenia 1 (DISC1) protein, Bardet-Biedl syndrome 4, and Huntingtin-associated protein 1, and is important in neuronal cell growth. In a separate study we found that clozapine but not haloperidol downregulated PCM1 expression in the mouse brain. We hypothesize that mutant PCM1 may be responsible for causing a subtype of schizophrenia through abnormal cell division and abnormal regeneration in dividing cells in the central nervous system. This is supported by our previous finding of orbitofrontal volumetric deficits in PCM1-associated schizophrenia patients as opposed to temporal pole deficits in non-PCM1-associated schizophrenia patients. Caution needs to be exercised in interpreting the actual biological effects of the mutations we have found without further cell biology. However, the DNA changes we have found deserve widespread genotyping in multiple case-control populations.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
248Hippocampus 2010 May 20: 659-71
PMID19499587
TitleThe effect of amygdala kindling on hippocampal neurogenesis coincides with decreased reelin and DISC1 expression in the adult dentate gyrus.
AbstractTemporal lobe seizures can induce the proliferation and abnormal migration of newly generated dentate granule cells, but little is known about the molecular mechanisms that govern these pathological events. Reelin and DISC1 (disrupted-in-schizophrenia 1) are proteins that play a regulatory role in the maturation and integration of new neurons in the developing and adult brain. In this study, we examined whether amygdala kindling results in aberrant neurogenesis and altered expression of reelin and DISC1 in the adult dentate gyrus. Using doublecortin immunohistochemistry, we found that short-term kindling (i.e., 30 electrical stimulations) significantly increased the number of immature neurons in the dentate subgranular zone (SGZ), whereas long-term kindling (i.e., 99 electrical stimulations) did not. However, doublecortin-labeled neurons in long-term kindled rats showed greater dendritic complexity than they did in short-term kindled or control rats. We also found that long-term kindling decreased the number of reelin-positive cells and decreased DISC1 expression in the dentate granule cell layer and subgranular zone. Interestingly, kindling-induced changes in reelin and DISC1 expression coincided with the appearance of ectopically located Prox1-labeled granule cells in the hilus. These effects occurred independently of alterations in granule cell layer length, dentate volume, or the number of hilar neurons. Taken together, these findings suggest a novel role for DISC1 in the pathophysiology of temporal lobe epilepsy and further suggest that changes in reelin and DISC1 expression may contribute to aberrant neurogenesis in the kindling model.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
249Mol. Psychiatry 2010 Jun 15: 615-28
PMID19048012
TitleA threonine to isoleucine missense mutation in the pericentriolar material 1 gene is strongly associated with schizophrenia.
AbstractMarkers at the pericentriolar material 1 gene (PCM1) have shown genetic association with schizophrenia in both a University College London (UCL) and a USA-based case-control sample. In this paper we report a statistically significant replication of the PCM1 association in a large Scottish case-control sample from Aberdeen. Resequencing of the genomic DNA from research volunteers who had inherited haplotypes associated with schizophrenia showed a threonine to isoleucine missense mutation in exon 24 which was likely to change the structure and function of PCM1 (rs370429). This mutation was found only as a heterozygote in 98 schizophrenic research subjects and controls out of 2246 case and control research subjects. Among the 98 carriers of rs370429, 67 were affected with schizophrenia. The same alleles and haplotypes were associated with schizophrenia in both the London and Aberdeen samples. Another potential aetiological base pair change in PCM1 was rs445422, which altered a splice site signal. A further mutation, rs208747, was shown by electrophoretic mobility shift assays to create or destroy a promoter transcription factor site. Five further non-synonymous changes in exons were also found. Genotyping of the new variants discovered in the UCL case-control sample strengthened the evidence for allelic and haplotypic association (P=0.02-0.0002). Given the number and identity of the haplotypes associated with schizophrenia, further aetiological base pair changes must exist within and around the PCM1 gene. PCM1 protein has been shown to interact directly with the disrupted-in-schizophrenia 1 (DISC1) protein, Bardet-Biedl syndrome 4, and Huntingtin-associated protein 1, and is important in neuronal cell growth. In a separate study we found that clozapine but not haloperidol downregulated PCM1 expression in the mouse brain. We hypothesize that mutant PCM1 may be responsible for causing a subtype of schizophrenia through abnormal cell division and abnormal regeneration in dividing cells in the central nervous system. This is supported by our previous finding of orbitofrontal volumetric deficits in PCM1-associated schizophrenia patients as opposed to temporal pole deficits in non-PCM1-associated schizophrenia patients. Caution needs to be exercised in interpreting the actual biological effects of the mutations we have found without further cell biology. However, the DNA changes we have found deserve widespread genotyping in multiple case-control populations.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
250Mol. Psychiatry 2011 Jun 16: 585-7
PMID21321563
TitleSynaptic modulators Nrxn1 and Nrxn3 are disregulated in a Disc1 mouse model of schizophrenia.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
251Mol. Psychiatry 2011 Apr 16: 358-60
PMID21339753
TitleIntegration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
252Proc. Natl. Acad. Sci. U.S.A. 2011 Dec 108: E1349-58
PMID22049344
TitleAltered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice.
AbstractCarefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous DISC1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the DISC1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based DISC1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
253Neuron 2011 Nov 72: 559-71
PMID22099459
TitleInteraction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia.
AbstractDisrupted-in schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates different aspects of neuronal development is not well understood. Here, we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
254ACS Chem Neurosci 2011 Nov 2: 609-632
PMID22116789
TitleDISC1: Structure, Function, and Therapeutic Potential for Major Mental Illness.
AbstractDisrupted in schizophrenia 1 (DISC1) is well established as a genetic risk factor across a spectrum of psychiatric disorders, a role supported by a growing body of biological studies, making the DISC1 protein interaction network an attractive therapeutic target. By contrast, there is a relative deficit of structural information to relate to the myriad biological functions of DISC1. Here, we critically appraise the available bioinformatics and biochemical analyses on DISC1 and key interacting proteins, and integrate this with the genetic and biological data. We review, analyze, and make predictions regarding the secondary structure and propensity for disordered regions within DISC1, its protein-interaction domains, subcellular localization motifs, and the structural and functional implications of common and ultrarare DISC1 variants associated with major mental illness. We discuss signaling pathways of high pharmacological potential wherein DISC1 participates, including those involving phosphodiesterase 4 (PDE4) and glycogen synthase kinase 3 (GSK3). These predictions and priority areas can inform future research in the translational and potentially guide the therapeutic processes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
255Neuron 2011 Nov 72: 545-58
PMID22099458
TitleCommon DISC1 polymorphisms disrupt Wnt/GSK3? signaling and brain development.
AbstractDisrupted in schizophrenia-1 (DISC1) is a candidate gene for psychiatric disorders and has many roles during brain development. Common DISC1 polymorphisms (variants) are associated with neuropsychiatric phenotypes including altered cognition, brain structure, and function; however, it is unknown how this occurs. Here, we demonstrate using mouse, zebrafish, and human model systems that DISC1 variants are loss of function in Wnt/GSK3? signaling and disrupt brain development. The DISC1 variants A83V, R264Q, and L607F, but not S704C, do not activate Wnt signaling compared with wild-type DISC1 resulting in decreased neural progenitor proliferation. In zebrafish, R264Q and L607F could not rescue DISC1 knockdown-mediated aberrant brain development. Furthermore, human lymphoblast cell lines endogenously expressing R264Q displayed impaired Wnt signaling. Interestingly, S704C inhibited the migration of neurons in the developing neocortex. Our data demonstrate DISC1 variants impair Wnt signaling and brain development and elucidatea possible mechanism for their role in neuropsychiatric phenotypes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
256Neuron 2011 Nov 72: 501-3
PMID22099453
TitleDISC1: a schizophrenia gene with multiple personalities.
AbstractTwo papers address the contribution of DISC1 to neural development and schizophrenia risk in this issue ofNeuron. These complementary studies elegantly bridge the gap between genetic and cellular studies ofschizophrenia, providing a level of functional validation that is often lacking in the field.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
257Nat. Rev. Neurosci. 2011 Dec 12: 707-22
PMID22095064
TitleLinking neurodevelopmental and synaptic theories of mental illness through DISC1.
AbstractRecent advances in our understanding of the underlying genetic architecture of psychiatric disorders has blown away the diagnostic boundaries that are defined by currently used diagnostic manuals. The disrupted in schizophrenia 1 (DISC1) gene was originally discovered at the breakpoint of an inherited chromosomal translocation, which segregates with major mental illnesses. In addition, many biological studies have indicated a role for DISC1 in early neurodevelopment and synaptic regulation. Given that DISC1 is thought to drive a range of endophenotypes that underlie major mental conditions, elucidating the biology of DISC1 may enable the construction of new diagnostic categories for mental illnesses with a more meaningful biological foundation.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
258J. Biol. Chem. 2011 Dec 286: 44266-76
PMID21998303
TitleMolecular characterization of disrupted in schizophrenia-1 risk variant S704C reveals the formation of altered oligomeric assembly.
AbstractDISC1 (Disrupted in schizophrenia-1) plays essential roles in neuronal proliferation, neuronal migration and axon guidance and has been implicated in schizophrenia and related psychiatric disorders. DISC1 forms a functional complex with nuclear distribution element-like protein-1 (NDEL1), a key component that regulates microtubule organization during cell division and neuronal migration. DISC1 polymorphisms at the binding interface of DISC1-NDEL1 complex have been implicated in schizophrenia. However, it is unknown how schizophrenia risk polymorphisms perturb its interaction with NDEL1 and how they change the inherent biochemical properties of DISC1. Here, we characterize the oligomerization and binding property of DISC1 and its natural schizophrenia risk variant, S704C. Our results show that DISC1 forms octamers via dimers as building blocks and directly interacts with tetramers of NDEL1. The schizophrenia risk variant S704C affects the formation of octamers of DISC1 and exhibits higher-order self-oligomerization. However, the observed formation of new oligomeric species did not influence its binding with NDEL1. These results suggest that the improper oligomeric assembly of DISC1-S704C may underlie the observed phenotypic variation due to the polymorphism.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
259Mol. Cell. Neurosci. 2011 Dec 48: 359-64
PMID21757008
TitleRegulation of the cytoskeleton by Disrupted-in-schizophrenia 1 (DISC1).
AbstractDisrupted in schizophrenia 1 (DISC1) is one of the strongest supported risk genes for psychiatric disorders, such as schizophrenia, major depression, bipolar disorder, and autism. Intensive study over the past 11 years, since the gene was cloned, has tried to understand at the molecular and cellular levels how mutations in DISC1 contribute to these diseases. The DISC1 protein has been reported to be localized to cytoskeleton-rich regions in cells, including the centrosome, base of primary cilia, axon and dendritic shafts and spines. Here we review the functions of DISC1 which are relevant for cytoskeletal regulation and its crucial roles during normal brain development and in adult brain function. This article is part of a Special Issue entitled Neuronal Function.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
260Am. J. Med. Genet. A 2011 Aug 155A: 1865-76
PMID21739582
TitleGenetic and functional analyses identify DISC1 as a novel callosal agenesis candidate gene.
AbstractAgenesis of the corpus callosum (AgCC) is a congenital brain malformation that occurs in approximately 1:1,000-1:6,000 births. Several syndromes associated with AgCC have been traced to single gene mutations; however, the majority of AgCC causes remain unidentified. We investigated a mother and two children who all shared complete AgCC and a chromosomal deletion at 1q42. We fine mapped this deletion and show that it includes Disrupted-in-schizophrenia 1 (DISC1), a gene implicated in schizophrenia and other psychiatric disorders. Furthermore, we report a de novo chromosomal deletion at 1q42.13 to q44, which includes DISC1, in another individual with AgCC. We resequenced DISC1 in a cohort of 144 well-characterized AgCC individuals and identified 20 sequence changes, of which 4 are rare potentially pathogenic variants. Two of these variants were undetected in 768 control chromosomes. One of these is a splice site mutation at the 5' boundary of exon 11 that dramatically reduces full-length mRNA expression of DISC1, but not of shorter forms. We investigated the developmental expression of mouse DISC1 and find that it is highly expressed in the embryonic corpus callosum at a critical time for callosal formation. Taken together our results suggest a significant role for DISC1 in corpus callosum development.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
261J. Neurosci. 2011 Jun 31: 9043-54
PMID21677187
TitlePKA phosphorylation of NDE1 is DISC1/PDE4 dependent and modulates its interaction with LIS1 and NDEL1.
AbstractNuclear distribution factor E-homolog 1 (NDE1), Lissencephaly 1 (LIS1), and NDE-like 1 (NDEL1) together participate in essential neurodevelopmental processes, including neuronal precursor proliferation and differentiation, neuronal migration, and neurite outgrowth. NDE1/LIS1/NDEL1 interacts with Disrupted in schizophrenia 1 (DISC1) and the cAMP-hydrolyzing enzyme phosphodiesterase 4 (PDE4). DISC1, PDE4, NDE1, and NDEL1 have each been implicated as genetic risk factors for major mental illness. Here, we demonstrate that DISC1 and PDE4 modulate NDE1 phosphorylation by cAMP-dependent protein kinase A (PKA) and identify a novel PKA substrate site on NDE1 at threonine-131 (T131). Homology modeling predicts that phosphorylation at T131 modulates NDE1-LIS1 and NDE1-NDEL1 interactions, which we confirm experimentally. DISC1-PDE4 interaction thus modulates organization of the NDE1/NDEL1/LIS1 complex. T131-phosphorylated NDE1 is present at the postsynaptic density, in proximal axons, within the nucleus, and at the centrosome where it becomes substantially enriched during mitosis. Mutation of the NDE1 T131 site to mimic PKA phosphorylation inhibits neurite outgrowth. Thus PKA-dependent phosphorylation of the NDE1/LIS1/NDEL1 complex is DISC1-PDE4 modulated and likely to regulate its neural functions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
262Neuropsychopharmacol 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, schizophrenias
263Schizophr. Res. 2011 Aug 130: 238-49
PMID21605958
TitleExpression of mutant human DISC1 in mice supports abnormalities in differentiation of oligodendrocytes.
AbstractAbnormalities in oligodendrocyte (OLG) differentiation and OLG gene expression deficit have been described in schizophrenia (SZ). Recent studies revealed a critical requirement for Disrupted-in-schizophrenia 1 (DISC1) in neural development. Transgenic mice with forebrain restricted expression of mutant human DISC1 (?hDISC1) are characterized by neuroanatomical and behavioral abnormalities reminiscent of some features of SZ. We sought to determine whether the expression of ?hDISC1 may influence the development of OLGs in this mouse model. OLG- and cell cycle-associated gene and protein expression were characterized in the forebrain of ?hDISC1 mice during different stages of neurodevelopment (E15 and P1 days) and in adulthood. The results suggest that the expression of ?hDISC1 exerts a significant influence on oligodendrocyte differentiation and function, evidenced by premature OLG differentiation and increased proliferation of their progenitors. Additional findings showed that neuregulin 1 and its receptors may be contributing factors to the observed upregulation of OLG genes. Thus, OLG function may be perturbed by mutant hDISC1 in a model system that provides new avenues for studying aspects of the pathogenesis of SZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
264Proc. Natl. Acad. Sci. U.S.A. 2011 Apr 108: 5795-800
PMID21436042
TitleImpaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner.
AbstractNMDA receptors are key regulators of synaptic plasticity, and their hypofunction is thought to contribute to the pathophysiology of CNS disorders. Furthermore, NMDA receptors participate in the formation, maintenance, and elimination of synapses. The consequences of NMDA receptor hypofunction on synapse biology were explored in a genetic mouse model, in which the levels of NMDA receptors are reduced to 10% of normal levels (i.e., NR1-knockdown mice). In these mice, synapse number is reduced in an age-dependent manner; reductions are observed at the postpubertal age of 6 wk, but normal at 2 wk of age. Efforts to uncover the biochemical underpinnings of this phenomenon reveal synapse-specific reductions in 14-3-3? protein and in Disrupted in schizophrenia-1 (DISC1), two schizophrenia susceptibility factors that have been implicated in the regulation of spine density. Subchronic administration of MK-801, an NMDA receptor antagonist, produces similar synaptic reductions in both spine density and DISC1, indicating that synaptic levels of DISC1 are regulated by NMDA receptor function. The synaptic reduction of DISC1 and 14-3-3? is developmentally correlated with the age-dependent decrease in striatal spine density.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
265Nihon Shinkei Seishin Yakurigaku Zasshi 2011 Feb 31: 23-8
PMID21409841
Title[Roles of DISC1-interacting protein Girdin in postnatal development and adult neurogenesis in the dentate gyrus].
AbstractThe dentate gyrus (DG) of the hippocampus is a unique brain region in that most of its neurons are formed postnatally, and neurogenesis persists throughout life. Adult neurogenesis in the DG is involved in a variety of physiological and pathological processes such as learning, memory, and neurodegenerative diseases, making the research field attractive to a number of developmental biologists, neuroscientists, and medical scientists. We found that mice lacking the expression of an actin-binding protein, Girdin, have severe defects in DG development. Girdin interacts with Disrupted-In-schizophrenia 1 (DISC1) in the neuroblasts, the loss of which causes mismigration and mispositioning of newborn dentate granule cells. It has been uncovered that the Girdin/DISC1 protein complex has a critical role not only in DG development but also in adult neurogenesis in the DG. In this review, we describe how we studied the function of Girdin and DISC1 in DG development and future perspectives on neurogenesis research.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
266J. Neurosci. 2011 Mar 31: 3197-206
PMID21368031
TitleDisc1 point mutations in mice affect development of the cerebral cortex.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a strong candidate gene for schizophrenia and other mental disorders. DISC1 regulates neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth, and neurotransmitter signaling. Abnormal neuronal morphology and cortical architecture are seen in human postmortem brain from patients with schizophrenia. However, the etiology and development of these histological abnormalities remain unclear. We analyzed the histology of two DISC1 mutant mice with point mutations (Q31L and L100P) and found a relative reduction in neuron number, decreased neurogenesis, and altered neuron distribution compared to wild-type littermates. Frontal cortical neurons have shorter dendrites and decreased surface area and spine density. Overall, the histology of DISC1 mutant mouse cortex is reminiscent of the findings in schizophrenia. These results provide further evidence that DISC1 participates in cortical development, including neurogenesis and neuron migration.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
267Transl Psychiatry 2011 -1 1: e43
PMID22832659
TitleAbnormal behavior in mice mutant for the Disc1 binding partner, Dixdc1.
AbstractDisrupted-in-schizophrenia-1 (DISC1) is a genetic susceptibility locus for major mental illness, including schizophrenia and depression. The DISC1 protein was recently shown to interact with the Wnt signaling protein, DIX domain containing 1 (Dixdc1). Both proteins participate in neural progenitor proliferation dependent on Wnt signaling, and in neural migration independently of Wnt signaling. Interestingly, their effect on neural progenitor proliferation is additive. By analogy to DISC1, mutations in Dixdc1 may lead to abnormal behavior in mice, and to schizophrenia or depression in humans. To explore this hypothesis further, we generated mice mutant at the Dixdc1 locus and analyzed their behavior. Dixdc1(-/-) mice had normal prepulse inhibition, but displayed decreased spontaneous locomotor activity, abnormal behavior in the elevated plus maze and deficits in startle reactivity. Our results suggest that Dixdc1(-/-) mice will be a useful tool to elucidate molecular pathophysiology involving DISC1 in major mental illnesses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
268Synapse 2011 Mar 65: 234-48
PMID20687111
TitleGenetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3.
AbstractRecent studies have identified disrupted-in-schizophrenia-1 (DISC1) as a strong genetic risk factor associated with schizophrenia. Previously, we have reported that a mutation in the second exon of the DISC1 gene [leucine to proline at amino acid position 100, L100P] leads to the development of schizophrenia-related behaviors in mice. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase that interacts with the N-terminal region of DISC1 (aa 1-220) and has been implicated as an important downstream component in the etiology of schizophrenia. Here, for the first time, we show that pharmacological and genetic inactivation of GSK-3 reverse prepulse inhibition and latent inhibition deficits as well as normalizing the hyperactivity of DISC1-L100P mutants. In parallel to these observations, interaction between DISC1 and GSK-3? and ? is reduced in DISC1-L100P mutants. Our data provide genetic, biochemical, and behavioral evidence for a molecular link between DISC1 and GSK-3 in relation to psychopathology and highlights the value of missense mutations in dissecting the underlying and complex molecular mechanisms of neurological disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
269PLoS ONE 2011 -1 6: e23450
PMID21853134
TitleSequencing of DISC1 pathway genes reveals increased burden of rare missense variants in schizophrenia patients from a northern Swedish population.
AbstractIn recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence--both genetic and functional--indicates that many of its protein interaction partners are also involved in the development of these diseases. In this study, we applied a pooled sample 454 sequencing strategy, to explore the contribution of genetic variation in DISC1 and 10 of its interaction partners (ATF5, Grb2, FEZ1, LIS-1, PDE4B, NDE1, NDEL1, TRAF3IP1, YWHAE, and ZNF365) to schizophrenia susceptibility in an isolated northern Swedish population. Mutation burden analysis of the identified variants in a population of 486 SZ patients and 514 control individuals, revealed that non-synonymous rare variants with a MAF<0.01 were significantly more present in patients compared to controls (8.64% versus 4.7%, P?=?0.018), providing further evidence for the involvement of DISC1 and some of its interaction partners in psychiatric disorders. This increased burden of rare missense variants was even more striking in a subgroup of early onset patients (12.9% versus 4.7%, P?=?0.0004), highlighting the importance of studying subgroups of patients and identifying endophenotypes. Upon investigation of the potential functional effects associated with the identified missense variants, we found that ?90% of these variants reside in intrinsically disordered protein regions. The observed increase in mutation burden in patients provides further support for the role of the DISC1 pathway in schizophrenia. Furthermore, this study presents the first evidence supporting the involvement of mutations within intrinsically disordered protein regions in the pathogenesis of psychiatric disorders. As many important biological functions depend directly on the disordered state, alteration of this disorder in key pathways may represent an intriguing new disease mechanism for schizophrenia and related neuropsychiatric diseases. Further research into this unexplored domain will be required to elucidate the role of the identified variants in schizophrenia etiology.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
270Schizophr. Res. 2011 Jun 129: 80-4
PMID21481569
TitleNo association between the PCM1 gene and schizophrenia: a multi-center case-control study and a meta-analysis.
AbstractAlterations in centrosomal function have been suggested in the pathology of schizophrenia. The molecule pericentriolar material 1 (PCM1) is involved in maintaining centrosome integrity and in the regulation of the microtubule cytoskeleton. PCM1 forms a complex at the centrosome with the disrupted-in-schizophrenia 1 (DISC1) protein, which is a major susceptibility factor for schizophrenia. The association between genetic variants in the PCM1 gene and schizophrenia has been reported by several case-control studies, linkage studies and a meta-analysis. The aims of this study are to replicate the association between four single-nucleotide polymorphisms (SNPs) in the PCM1 gene and schizophrenia in a Japanese population (1496 cases and 1845 controls) and to perform a meta-analysis of the combined sample groups (3289 cases and 3567 controls). We failed to find a significant association between SNPs or haplotypes of the PCM1 gene and schizophrenia in the Japanese population (P>0.28). The meta-analysis did not reveal an association between the four examined SNPs and schizophrenia. Our data did not support genetic variants in the PCM1 gene as a susceptibility locus for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
271Mol. Psychiatry 2011 Oct 16: 1006-23
PMID20838393
TitleThe psychiatric disease risk factors DISC1 and TNIK interact to regulate synapse composition and function.
AbstractDisrupted in schizophrenia 1 (DISC1), a genetic risk factor for multiple serious psychiatric diseases including schizophrenia, bipolar disorder and autism, is a key regulator of multiple neuronal functions linked to both normal development and disease processes. As these diseases are thought to share a common deficit in synaptic function and architecture, we have analyzed the role of DISC1 using an approach that focuses on understanding the protein-protein interactions of DISC1 specifically at synapses. We identify the Traf2 and Nck-interacting kinase (TNIK), an emerging risk factor itself for disease, as a key synaptic partner for DISC1, and provide evidence that the DISC1-TNIK interaction regulates synaptic composition and activity by stabilizing the levels of key postsynaptic density proteins. Understanding the novel DISC1-TNIK interaction is likely to provide insights into the etiology and underlying synaptic deficits found in major psychiatric diseases.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
272Neurosci. Res. 2011 Sep 71: 71-7
PMID21664390
TitleDISC1 regulates synaptic vesicle transport via a lithium-sensitive pathway.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a susceptibility gene for major mental illnesses, including bipolar disorder and schizophrenia. Although the roles of DISC1 in nervous system development and functions are increasingly recognized, pathophysiological mechanisms underlying a range of neuropsychiatric symptoms caused by DISC1 mutations remain unclear. Here we show that DISC1 enhances synaptic vesicle transport along microtubules. Knocking down DISC1 expression results in attenuated vesicle transport in primary cortical neurons. Likewise, expressing the dominant-negative, breakpoint mutant version of DISC1 causes defective vesicle transport, by disrupting the assembly between the kinesin-1 adaptor FEZ1 and the cargo protein Synaptotagmin-1 (Syt-1). In addition, lithium, a mood-stabilizing agent used for the treatment of bipolar disorder, can restore the assembly of FEZ1 and Syt-1, and normalizes the defective transport caused by the dominant-negative DISC1. Thus, this study addresses a new role of DISC1 in organelle transport in neurons, and suggests that this cellular pathway could be therapeutically targeted for the treatment against neuropsychiatric diseases.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
273Nihon Shinkei Seishin Yakurigaku Zasshi 2011 Nov 31: 201-7
PMID22256608
Title[PolyI:C-induced neurodevelopmental animal model for schizophrenia].
Abstractschizophrenia affects nearly 1% of the population and is clinically characterized by positive symptoms (e.g. delusions and hallucinations), negative symptoms (e.g. affective flattening, apathy and social withdrawal) and cognitive dysfunction. Genetic susceptibility factors for schizophrenia, such as neuregulinl, dysbindin and disrupted-in-schizophrenia 1 (DISC1), have recently been reported, some of which play a role in neurodevelopment. Furthermore, epidemiologic studies suggest that environmental insults, such as prenatal infection and perinatal complication, are involved in the development of schizophrenia. The possible interaction between environment and genetic susceptibility factors is proposed as a promising disease etiology of schizophrenia. Polyriboinosinic-polyribocytidylic acid (polyI:C), a toll-like receptor 3 ligand, induces a strong innate immune response. Maternal immune activation by polyI:C exposure in rodents induces a wide spectrum of behavioral and neurochemical abnormalities in adult offspring. We have reported that neonatal injection of polyI:C in mice results in schizophrenia-like behavioral abnormalities in adulthood. In this review, we show how gene-environment interactions during neurodevelopment result in phenotypic changes in adulthood, by injecting polyI:C into transgenic mice that express a dominant-negative form of human DISC1 (DN-DISC1). Our findings suggest that polyI:C-treated DN-DISC1 mice are a validated animal model for schizophrenia with gene-environment interactions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
274Commun Integr Biol 2011 Mar 4: 211-2
PMID21655443
TitleReaddressing synaptic pruning theory for schizophrenia: Combination of brain imaging and cell biology.
AbstractDisturbance in the synapse has been suggested in the pathology of schizophrenia, especially through examination of autopsied brains from patients with the disease. Nonetheless, it has been unclear whether and how such disturbance is associated with the onset and progression of the disease in young adulthood. Some studies with magnetic resonance spectroscopy (MRS) have suggested that overpruning of dendritic spines may occur in the prodromal and early stages of schizophrenia. In addition, our recent study indicates that DISC1, a promising risk factor for schizophrenia, has a crucial role in the maintenance of the dendritic spine in association with activation of the NMDA-type glutamate receptor.1 Disturbance of spine maintenance can be linked to aberrant synaptic pruning during postnatal brain maturation. Biological studies with genetic models may provide us with an opportunity to validate experimentally the synaptic pruning theory for schizophrenia. An integrative strategy of brain imaging and cell biology may be a promising approach to address a key biological question for mental illnesses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
275J. Neurosci. 2011 Nov 31: 16194-207
PMID22072671
TitleDeletion of densin-180 results in abnormal behaviors associated with mental illness and reduces mGluR5 and DISC1 in the postsynaptic density fraction.
AbstractDensin is an abundant scaffold protein in the postsynaptic density (PSD) that forms a high-affinity complex with ?CaMKII and ?-actinin. To assess the function of densin, we created a mouse line with a null mutation in the gene encoding it (LRRC7). Homozygous knock-out mice display a wide variety of abnormal behaviors that are often considered endophenotypes of schizophrenia and autism spectrum disorders. At the cellular level, loss of densin results in reduced levels of ?-actinin in the brain and selective reduction in the localization of mGluR5 and DISC1 in the PSD fraction, whereas the amounts of ionotropic glutamate receptors and other prominent PSD proteins are unchanged. In addition, deletion of densin results in impairment of mGluR- and NMDA receptor-dependent forms of long-term depression, alters the early dynamics of regulation of CaMKII by NMDA-type glutamate receptors, and produces a change in spine morphology. These results indicate that densin influences the function of mGluRs and CaMKII at synapses and contributes to localization of mGluR5 and DISC1 in the PSD fraction. They are consistent with the hypothesis that mutations that disrupt the organization and/or dynamics of postsynaptic signaling complexes in excitatory synapses can cause behavioral endophenotypes of mental illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
276Hum. Mol. Genet. 2011 Dec 20: 4666-83
PMID21903668
TitleBehavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse.
AbstractDisrupted-In-schizophrenia 1 (DISC1) is a promising candidate gene for susceptibility to psychiatric disorders, including schizophrenia. DISC1 appears to be involved in neurogenesis, neuronal migration, axon/dendrite formation and synapse formation; during these processes, DISC1 acts as a scaffold protein by interacting with various partners. However, the lack of DISC1 knockout mice and a well-characterized antibody to DISC1 has made it difficult to determine the exact role of DISC1 in vivo. In this study, we generated mice lacking exons 2 and 3 of the DISC1 gene and prepared specific antibodies to the N- and C-termini of DISC1. The DISC1 mutant mice are viable and fertile, and no gross phenotypes, such as disorganization of the brain's cytoarchitecture, were observed. Western blot analysis revealed that the DISC1-specific antibodies recognize a protein with an apparent molecular mass of ~100 kDa in brain extracts from wild-type mice but not in brain extracts from DISC1 mutant mice. Immunochemical studies demonstrated that DISC1 is mainly localized to the vicinity of the Golgi apparatus in hippocampal neurons and astrocytes. A deficiency of full-length DISC1 induced a threshold shift in the induction of long-term potentiation in the dentate gyrus. The DISC1 mutant mice displayed abnormal emotional behavior as assessed by the elevated plus-maze and cliff-avoidance tests, thereby suggesting that a deficiency of full-length DISC1 may result in lower anxiety and/or higher impulsivity. Based on these results, we suggest that full-length DISC1-deficient mice and DISC1-specific antibodies are powerful tools for dissecting the pathophysiological functions of DISC1.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
277Nihon 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, schizophrenias
278Biol. Pharm. Bull. 2011 -1 34: 1364-8
PMID21881218
TitleAnimal model for schizophrenia that reflects gene-environment interactions.
Abstractschizophrenia is a devastating psychiatric disorder that impairs mental and social functioning and affects approximately 1% of the population worldwide. Genetic susceptibility factors for schizophrenia have recently been reported, some of which are known to play a role in neurodevelopment; these include neuregulin-1, dysbindin, and disrupted-in-schizophrenia 1 (DISC1). Moreover, epidemiologic studies suggest that environmental insults, such as prenatal infection and perinatal complication, are involved in the development of schizophrenia. The possible interaction between environment and genetic susceptibility factors, especially during neurodevelopment, is proposed as a promising disease etiology of schizophrenia. Polyriboinosinic-polyribocytidilic acid (polyI : C) is a synthetic analogue of double-stranded RNA that leads to the pronounced but time-limited production of pro-inflammatory cytokines. Maternal immune activation by polyI : C exposure in rodents is known to precipitate a wide spectrum of behavioral, cognitive, and pharmacological abnormalities in adult offspring. Recently, we have reported that neonatal injection of polyI : C in mice results in schizophrenia-like behavioral alterations in adulthood. In this review, we show how gene-environment interactions during neurodevelopment result in phenotypic changes in adulthood by injecting polyI : C into transgenic mice that express a dominant-negative form of human DISC1 (DN-DISC1). Our findings suggest that polyI : C-treated DN-DISC1 mice are a well-validated animal model for schizophrenia that reflects gene-environment interactions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
279Psychiatry Res 2011 Apr 192: 20-8
PMID21376542
TitleThe effects of DISC1 risk variants on brain activation in controls, patients with bipolar disorder and patients with schizophrenia.
AbstractThree risk variants (rs1538979, rs821577, and rs821633) in the Disrupted-in-schizophrenia-1 (DISC1) gene have previously been associated with both schizophrenia and bipolar disorder in a recent collaborative analysis of European cohorts. In this study we examined the effects of these risk variants on brain activation during functional magnetic resonance imaging (fMRI) of the Hayling Sentence Completion Task (HSCT) in healthy volunteers (n=33), patients with schizophrenia (n=20) and patients with bipolar disorder (n=36). In the healthy controls the risk associated allele carriers of SNPs rs1538979 and rs821633 demonstrated decreased activation of the cuneus. Moreover, there was an effect of SNP rs1538979 in the pre/postcentral gyrus with decreased activation in healthy controls and increased activation in patients with schizophrenia. In the bipolar group there was decreased activation in the risk carriers of SNP rs821633 in the inferior parietal lobule and left cingulate cortex. Clusters in the precentral gyrus, left middle temporal gyrus and left cerebellum were found to be significant on examining the group genotype interactions. These findings may provide a better understanding of the neural effects of DISC1 variants and on the pathophysiology of schizophrenia and bipolar disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
280Behav. Brain Res. 2011 Nov 225: 305-10
PMID21835207
TitleEffects of antipsychotics on the behavioral deficits in human dominant-negative DISC1 transgenic mice with neonatal polyI:C treatment.
AbstractInteractions of environmental and genetic factors may play a role in the pathoetiology of schizophrenia. We have recently developed a novel animal model of mental disorders such as schizophrenia by inducing abnormal immune response during the perinatal period in mice with overexpression of the human dominant-negative form of disrupted-in-schizophrenia 1 (DN-DISC1). In the present study, we investigated the effects of antipsychotics on the behavioral deficits in this animal model for mental disorders with gene-environment interaction. Neonatal DN-DISC1 transgenic (DN-DISC1 tg) mice were repeatedly injected with polyriboinosinic-polyribocytidylic acid (polyI:C) for 5 days from postnatal days 2 to 6. The behavioral analyses were performed in adulthood. Clozapine (3mg/kg) or haloperidol (1mg/kg) was administered orally once a day from 1 week before starting a series of behavioral experiments and continued until the end of the study. Cognitive impairment in polyI:C-treated DN-DISC1 tg mice was improved by repeated administration of clozapine while haloperidol had no effect. Both antipsychotics suppressed the augmentation of MK-801-induced hyperactivity in the model mice. Neither clozapine nor haloperidol ameliorated the impairments of social behaviors in polyI:C-treated DN-DISC1 tg mice. These results suggest that the polyI:C-treated DN-DISC tg mice are quite unique as an animal model for mental disorders. Furthermore, this mouse model may be useful for the screening of potential antipsychotic compounds that could be more effective than clozapine in ameliorating negative symptoms and cognitive impairment in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
281Psychiatr. Genet. 2011 Feb 21: 42-6
PMID21222298
TitleLimited association between Disrupted in Schizophrenia 1 (DISC1) gene and bipolar disorder in the Chinese population.
AbstractBipolar disorder is a common, severe, and recurrent psychiatric disorder. The Disrupted in schizophrenia 1 (DISC1) gene has been associated with the risk of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism, and Asperger syndrome in different populations. Here, we report the first association study for the DISC1 with bipolar disorder in Chinese cohorts.
We conducted a case-control study and genotyped 12 single nucleotide polymorphisms in 506 bipolar patients and 507 controls recruited from Anhui province in China. The genotyping procedure was carried on the ABI 7900 DNA detection platform by using TaqMan probe technology.
Although the data did not show association between any individual single nucleotide polymorphism in the DISC1 gene and bipolar disorder, a haplotype [rs2738864 (C)-rs16841582 (C)] was found to be associated with the disorder (P = 0.0191).
This finding provides evidence supporting the role of DISC1 gene in bipolar disorder, and shows the presence of population heterogeneity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
282FASEB J. 2011 Dec 25: 4184-97
PMID21859895
TitleDisc1 regulates both ?-catenin-mediated and noncanonical Wnt signaling during vertebrate embryogenesis.
AbstractDISC1 is a schizophrenia risk gene that engages multiple signaling pathways during neurogenesis and brain development. Using the zebrafish as a tool, we analyze the function of zebrafish DISC1 (zDISC1) at the earliest stages of brain and body development. We define a "tool" as a biological system that gives insight into mechanisms underlying a human disorder, although the system does not phenocopy the disorder. A zDISC1 peptide binds to GSK3?, and zDISC1 directs early brain development and neurogenesis, by promoting ?-catenin-mediated Wnt signaling and inhibiting GSK3? activity. zDISC1 loss-of-function embryos additionally display a convergence and extension phenotype, demonstrated by abnormal movement of dorsolateral cells during gastrulation, through changes in gene expression, and later through formation of abnormal, U-shaped muscle segments, and a truncated tail. These phenotypes are caused by alterations in the noncanonical Wnt pathway, via Daam and Rho signaling. The convergence and extension phenotype can be rescued by a dominant negative GSK3? construct, suggesting that zDISC1 inhibits GSK3? activity during noncanonical Wnt signaling. This is the first demonstration that DISC1 modulates the noncanonical Wnt pathway and suggests a previously unconsidered mechanism by which DISC1 may contribute to the etiology of neuropsychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
283Hum. Mol. Genet. 2011 Oct 20: R175-81
PMID21852244
TitleStructure and evolutionary history of DISC1.
AbstractEvolutionary and protein structural analyses can provide functional insights into genes implicated in human psychiatric diseases. Even eukaryotic organisms lacking nervous systems contain homologues of many key signalling molecules of animal neurons implying that human cognition derives, in part, from modifications of ancestral molecules and complexes. One protein whose evolutionary origin is obscure is DISC1 (disrupted in schizophrenia 1) whose gene locus has been associated with many psychiatric conditions including schizophrenia, clinical depression and bipolar disorder. This protein's rapid evolution and its unusual amino acid and ?-helix composition have hindered searches for DISC1 homologues in species other than vertebrates. Here, we review the evolution and structure of the DISC1 protein in the light of in-depth sequence analyses. These predict DISC1 orthologues in diverse eukaryotic organisms, including early-branching animals such as amphioxus, sea anemone, amoebas and Trichoplax, and in plants and algae. DISC1 thus is widespread among eukaryotes, although it remains absent from fungi, nematodes and Diptera, including fruit flies. These observations now permit studies of DISC1 function in simple non-vertebrate model organisms. Surprisingly, these analyses also identify between two and four sequence repeats in DISC1 orthologues. The first two of these repeats show significant sequence similarity to the UVR family of globular domains. These UVR-like repeats are predicted to contain, not coiled coil structures, but rather two closely associated antiparallel ?-helices. One common missense variant in DISC1 (L607F) lies within the second DISC1 UVR-like domain. These observations should assist in delineating the functional regions of the DISC1 protein.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
284Pharmacogenomics J. 2011 Aug 11: 267-73
PMID20531374
TitleAssociation of Disrupted in Schizophrenia 1 (DISC1) missense variants with ultra-resistant schizophrenia.
AbstractThree common missense variants of the Disrupted in schizophrenia 1 (DISC1) gene, rs3738401 (Q264R), rs6675281 (L607F) and rs821616 (S704C), have been variably associated with the risk of schizophrenia. In a case-control study, we examine whether these gene variants are associated with schizophrenia and ultra-resistant schizophrenia (URS) in a population of French Caucasian patients. The URS phenotype is characterized according to stringent criteria as patients who experience no clinical, social and/or occupational remission in spite of treatment with clozapine and at least two periods of treatment with distinct conventional or atypical antipsychotic drugs. We find a significant association between DISC1 missense variants and URS. The association with rs3738401 remains significant after appropriate correction for multiple testing. These results suggest that the DISC1 rs3738401 missense variant is statistically linked with ultra-resistance to antipsychotic treatment.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
285Transl Biomed 2011 -1 2: -1
PMID22319686
TitleElevated DISC1 transcript levels in PBMCs during acute psychosis in patients with schizophrenia.
AbstractBACKGROUND: Severe mental disorders like schizophrenia are a leading cause of disability in people in the prime years of their lives (aged 15 to 44 years). Relapse is a primary contributor to schizophrenia disease burden and is frequently attributed to medication noncompliance and inadequate doses. Currently, a patient's neuroleptic dose is titrated to clinical response within recommended dose ranges. Use of unbiased biomarkers of effective neuroleptic treatment-response would greatly facilitate the identification of a person's lowest effective dose to minimize unsafe side effects and improve compliance. Biomarkers may allow precisely tailored adjustments of neuroleptic dose to reduce relapse due to variable disease course. METHODS AND FINDINGS: Biomarkers of active psychosis were sought among persons with schizophrenia hospitalized with acute psychosis. The transcriptional response of peripheral blood mononuclear cells (PBMCs) to treatment of psychosis was measured using RNA expression profiling in 12-paired samples from patients with schizophrenia. The paired samples were collected early after treatment initiation and again just before patients were released from the hospital. Patients showed significant improvement in positive symptoms of psychosis assessed at each sample collection using a brief psychiatric rating scale (BPRS) (P<0.05). Preliminary evidence is presented indicating that decreased transcript levels of isoforms of disrupted in schizophrenia 1 (DISC1) measured in PBMCs were associated with treatment in 91% of samples (P=0.037). CONCLUSION: Further studies are warranted to identify neuroleptic-response biomarkers and to replicate this initial finding of association of DISC1 transcript levels with treatment of psychosis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
286Hum. Mol. Genet. 2011 Jul 20: 2834-45
PMID21540240
TitleDisrupted-in-Schizophrenia-1 (Disc1) is necessary for migration of the pyramidal neurons during mouse hippocampal development.
AbstractThe hippocampus has a highly ordered structure and is composed of distinct layers. Neuronal migration is an essential part of the process of the layer formation because neurons are primarily generated near the ventricle and must migrate to arrive at their final locations during brain development. Impairment of brain development is thought to underlie the etiology of psychiatric disorders. Consistent with this idea, many genetic risk factors for psychiatric disorders play critical roles during brain development. As one example, Disrupted-in-schizophrenia-1 (DISC1) is a genetic risk factor for major psychiatric disorders and plays various roles during neurodevelopment. To examine the role of DISC1 in the hippocampal development, we suppressed expression of DISC1 in the CA1 region of the developing mouse hippocampus by using the RNA interference (RNAi) technology and an in utero electroporation system. DISC1 suppression was found to impair migration of the CA1 pyramidal neurons. This effect was especially apparent while the majority of the transfected neurons were passing through the stratum pyramidale of the developing hippocampus. The migration of neurons was restored by expression of an RNAi-resistant wild-type mouse DISC1, indicating that the migration defect was caused by specific suppression of DISC1. In the mature hippocampus, the migration defect resulted in malposition and disarray of the pyramidal neurons. These findings indicate that DISC1 is required for migration and layer formation by the CA1 pyramidal neurons during hippocampal development.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
287Biochem. J. 2011 May 435: 755-69
PMID21323643
TitlePhosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation.
AbstractcAMP-specific PDE (phosphodiesterase) 4 isoforms underpin compartmentalized cAMP signalling in mammalian cells through targeting to specific signalling complexes. Their importance is apparent as PDE4 selective inhibitors exert profound anti-inflammatory effects and act as cognitive enhancers. The p38 MAPK (mitogen-activated protein kinase) signalling cascade is a key signal transduction pathway involved in the control of cellular immune, inflammatory and stress responses. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP. Such reprogramming of cAMP accumulation is recapitulated in wild-type primary macrophages, but not MK2/3-null macrophages. Phosphorylation by MK2 also triggers a conformational change in PDE4A5 that attenuates PDE4A5 interaction with proteins whose binding involves UCR2, such as DISC1 (disrupted in schizophrenia 1) and AIP (aryl hydrocarbon receptor-interacting protein), but not the UCR2-independent interacting scaffold protein ?-arrestin. Long PDE4 isoforms thus provide a novel node for cross-talk between the cAMP and p38 MAPK signalling systems at the level of MK2.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
288Transl Psychiatry 2011 -1 1: e22
PMID22832524
TitleAssociation of VSNL1 with schizophrenia, frontal cortical function, and biological significance for its gene product as a modulator of cAMP levels and neuronal morphology.
AbstractWe report an association of single-nucleotide polymorphisms (SNPs) for the VSNL1 gene (visinin-like 1) with schizophrenia and frontal cortical function in a sample of patients with Diagnostic and Statistical Manual of Mental Disorder-IV (DSM-IV) diagnoses of schizophrenia, compared with healthy controls. Moreover, VSNL1 SNPs were associated with performance in the Wisconsin Card Sorting Test, a measure for the assessment of frontal cortical function. The VSNL1 gene product, Visinin-like-protein-1 (VILIP-1), is a member of the neuronal EF-hand Ca(2+)-sensor protein family. Previously, VILIP-1 mRNA and protein expression were shown to be altered in animal models and in schizophrenia patients. VILIP-1 influences cytosolic cyclic adenosine mono phosphate (cAMP) levels, cell migration, exocytotic processes and differentiation in the periphery. This raises the question, whether, similar to other potential schizophrenia susceptibility genes such as DISC1, PDE4B and Akt, VSNL1 may affect cAMP signaling and neurite outgrowth in neurons. In dissociated rat hippocampal neurons, VILIP-1 small interfering RNA knockdown decreased cAMP levels and reduced dendrite branching, compared with control-transfected cells. In contrast, VILIP-1 overexpression had the opposite effect. Similar results have been obtained in the human dopaminergic neuronal cell line SH-SY5Y, where the effect on neurite branching and length was attenuated by the adenylyl cyclase inhibitor 2',5'-dideoxyadenosine and the protein kinase A inhibitor KT5720. These results show that the association of VSNL1 SNPs with the disease and cognitive impairments, together with previously observed pathological changes in VILIP-1 protein expression, possibly occurring during brain development, may contribute to the morphological and functional deficits observed in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
289Mol. Cell. Neurosci. 2011 Jun 47: 93-9
PMID21440632
TitleKnockdown of mental disorder susceptibility genes disrupts neuronal network physiology in vitro.
Abstractschizophrenia and bipolar disorder are common diseases caused by multiple genes that disrupt brain circuits. While great progress has been made in identifying schizophrenia susceptibility genes, these studies have left two major unanswered mechanistic questions: is there a core biochemical mechanism that these genes regulate, and what are the electrophysiological consequences of the altered gene expression? Because clinical studies implicate abnormalities in neuronal networks, we developed a system for studying the neurophysiology of neuronal networks in vitro where the role of candidate disease genes can be rapidly assayed. Using this system we focused on three postsynaptic proteins DISC1, TNIK and PSD-93/DLG2 each of which is encoded by a schizophrenia susceptibility gene. We also examined the utility of this assay system in bipolar disorder (BD), which has a strong genetic overlap with schizophrenia, by examining the bipolar disorder susceptibility gene Dctn5. The global neuronal network firing behavior of primary cultures of mouse hippocampus neurons was examined on multi-electrode arrays (MEAs) and genes of interest were knocked down using RNAi interference. Measurement of multiple neural network parameters demonstrated phenotypes for these genes compared with controls. Moreover, the different genes disrupted network properties and showed distinct and overlapping effects. These data show multiple susceptibility genes for complex psychiatric disorders, regulate neural network physiology and demonstrate a new assay system with wide application.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
290Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Mar 156: 204-14
PMID21302349
TitleInherited balanced translocation t(9;17)(q33.2;q25.3) concomitant with a 16p13.1 duplication in a patient with schizophrenia.
AbstractWe report two rare genetic aberrations in a schizophrenia patient that may act together to confer disease susceptibility. A previously unreported balanced t(9;17)(q33.2;q25.3) translocation was observed in two schizophrenia-affected members of a small family with diverse psychiatric disorders. The proband also carried a 1.5?Mbp microduplication at 16p13.1 that could not be investigated in other family members. The duplication has been reported to predispose to schizophrenia, autism and mental retardation, with incomplete penetrance and variable expressivity. The t(9;17) (q33.2;q25.3) translocation breakpoint occurs within the open reading frames of KIAA1618 on 17q25.3, and TTLL11 (tyrosine tubulin ligase like 11) on 9q33.2, causing no change in the expression level of KIAA1618 but leading to loss of expression of one TTLL11 allele. TTLL11 belongs to a family of enzymes catalyzing polyglutamylation, an unusual neuron-specific post-translational modification of microtubule proteins, which modulates microtubule development and dynamics. The 16p13.1 duplication resulted in increased expression of NDE1, encoding a DISC1 protein partner mediating DISC1 functions in microtubule dynamics. We hypothesize that concomitant TTLL11-NDE1 deregulation may increase mutation load, among others, also on the DISC1 pathway, which could contribute to disease pathogenesis through multiple effects on neuronal development, synaptic plasticity, and neurotransmission. Our data illustrate the difficulties in interpreting the contribution of multiple potentially pathogenic changes likely to emerge in future next-generation sequencing studies, where access to extended families will be increasingly important.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
291Biochem. Biophys. Res. Commun. 2011 May 408: 707-12
PMID21539806
TitleWorking memory deficits in neuronal nitric oxide synthase knockout mice: potential impairments in prefrontal cortex mediated cognitive function.
AbstractNeuronal nitric oxide synthase (nNOS) forms nitric oxide (NO), which functions as a signaling molecule via S-nitrosylation of various proteins and regulation of soluble guanylate cyclase (cGC)/cyclic guanosine monophosphate (cGMP) pathway in the central nervous system. nNOS signaling regulates diverse cellular processes during brain development and molecular mechanisms required for higher brain function. Human genetics have identified nNOS and several downstream effectors of nNOS as risk genes for schizophrenia. Besides the disease itself, nNOS has also been associated with prefrontal cortical functioning, including cognition, of which disturbances are a core feature of schizophrenia. Although mice with genetic deletion of nNOS display various behavioral deficits, no studies have investigated prefrontal cortex-associated behaviors. Here, we report that nNOS knockout (KO) mice exhibit hyperactivity and impairments in contextual fear conditioning, results consistent with previous reports. nNOS KO mice also display mild impairments in object recognition memory. Most importantly, we report for the first time working memory deficits, potential impairments in prefrontal cortex mediated cognitive function in nNOS KO mice. Furthermore, we demonstrate Disrupted-in-schizophrenia 1 (DISC1), another genetic risk factor for schizophrenia that plays roles for cortical development and prefrontal cortex functioning, including working memory, is a novel protein binding partner of nNOS in the developing cerebral cortex. Of note, genetic deletion of nNOS appears to increase the binding of DISC1 to NDEL1, regulating neurite outgrowth as previously reported. These results suggest that nNOS KO mice are useful tools in studying the role of nNOS signaling in cortical development and prefrontal cortical functioning.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
292J. Neurochem. 2011 Jul 118: 34-44
PMID21517847
TitleNMDA receptor regulates migration of newly generated neurons in the adult hippocampus via Disrupted-In-Schizophrenia 1 (DISC1).
AbstractIn the mammalian brain, new neurons are continuously generated throughout life in the dentate gyrus (DG) of the hippocampus. Previous studies have established that newborn neurons migrate a short distance to be integrated into a pre-existing neuronal circuit in the hippocampus. How the migration of newborn neurons is governed by extracellular signals, however, has not been fully understood. Here, we report that NMDA receptor (NMDA-R)-mediated signaling is essential for the proper migration and positioning of newborn neurons in the DG. An intraperitoneal injection of the NMDA-R antagonists, memantine, or 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) into adult male mice caused the aberrant positioning of newborn neurons, resulting in the overextension of their migration in the DG. Interestingly, we revealed that the administration of NMDA-R antagonists leads to a decrease in the expression of Disrupted-In-schizophrenia 1 (DISC1), a candidate susceptibility gene for major psychiatric disorders such as schizophrenia, which is also known as a critical regulator of neuronal migration in the DG. Furthermore, the overextended migration of newborn neurons induced by the NMDA-R antagonists was significantly rescued by exogenous expression of DISC1. Collectively, these results suggest that the NMDA-R signaling pathway governs the migration of newborn neurons via the regulation of DISC1 expression in the DG.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
293Schizophr. Res. 2011 Jun 129: 74-9
PMID21498050
TitleGenetic inactivation of GSK3? rescues spine deficits in Disc1-L100P mutant mice.
AbstractDisrupted-in-schizophrenia 1 (DISC1), a strong candidate gene for schizophrenia and other mental disorders, regulates neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth and spine development. Glycogen synthase kinase-3 (GSK3) directly interacts with DISC1 and also plays a role in neurodevelopment. Recently, our group showed that the DISC1-L100P mutant protein has reduced interaction with both GSK3? and ?. Genetic and pharmacological inhibition of GSK3 activity rescued behavioral abnormalities in DISC1-L100P mutant mice. However, the cellular mechanisms mediating these effects of GSK3 inhibition in DISC1 mutant mice remain unclear. We sought to investigate the effects of genetic inactivation of GSK3? on frontal cortical neuron morphology in DISC1 L100P mutant mice using Golgi staining. We found a significant decrease in dendritic length and surface area in DISC1-L100P, GSK3? null and L100P/GSK3? double mutants. Dendritic spine density was significantly reduced only in DISC1-L100P and L100P/GSK3? +/- mice when compared to wild-type littermates. There was no difference in dendritic arborization between the various genotypes. No significant rescue in dendritic length and surface area was observed in L100P/GSK3? mutants versus L100P mice, but spine density in L100P/GSK3? mice was comparable to wild-type. Neurite outgrowth and spine development abnormalities induced by DISC1 mutation may be partially corrected through GSK3? inactivation, which also normalizes behavior. However, many of the other dendritic abnormalities in the DISC1-L100P mutant mice were not corrected by GSK3? inactivation, suggesting that only some of the anatomical defects have observable behavioral effects. These findings suggest novel treatment approaches for schizophrenia, and identify a histological read-out for testing other therapeutic interventions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
294Brain Res. 2011 May 1392: 47-53
PMID21458426
TitleImpairment of the tyrosine hydroxylase neuronal network in the orbitofrontal cortex of a genetically modified mouse model of schizophrenia.
AbstractImportant genes have been identified that are associated with susceptibility to schizophrenia. DISC1 is one of these candidate genes. The protein 14-3-3 epsilon is a DISC1-interacting molecule and is associated with axon elongation. The genetically modified 14-3-3 epsilon heterozygous knockout mice are considered to be an animal model of schizophrenia because they present endophenotypes of schizophrenia including working memory impairment. This study investigated the immunohistochemical expression of tyrosine hydroxylase (TH) to reveal the alterations in the functional structure of the axon elongation caused by the deficit of 14-3-3 epsilon. The study focused on the orbitofrontal cortex in the prefrontal cortex which is a region of interest in schizophrenia research. The investigation used eight 15-week-old knockout mice and six age-matched wild-type mice. The TH immunopositive fibers were linear and dense in the wild-type mice. These fibers were serpentine, thin and short in the knockout mice. Although it appeared that dendritic spine-like immunopositive varices were strung tightly in the fibers of wild-type mice, these were few and sparse in those of the of the knockout mice. Quantitative analysis showed a significant decrease in the total extent of the TH-immunopositive fibers in the orbital cortex of the knockout mouse. There is thought to be a dysfunction of a neurotransmitter such as dopamine and noradrenalin in the prefrontal cortex of these knockout mice.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
295Mol. Psychiatry 2011 Mar 16: 293-306
PMID20048751
TitleDifferential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disorders.
AbstractStrong genetic evidence implicates mutations and polymorphisms in the gene Disrupted-In-schizophrenia-1 (DISC1) as risk factors for both schizophrenia and mood disorders. Recent studies have shown that DISC1 has important functions in both brain development and adult brain function. We have described earlier a transgenic mouse model of inducible expression of mutant human DISC1 (hDISC1) that acts in a dominant-negative manner to induce the marked neurobehavioral abnormalities. To gain insight into the roles of DISC1 at various stages of neurodevelopment, we examined the effects of mutant hDISC1 expressed during (1) only prenatal period, (2) only postnatal period, or (3) both periods. All periods of expression similarly led to decreased levels of cortical dopamine (DA) and fewer parvalbumin-positive neurons in the cortex. Combined prenatal and postnatal expression produced increased aggression and enhanced response to psychostimulants in male mice along with increased linear density of dendritic spines on neurons of the dentate gyrus of the hippocampus, and lower levels of endogenous DISC1 and LIS1. Prenatal expression only resulted in smaller brain volume, whereas selective postnatal expression gave rise to decreased social behavior in male mice and depression-like responses in female mice as well as enlarged lateral ventricles and decreased DA content in the hippocampus of female mice, and decreased level of endogenous DISC1. Our data show that mutant hDISC1 exerts differential effects on neurobehavioral phenotypes, depending on the stage of development at which the protein is expressed. The multiple and diverse abnormalities detected in mutant DISC1 mice are reminiscent of findings in major mental diseases.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
296Transl Psychiatry 2011 -1 1: e30
PMID22832604
TitleInteractions of human truncated DISC1 proteins: implications for schizophrenia.
AbstractNumerous genetic linkage and association reports have implicated the Disrupted-in-schizophrenia (DISC1) gene in psychiatric illness. The Scottish family translocation, predicted to encode a C-terminus-truncated protein, suggests involvement of short isoforms in the pathophysiology of mental disorders. We recently reported complex alternative splicing patterns for the DISC1 gene and found that short isoforms are overexpressed in the brains of patients with schizophrenia and in carriers of risk-associated alleles. Investigation into the protein-protein interactions of alternative DISC1 isoforms may provide information about the functional consequences of overexpression of truncated forms in mental illness. Human embryonic kidney (HEK293) cells were transiently co-transfected with human epitope-tagged DISC1 variants and epitope-tagged NDEL1, FEZ1, GSK3? and PDE4B constructs. Co-immunoprecipitation assays demonstrated that all truncated DISC1 variants formed complexes with full-length DISC1. Short DISC1 splice variants L?78, L?3 and Esv1 showed reduced or no binding to NDEL1 and PDE4B proteins, but fully interacted with FEZ1 and GSK3?. The temporal expression pattern of GSK3? in the human postmortem tissue across the lifespan closely resembled that of the truncated DISC1 variants, suggesting the possibility of interactions between these proteins in the human brain. Our results suggest that complexes of full-length DISC1 with truncated DISC1 variants may result in cellular disturbances critical to DISC1 function.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
297Proc. Natl. Acad. Sci. U.S.A. 2011 Apr 108: 5861-6
PMID21422296
TitleDisrupted-in-Schizophrenia 1-mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling.
AbstractDefects in neuronal connectivity of the brain are well documented among schizophrenia patients. Although the schizophrenia susceptibility gene Disrupted-in-schizophrenia 1 (DISC1) has been implicated in various neurodevelopmental processes, its role in regulating axonal connections remains elusive. Here, a heterologous DISC1 transgenic system in the relatively simple and well-characterized Caenorhabditis elegans motor neurons has been established to investigate whether DISC1 regulates axon guidance during development. Transgenic DISC1 in C. elegans motor neurons is enriched in the migrating growth cones and causes guidance defects of their growing axons. The abnormal axonal phenotypes induced by DISC1 are similar to those by gain-of-function rac genes. In vivo genetic interaction studies revealed that the UNC-73/TRIO-RAC-PAK signaling pathway is activated by ectopic DISC1 in C. elegans motor axons. Using in vitro GST pull-down and coimmunoprecipitation assays, we found that DISC1 binds specifically to the amino half of spectrin repeats of TRIO, thereby preventing TRIO's amino half of spectrin repeats from interacting with its first guanine nucleotide exchange factor (GEF) domain, GEF1, and facilitating the recruitment of RAC1 to TRIO. In cultured mammalian cells, RAC1 is activated by increased TRIO's GEF activity when DISC1 is present. These results together indicate that the TRIO-RAC-PAK signaling pathway can be exploited and modulated by DISC1 to regulate axonal connectivity in the developing brain.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
298Behav Brain Funct 2011 -1 7: 14
PMID21569632
TitleEvidence for association between Disrupted-in-Schizophrenia 1 (DISC1) gene polymorphisms and autism in Chinese Han population: a family-based association study.
AbstractDisrupted-in-schizophrenia 1 (DISC1) gene is one of the most promising candidate genes for major mental disorders. In a previous study, a Finnish group demonstrated that DISC1 polymorphisms were associated with autism and Asperger syndrome. However, the results were not replicated in Korean population. To determine whether DISC1 is associated with autism in Chinese Han population, we performed a family-based association study between DISC1 polymorphisms and autism.
We genotyped seven tag single nucleotide polymorphisms (SNPs) in DISC1, spanning 338 kb, in 367 autism trios (singleton and their biological parents) including 1,101 individuals. Single SNP association and haplotype association analysis were performed using the family-based association test (FBAT) and Haploview software.
We found three SNPs showed significant associations with autism (rs4366301: G>C, Z=2.872, p=0.004; rs11585959: T>C, Z=2.199, p=0.028; rs6668845: A>G, Z=2.326, p=0.02). After the Bonferroni correction, SNP rs4366301, which located in the first intron of DISC1, remained significant. When haplotype were constructed with two-markers, three haplotypes displayed significant association with autism. These results were still significant after using the permutation method to obtain empirical p values.
Our study provided evidence that the DISC1 may be the susceptibility gene of autism. It suggested DISC1 might play a role in the pathogenesis of autism.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
299Schizophr Bull 2011 Jan 37: 14-20
PMID21149852
TitleDISC1 in schizophrenia: genetic mouse models and human genomic imaging.
Abstractschizophrenia and related disorders have a major genetic component. Several large-scale studies have uncovered a number of possible candidate genes, but these have yet to be consistently replicated and their underlying biological function remains elusive. One exception is 'Disrupted in schizophrenia 1' (DISC1), a gene locus originally identified in a large Scottish family, showing a heavy burden of major mental illnesses associated with a balanced t(1;11)(q42.1;q14.3) chromosome translocation. Substantial genetic and biological research on DISC1 has been reported in the intervening 10 years: DISC1 is now recognized as a genetic risk factor for a spectrum of psychiatric disorders and DISC1 impacts on many aspects of central nervous system (CNS) function, including neurodevelopment, neurosignaling, and synaptic functioning. Evidence has emerged from genetic studies showing a relationship between DISC1 and quantitative traits, including working memory, cognitive aging, gray matter volume in the prefrontal cortex, and abnormalities in hippocampal structures and function. DISC1 interacts with numerous proteins also involved in neuronal migration, neurite outgrowth, cytoskeletal modulation, and signal transduction, some of which have been reported as independent genetic susceptibility factors for psychiatric morbidity. Here, we focus on the growing literature relating genetic variation in the DISC1 pathway to functional and structural studies of the brain in humans and in the mouse.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
300Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Aug 35: 1618-22
PMID21683752
TitleLack of association between translin-associated factor X gene (TSNAX) and methamphetamine dependence in the Japanese population.
AbstractRecently, we detected that the prokineticin 2 receptor gene was associated with not only major depressive disorder (MDD) but also methamphetamine dependence. Therefore, it is possible that mood disorders and drug addiction have shared susceptibility genes. The translin-associated factor X gene (TSNAX)/disrupted-in-schizophrenia-1 gene (DISC1) has been associated with psychiatric disorders, including schizophrenia, MDD and bipolar disorder. TSNAX is located immediately upstream of DISC1 and has been shown to undergo intergenic splicing with DISC1. Based on this evidence, we hypothesized that TSNAX might be a good candidate gene for methamphetamine dependence.
We conducted a case-control study of Japanese individuals (215 with methamphetamine dependence and 318 age- and sex-matched controls) with three tagging SNPs (rs1630250, rs766288 and rs6662926) selected by HapMap database.
rs1630250 was associated in males with methamphetamine dependence in the allele analysis (P-value: 0.0253). However, these results did not remain significant after Bonferroni correction to adjust for multiple comparisons (corrected P-value: 0.152).
Our findings suggest that TSNAX does not play a role in methamphetamine dependence in the Japanese population. A replication study using larger samples needs to be conducted to obtain conclusive results.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
301Neuroimage 2011 Aug 57: 1591-600
PMID21642004
TitleDISC1 is associated with cortical thickness and neural efficiency.
AbstractDisrupted in schizophrenia 1 (DISC1) is known to play a major role during brain development and is a candidate gene for schizophrenia. Cortical thickness is highly heritable and several MRI studies have shown widespread reductions of cortical thickness in patients with schizophrenia. Here, we investigated the effects of variation in DISC1 on cortical thickness. In a subsequent analysis we tested whether the identified DISC1 risk variant is also associated with neural activity during working memory functioning.
We acquired structural MRI (sMRI), functional MRI (fMRI) and genotype data from 96 healthy volunteers. Separate cortical statistical maps for five single nucleotide polymorphisms (SNP) of DISC1 were generated to detect differences of cortical thickness in genotype groups across the entire cortical surface. Working-memory related load-dependent activation was measured during the Sternberg Item Recognition Paradigm and analyzed using a region-of-interest approach.
Phe allele carriers of the DISC1 SNP Leu607Phe had significantly reduced cortical thickness in the left supramarginal gyrus compared to Leu/Leu homozygotes. Neural activity in the left dorsolateral prefrontal cortex (DLPFC) during working memory task was increased in Phe allele carriers, whereas working memory performance did not differ between genotype groups.
This study provides convergent evidence for the effect of DISC1 risk variants on two independent brain-based intermediate phenotypes of schizophrenia. The same risk variant was associated with cortical thickness reductions and signs of neural inefficiency during a working memory task. Our findings provide further evidence for a neurodevelopmental model of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
302Biol. Psychiatry 2011 Oct 70: 604-10
PMID21531389
TitleConvergence of two independent mental disease genes on the protein level: recruitment of dysbindin to cell-invasive disrupted-in-schizophrenia 1 aggresomes.
AbstractBoth disrupted-in-schizophrenia 1 (DISC1) and dysbindin have been identified as schizophrenia candidate genes in independent genetic linkage studies. The proteins have been assigned distinct subcellular locations and functions. We investigated whether both proteins converge into a common pathway specific for schizophrenia or mental diseases.
DISC1 and dysbindin were expressed as recombinant proteins with or without a fluorescent protein-tag in human or mouse neuroblastoma cells and as recombinant proteins in E. coli. Postmortem brains of patients with mental diseases from the Stanley Research Medical Institute's Consortium Collection were used to demonstrate molecular interactions in biochemically purified protein fractions.
First, upon overexpression in neuroblastoma cells, DISC1 formed aggresomes that recruited homologous soluble C-terminal DISC1 fragment or heterologous dysbindin. Domains involved in binding could be mapped to DISC1 (316-597) and dysbindin (82-173), indicating a specific interaction. In addition, recruitment was demonstrated when externally added, purified DISC1 aggresomes penetrated recipient cells after coincubation. Second, a direct interaction between soluble DISC1 protein and dysbindin was demonstrated in a cell free system using E. coli-expressed proteins. Third, co-aggregation of DISC1 and dysbindin was demonstrated in postmortem brains for a subgroup of cases with chronic mental disease but not healthy control subjects.
A direct interaction of soluble and insoluble DISC1 protein with dysbindin protein demonstrates convergence of so far considered independent mental disease genes by direct molecular interaction. Our findings highlight protein aggregation and recruitment as a biological mechanism in mental disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
303Mol. Psychiatry 2011 Nov 16: 1096-104, 1063
PMID21483430
TitleImpact of DISC1 variation on neuroanatomical and neurocognitive phenotypes.
AbstractAlthough disrupted in schizophrenia 1 (DISC1) has been implicated in many psychiatric disorders, including schizophrenia, bipolar disorder, schizoaffective disorder and major depression, its biological role in these disorders is unclear. To better understand this gene and its role in psychiatric disease, we conducted transcriptional profiling and genome-wide association analysis in 1232 pedigreed Mexican-American individuals for whom we have neuroanatomic images, neurocognitive assessments and neuropsychiatric diagnoses. SOLAR was used to determine heritability, identify gene expression patterns and perform association analyses on 188 quantitative brain-related phenotypes. We found that the DISC1 transcript is highly heritable (h(2)=0.50; P=1.97 10(-22)), and that gene expression is strongly cis-regulated (cis-LOD=3.89) but is also influenced by trans-effects. We identified several DISC1 polymorphisms that were associated with cortical gray matter thickness within the parietal, temporal and frontal lobes. Associated regions affiliated with memory included the entorhinal cortex (rs821639, P=4.11 10(-5); rs2356606, P=4.71 10(-4)), cingulate cortex (rs16856322, P=2.88 10(-4)) and parahippocampal gyrus (rs821639, P=4.95 10(-4)); those affiliated with executive and other cognitive processing included the transverse temporal gyrus (rs9661837, P=5.21 10(-4); rs17773946, P=6.23 10(-4)), anterior cingulate cortex (rs2487453, P=4.79 10(-4); rs3738401, P=5.43 10(-4)) and medial orbitofrontal cortex (rs9661837; P=7.40 10(-4)). Cognitive measures of working memory (rs2793094, P=3.38 10(-4)), as well as lifetime history of depression (rs4658966, P=4.33 10(-4); rs12137417, P=4.93 10(-4)) and panic (rs12137417, P=7.41 10(-4)) were associated with DISC1 sequence variation. DISC1 has well-defined genetic regulation and clearly influences important phenotypes related to psychiatric disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
304Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Mar 35: 636-9
PMID21256178
TitleAssociation study between Disrupted-in-Schizophrenia-1 (DISC1) and Japanese patients with treatment-resistant schizophrenia (TRS).
AbstractTreating the 20-30% of patients with schizophrenia whose symptoms are resistant to antipsychotic treatment, a condition known as treatment-resistant schizophrenia (TRS), can be problematic. Recently, an association between Disrupted-in-schizophrenia-1 (DISC1), a candidate susceptibility gene for schizophrenia, and TRS was reported. Associations between three missense SNPs, rs3738401 (Q264R), rs6675281 (L607F), and rs821616 (S704C) in DISC1, especially rs3738401, showed strong significance. Thus, the main aim of our current study was to examine if the reported possible functional polymorphisms in DISC1 were related to Japanese TRS. First, DISC1 was re-investigated in 485 Japanese patients with schizophrenia and 660 healthy controls with a case-control study using four candidate SNPs, rs751229, rs3738401, rs821597, and rs821616. DISC1 was not associated with schizophrenia in the Japanese population. Second, we investigated whether these SNPs contributed to TRS in 127 inpatients with schizophrenia (35 patients; TRS and 92 patients; non-TRS). The genotypic distributions of these four SNPs were not significantly different between TRS and non-TRS in either genotypic or recessive models of minor alleles. In addition, clinical variables, such as improvement in clinical symptoms, duration of hospitalization, and total antipsychotics dose amounts, were not different among the genotypes of these SNPs. Taken together, results showed that DISC1 had no apparent degree of association with Japanese patients with schizophrenia as a candidate susceptibility gene for disease per se or TRS.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
305Schizophr Bull 2011 Jul 37: 674-80
PMID21097511
TitleAlterations in postnatal neurogenesis and dopamine dysregulation in schizophrenia: a hypothesis.
AbstractAn increasing number of studies demonstrate the important role of several susceptibility genes for schizophrenia, such as neuregulin-1 and DISC1, in early postnatal and adult neurogenesis. Its significance for the pathophysiology of the disease, including its relation to neurotransmitter systems implicated in schizophrenia (like the dopamine system), remains, however, unknown. Here, we review molecular and cellular components of the dopamine system associated with postnatal neurogenesis and plasticity, both in rodents and in primates, and discuss their possible implication in schizophrenia. We focus mainly on the islands of Calleja, complex aggregations of granule cells in the ventral striatum, generated early postnatally in the subventricular zone. In contrast to the involution of the primate olfactory bulb, the islands of Calleja attain their maximal development in humans, an evolution paralleled by a larger ventral subventricular zone and more connections with other structures, including temporal cortical areas. The islands of Calleja express high levels of neuronal nitric oxide (NO) synthase and D3 dopamine receptors and are densely interconnected by dopaminergic projections with the ventral tegmental area. D3 receptors modulate subventricular zone neurogenesis and dopamine release. Their genetic deletion induces striatal hyperdopaminergia. We review data indicating a high plasticity of postnatal islands of Calleja, potentially facilitating susceptibility to schizophrenia-related risk factors. In this context, we propose a new pathophysiological model, where altered neurogenesis of the islands of Calleja may contribute to dysfunction of the dopamine and NO systems and psychosis through convergence of genetic and environmental disease-associated factors.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
306Genes Brain Behav. 2011 Apr 10: 276-85
PMID21091867
TitleNo association of Disrupted-in-Schizophrenia-1 variation with prefrontal function in patients with schizophrenia and bipolar disorder.
AbstractThe Disrupted-in-schizophrenia-1 (DISC1) gene has been implicated in both schizophrenia and bipolar disorder by linkage and genetic association studies. Altered prefrontal cortical function is a pathophysiological feature of both disorders, and we have recently shown that variation in DISC1 modulates prefrontal activation in healthy volunteers. Our goal was to examine the influence of the DISC1 polymorphism Cys704Ser on prefrontal function in schizophrenia and bipolar disorder. From 2004 to 2008, patients with schizophrenia (N = 44), patients with bipolar disorder (N = 35) and healthy volunteers (N = 53) were studied using functional magnetic resonance imaging while performing a verbal fluency task. The effect of Cys704Ser on cortical activation was compared between groups as Cys704 carriers vs. Ser704 homozygotes. In contrast to the significant effect on prefrontal activation we had previously found in healthy subjects, no significant effect of Cys704Ser was detected in this or any other region in either the schizophrenia or bipolar groups. When controls were compared with patients with schizophrenia, there was a diagnosis by genotype interaction in the left middle/superior frontal gyrus [family-wise error (FWE) P = 0.002]. In this region, Ser704/ser704 controls activated more than Cys704 carriers, and there was a trend in the opposite direction in schizophrenia patients. In contrast to its effect in healthy subjects, variation in DISC1 Cys704Ser704 genotype was not associated with altered prefrontal activation in patients with schizophrenia or bipolar disorder. The absence of an effect in patients may reflect interactions of the effects of DISC1 genotype with the effects of other genes associated with these disorders, and/or with the effects of the disorders on brain function.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
307Mol. Psychiatry 2011 Sep 16: 917-26
PMID20628343
TitleCommon functional polymorphisms of DISC1 and cortical maturation in typically developing children and adolescents.
AbstractDisrupted-in-schizophrenia-1 (DISC1), contains two common non-synonymous single-nucleotide polymorphisms (SNPs)--Leu607Phe and Ser704Cys--that modulate (i) facets of DISC1 molecular functioning important for cortical development, (ii) fronto-temporal cortical anatomy in adults and (iii) risk for diverse psychiatric phenotypes that often emerge during childhood and adolescence, and are associated with altered fronto-temporal cortical development. It remains unknown, however, if Leu607Phe and Ser704Cys influence cortical maturation before adulthood, and whether each SNP shows unique or overlapping effects. Therefore, we related genotype at Leu607Phe and Ser704Cys to cortical thickness (CT) in 255 typically developing individuals aged 9-22 years on whom 598 magnetic resonance imaging brain scans had been acquired longitudinally. Rate of cortical thinning varied with DISC1 genotype. Specifically, the rate of cortical thinning was attenuated in Phe-carrier compared with Leu-homozygous groups (in bilateral superior frontal and left angular gyri) and accelerated in Ser-homozygous compared with Cys-carrier groups (in left anterior cingulate and temporal cortices). Both SNPs additively predicted fixed differences in right lateral temporal CT, which were maximal between Phe-carrier/Ser-homozygous (thinnest) vs Leu-homozygous/Cys-carrier (thickest) groups. Leu607Phe and Ser704Cys genotype interacted to predict the rate of cortical thinning in right orbitofrontal, middle temporal and superior parietal cortices, wherein a significantly reduced rate of CT loss was observed in Phe-carrier/Cys-carrier participants only. Our findings argue for further examination of Leu607Phe and Ser704Cys interactions at a molecular level, and suggest that these SNPs might operate (in concert with other genetic and environmental factors) to shape risk for diverse phenotypes by impacting on the early maturation of fronto-temporal cortices.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
308Nihon 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, schizophrenias
309J. Hum. Genet. 2012 Aug 57: 475-6
PMID22763722
TitleA commentary on the gender-specific association of TSNAX/DISC1 locus for schizophrenia and bipolar affective disorder in South Indian population.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
310Schizophr. Res. 2012 Nov 141: 271-3
PMID22901592
TitleMeta-analysis of association studies between DISC1 missense variants and schizophrenia in the Japanese population.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
311Integr Biol (Camb) 2012 Sep 4: 1096-101
PMID22777684
TitleThe severity of mental disorders is linked to interaction among candidate genes.
AbstractThere is a considerable overlap in the manifestation of symptoms in three mental disorders namely unipolar disorder, bipolar disorder and schizophrenia. A gene coexpression network was developed based on a mutual information approach including four candidate genes (NRG1, DISC1, BDNF and COMT) along with other coexpressing genes in unipolar disorder, bipolar disorder and schizophrenia. There is a significant difference in the degree distribution of nodes between normal and bipolar disorder network and bipolar disorder network and schizophrenia network. Moreover, there is a differential direct connectivity among candidate genes in various mental disorders and between normal and mental disorders. All candidate genes are directly connected to each other in schizophrenia except one pair (NRG1-BDNF) indicating a strong role of inter-gene interactions in the manifestation of severe symptoms in this disease. DISC1 and NRG1 are key hub genes in the unipolar disorder network and the bipolar disorder network but have lost the role of hub genes in schizophrenia network, despite their significant association with schizophrenia. This study indicates that the three psychiatric diseases may not have discrete classes but three phenotypic manifestations of the same continuous disease based on severity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
312Cell 2012 Mar 148: 1051-64
PMID22385968
TitleInterplay between DISC1 and GABA signaling regulates neurogenesis in mice and risk for schizophrenia.
AbstractHow extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn neurons by Disrupted-in-schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early-postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization or maternal deprivation stress restores DISC1-dependent dendritic regulation through mTOR pathway during early-postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
313PLoS ONE 2012 -1 7: e51562
PMID23272119
TitleProphylactic valproic acid treatment prevents schizophrenia-related behaviour in Disc1-L100P mutant mice.
Abstractschizophrenia is a neurodevelopmental disorder with onset early in adulthood. Disrupted-In-schizophrenia-1 (DISC1) is a susceptibility gene for schizophrenia and other psychiatric disorders. DISC1-L100P mutant mice show behaviors relevant to schizophrenia at 12 weeks, but not at 8 weeks of age, and may be useful for investigating the onset of schizophrenia in early adulthood.
We investigated whether early valproic acid treatment would prevent behavioral, cellular and gene expression abnormalities in DISC1-L100P mutants.
Valproic acid prevented hyperactivity and deficits in prepulse inhibition and latent inhibition in DISC1-L100P mice. Genome-wide transcription profiling identified Lcn2 (lipocalin2) transcripts as being elevated by the DISC1 mutation and corrected by valproate. DISC1-L100P mice also had increased glial cell numbers in the subventricular zone, which was normalized by valproate. Genetic deletion of Lcn2 normalized glial cell numbers and behavior in DISC1-L100P mutants.
Pharmacological treatments are a feasible way of preventing abnormal behaviour in a genetic model of schizophrenia. Lcn2 is a potential novel drug target for early intervention in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
314Hum. Genet. 2012 Jul 131: 1047-56
PMID22160351
TitleAssociation of PDE4B polymorphisms and schizophrenia in Northwestern Han Chinese.
AbstractThe phosphodiesterase 4B (PDE4B) is a candidate susceptibility gene for schizophrenia (SCZ), interacting with DISC1, a known genetic risk factor for SCZ. To examine if variants within PDE4B gene are associated with SCZ in Northwestern Han Chinese, and if these effects vary in gender-specific subgroup, we analyzed 20 SNPs, selected from previous studies and preliminary HapMap data analyses with minor allele frequency (MAF) ? 20%, in a cohort of 428 cases and 572 controls from genetically independent Northwestern Han Chinese. Single SNP association, haplotype association and sex-specific association analysis were performed. We found that rs472952 is significantly associated with SCZ and rs7537440 is associated with SCZ in females. Further analysis indicated that a haplotype block spanning PDE4B2 splice site is highly associated with SCZ and several haplotypes in this block have about twofold to threefold increase in cases. Our results provide further evidence that PDE4B may play important roles in the etiology of SCZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
315Behav. Brain Res. 2012 Aug 233: 337-44
PMID22659396
TitleSocial defeat interacts with Disc1 mutations in the mouse to affect behavior.
AbstractDISC1 (Disrupted-in-schizophrenia 1) is a strong candidate susceptibility gene for psychiatric disease that was originally discovered in a family with a chromosomal translocation severing this gene. Although the family members with the translocation had an identical genetic mutation, their clinical diagnosis and presentation varied significantly. Gene-environment interactions have been proposed as a mechanism underlying the complex heritability and variable phenotype of psychiatric disorders such as major depressive disorder and schizophrenia. We hypothesized that gene-environment interactions would affect behavior in a mutant DISC1 mouse model. We examined the effect of chronic social defeat (CSD) as an environmental stressor in two lines of mice carrying different DISC1 point mutations, on behaviors relevant to psychiatric illness: locomotion in a novel open field (OF), pre-pulse inhibition (PPI) of the acoustic startle response, latent inhibition (LI), elevated plus maze (EPM), forced swim test (FST), sucrose consumption (SC), and the social interaction task for sociability and social novelty (SSN). We found that DISC1-L100P +/- and wild-type mice have similar anxiety responses to CSD, while Q31L +/- mice had a very different response. We also found evidence of significant gene-environment interactions in the OF, EPM and SSN.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
316J. Neurosci. 2012 Jan 32: 738-45
PMID22238109
TitleDisrupted-in-Schizophrenia 1 (DISC1) is necessary for the correct migration of cortical interneurons.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a prominent susceptibility gene for major psychiatric disorders. Previous work indicated that DISC1 plays an important role during neuronal proliferation and differentiation in the cerebral cortex and that it affects the positioning of radial migrating pyramidal neurons. Here we show that in mice, DISC1 is necessary for the migration of the cortical interneurons generated in the medial ganglionic eminence (MGE). RT-PCR, in situ hybridizations, and immunocytochemical data revealed expression of DISC1 transcripts and protein in MGE-derived cells. To study the possible functional role of DISC1 during tangential migration, we performed in utero and ex utero electroporation to suppress DISC1 in the MGE in vivo and in vitro. Results indicate that after DISC1 knockdown, the proportion of tangentially migrating MGE neurons that reached their cortical target was strongly reduced. In addition, there were profound alterations in the morphology of DISC1-deficient neurons, which exhibited longer and less branched leading processes than control cells. These findings provide a possible link between clinical studies reporting alterations of cortical interneurons in schizophrenic patients and the current notion of schizophrenia as a neurodevelopmental disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
317Mol. Psychiatry 2012 Apr 17: 451-66
PMID22124272
TitleNeurodevelopmental and neuropsychiatric behaviour defects arise from 14-3-3? deficiency.
AbstractComplex neuropsychiatric disorders are believed to arise from multiple synergistic deficiencies within connected biological networks controlling neuronal migration, axonal pathfinding and synapse formation. Here, we show that deletion of 14-3-3? causes neurodevelopmental anomalies similar to those seen in neuropsychiatric disorders such as schizophrenia, autism spectrum disorder and bipolar disorder. 14-3-3?-deficient mice displayed striking behavioural and cognitive deficiencies including a reduced capacity to learn and remember, hyperactivity and disrupted sensorimotor gating. These deficits are accompanied by subtle developmental abnormalities of the hippocampus that are underpinned by aberrant neuronal migration. Significantly, 14-3-3?-deficient mice exhibited abnormal mossy fibre navigation and glutamatergic synapse formation. The molecular basis of these defects involves the schizophrenia risk factor, DISC1, which interacts isoform specifically with 14-3-3?. Our data provide the first evidence of a direct role for 14-3-3? deficiency in the aetiology of neurodevelopmental disorders and identifies 14-3-3? as a central risk factor in the schizophrenia protein interaction network.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
318PLoS ONE 2012 -1 7: e36023
PMID22558309
TitleIntersectin (ITSN) family of scaffolds function as molecular hubs in protein interaction networks.
AbstractMembers of the intersectin (ITSN) family of scaffold proteins consist of multiple modular domains, each with distinct ligand preferences. Although ITSNs were initially implicated in the regulation of endocytosis, subsequent studies have revealed a more complex role for these scaffold proteins in regulation of additional biochemical pathways. In this study, we performed a high throughput yeast two-hybrid screen to identify additional pathways regulated by these scaffolds. Although several known ITSN binding partners were identified, we isolated more than 100 new targets for the two mammalian ITSN proteins, ITSN1 and ITSN2. We present the characterization of several of these new targets which implicate ITSNs in the regulation of the Rab and Arf GTPase pathways as well as regulation of the disrupted in schizophrenia 1 (DISC1) interactome. In addition, we demonstrate that ITSN proteins form homomeric and heteromeric complexes with each other revealing an added level of complexity in the function of these evolutionarily conserved scaffolds.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
319Hum. Mol. Genet. 2012 May 21: 2017-28
PMID22291444
TitleDisrupted in Schizophrenia 1 forms pathological aggresomes that disrupt its function in intracellular transport.
AbstractDisrupted in schizophrenia 1 (DISC1) is a key susceptibility gene implicated in major mental illnesses, such as schizophrenia, depression, bipolar disorder and autism, but the link between this protein and the pathology of these diseases remains unclear. Recently, DISC1 has been demonstrated to form insoluble protein aggregates in vitro and in human post-mortem brain tissue but the cellular dynamics of these DISC1 aggregates and their effects on neuronal function are unknown. Using a combination of biochemistry and live cell confocal and video microscopy, we characterize the properties of DISC1 aggregates and their effects on cellular function. We demonstrate that DISC1 protein aggregates are recruited to the aggresome and degraded there by the autophagic pathway. We show that there is a compromised exchange between DISC1 in aggresomes and the cytosolic DISC1 pool, and that the large DISC1 aggregates, which can also co-recruit endogenous soluble DISC1, exhibit altered trafficking. Moreover, we demonstrate that large DISC1 aggregates have a pathological effect in neurons by causing the disruption of intracellular transport of key organellar cargo, such as mitochondria. These data, therefore, show that DISC1 is recruited to aggresomes with negative effects on neuronal function, and suggests a novel DISC1-based mechanism for neuronal pathology.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
320Expert Opin. Ther. Targets 2012 Dec 16: 1151-60
PMID23130881
TitleDISC1 as a therapeutic target for mental illnesses.
AbstractMany genetic studies have indicated that DISC1 is not merely "disrupted-in-schizophrenia," but is more generally implicated in various brain dysfunctions associated with aberrant neurodevelopment and intracellular signaling pathways. Thus, the DISC1 gene is mildly associated with a variety of brain disorders, including schizophrenia, mood disorders, and autism. This novel concept fits with the results from biological studies of DISC1, which include cell and animal models.
We review the molecular structure and functions of DISC1, particularly those in conjunction with its important interactors. Functions of these interacting proteins are also introduced under the concept of the "DISC1 interactome." Finally, we discuss how the DISC1 interactome can provide potential therapeutic targets for mental illnesses.
Modulation of DISC1 stability and post-transcriptional modifications may be key targets to address DISC1-related pathology. In addition, modulation of DISC1 interactors and the mechanisms of their interactions with DISC1 may also provide drug targets. DISC1 rodent models can subsequently be used as templates for in vivo validations of compounds designed for DISC1 and its interacting proteins. Furthermore, these rodents will serve as genetic models for schizophrenia and related conditions, especially in conjunction with their pathologies during the neurodevelopmental trajectory.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
321Autophagy 2012 May 8: 851-2
PMID22617441
TitleDISC1 and the aggresome: a disruption to cellular function?
AbstractDisrupted in schizophrenia 1 (DISC1) is a key susceptibility gene for major psychiatric disorders. DISC1 plays a role in key neuronal processes such as neuronal proliferation, migration, integration and function via DISC1's roles at the centrosome and synapse, and in the regulation of intracellular signaling pathways. Recently, the idea of protein aggregation as a disease mechanism for DISC1 has been suggested. In our recent paper we explore these DISC1 protein aggregates in cell lines and neurons and find they are recruited to the aggresome and cause disruption of DISC1 function in intracellular transport.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
322Neurosci. Lett. 2012 May 517: 21-4
PMID22516458
TitleThe effect of DISC1 on regional gray matter density of schizophrenia in Han Chinese population.
Abstractschizophrenia is thought to arise in part from abnormal gray matter (GM), which are partly shared by the relatives of the probands. DISC1 is one of the most promising susceptibility genes of schizophrenia and a SNP rs821597 (A) in the gene was associated with schizophrenia in Han Chinese population. In this study, 61 healthy controls and 72 with schizophrenic patients were genotyped at rs821597, and underwent T1-weighted MRI for the density of GM. The results showed that the risk allele (A) carriers had higher GM density in regional left parahippocampal gyrus and right orbitofrontal cortex in schizophrenic patients, but had reduced GM density of these brain regions in healthy controls. The DISC1 variant rs821597 may confer risk for schizophrenia by its effects on the regional GM in left parahippocampal gyrus and right orbitofrontal cortex with other risk factors for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
323PLoS ONE 2012 -1 7: e34053
PMID22479520
TitleDisrupted-in-schizophrenia (DISC1) functions presynaptically at glutamatergic synapses.
AbstractThe pathophysiology of schizophrenia is believed to involve defects in synaptic transmission, and the function of many schizophrenia-associated genes, including DISC1, have been linked to synaptic function at glutamatergic synapses. Here we develop a rodent model via in utero electroporation to assay the presynaptic function of DISC1 at glutamatergic synapses. We used a combination of mosaic transgene expression, RNAi knockdown and optogenetics to restrict both genetic manipulation and synaptic stimulation of glutamatergic neurons presynaptic to other layer 2/3 neocortical pyramidal neurons that were then targeted for whole-cell patch-clamp recording. We show that expression of the DISC1 c-terminal truncation variant that is associated with schizophrenia alters the frequency of mEPSCs and the kinetics of evoked glutamate release. In addition, we show that expression level of DISC1 is correlated with the probability of glutamate release such that increased DISC1 expression results in paired-pulse depression and RNAi knockdown of DISC1 produces paired-pulse facilitation. Overall, our results support a direct presynaptic function for the schizophrenia-associated gene, DISC1.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
324Mol. Cells 2012 Feb 33: 105-10
PMID22358509
TitleMolecular links between mitochondrial dysfunctions and schizophrenia.
Abstractschizophrenia is a complex neuropsychiatric disorder with both neurochemical and neurodevelopmental components in the pathogenesis. Growing pieces of evidence indicate that schizophrenia has pathological components that can be attributable to the abnormalities of mitochondrial function, which is supported by the recent finding suggesting mitochondrial roles for Disrupted-in-schizophrenia 1 (DISC1). In this minireview, we briefly summarize the current understanding of the molecular links between mitochondrial dysfunctions and the pathogenesis of schizophrenia, covering recent findings from human genetics, functional genomics, proteomics, and molecular and cell biological approaches.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
325Neuropharmacology 2012 Mar 62: 1230-41
PMID21195721
TitleDISC1-binding proteins in neural development, signalling and schizophrenia.
AbstractIn the decade since Disrupted in schizophrenia 1 (DISC1) was first identified it has become one of the most convincing risk genes for major mental illness. As a multi-functional scaffold protein, DISC1 has multiple identified protein interaction partners that highlight pathologically relevant molecular pathways with potential for pharmaceutical intervention. Amongst these are proteins involved in neuronal migration (e.g. APP, Dixdc1, LIS1, NDE1, NDEL1), neural progenitor proliferation (GSK3?), neurosignalling (Girdin, GSK3?, PDE4) and synaptic function (Kal7, TNIK). Furthermore, emerging evidence of genetic association (NDEL1, PCM1, PDE4B) and copy number variation (NDE1) implicate several DISC1-binding partners as risk factors for schizophrenia in their own right. Thus, a picture begins to emerge of DISC1 as a key hub for multiple critical developmental pathways within the brain, disruption of which can lead to a variety of psychiatric illness phenotypes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
326Mol. 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, schizophrenias
327Development 2012 Nov 139: 3986-96
PMID22992957
TitlePancortins interact with amyloid precursor protein and modulate cortical cell migration.
AbstractNeuronal precursor cell migration in the developing mammalian brain is a complex process requiring the coordinated interaction of numerous proteins. We have recently shown that amyloid precursor protein (APP) plays a role in migration into the cortical plate through its interaction with two cytosolic signaling proteins, disabled 1 (DAB1) and disrupted in schizophrenia 1 (DISC1). In order to identify extracellular factors that may signal through APP to regulate migration, we performed an unbiased mass spectrometry-based screen for factors that bind to the extracellular domain of APP in the rodent brain. Through this screen, we identified an interaction between APP and pancortins, proteins expressed throughout the developing and mature cerebral cortex. Via co-immunoprecipitation, we show that APP interacts with all four of the mammalian pancortin isoforms (AMY, AMZ, BMY, BMZ). We demonstrate that the BMZ and BMY isoforms of pancortin can specifically reduce ?-secretase- but not ?-secretase-mediated cleavage of endogenous APP in cell culture, suggesting a biochemical consequence of the association between pancortins and APP. Using in utero electroporation to overexpress and knock down specific pancortin isoforms, we reveal a novel role for pancortins in migration into the cortical plate. Interestingly, we observe opposing roles for alternate pancortin isoforms, with AMY overexpression and BMZ knock down both preventing proper migration of neuronal precursor cells. Finally, we show that BMZ can partially rescue a loss of APP expression and that APP can rescue effects of AMY overexpression, suggesting that pancortins act in conjunction with APP to regulate entry into the cortical plate. Taken together, these results suggest a biochemical and functional interaction between APP and pancortins, and reveal a previously unidentified role for pancortins in mammalian cortical development.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
328Hum. Mol. Genet. 2012 Jun 21: 2779-92
PMID22422769
TitleDISC1 variants 37W and 607F disrupt its nuclear targeting and regulatory role in ATF4-mediated transcription.
AbstractDisrupted-In-schizophrenia 1 (DISC1), a strong genetic candidate for psychiatric illness, encodes a multicompartmentalized molecular scaffold that regulates interacting proteins with key roles in neurodevelopment and plasticity. Missense DISC1 variants are associated with the risk of mental illness and with brain abnormalities in healthy carriers, but the underlying mechanisms are unclear. We examined the effect of rare and common DISC1 amino acid substitutions on subcellular targeting. We report that both the rare putatively causal variant 37W and the common variant 607F independently disrupt DISC1 nuclear targeting in a dominant-negative fashion, predicting that DISC1 nuclear expression is impaired in 37W and 607F carriers. In the nucleus, DISC1 interacts with the transcription factor Activating Transcription Factor 4 (ATF4), which is involved in the regulation of cellular stress responses, emotional behaviour and memory consolidation. At basal cAMP levels, wild-type DISC1 inhibits the transcriptional activity of ATF4, an effect that is weakened by both 37W and 607F independently, most likely as a consequence of their defective nuclear targeting. The common variant 607F additionally reduces DISC1/ATF4 interaction, which likely contributes to its weakened inhibitory effect. We also demonstrate that DISC1 modulates transcriptional responses to endoplasmic reticulum stress, and that this modulatory effect is ablated by 37W and 607F. By showing that DISC1 amino acid substitutions associated with psychiatric illness affect its regulatory function in ATF4-mediated transcription, our study highlights a potential mechanism by which these variants may impact on transcriptional events mediating cognition, emotional reactivity and stress responses, all processes of direct relevance to psychiatric illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
329Psychopharmacology (Berl.) 2012 Feb 219: 1065-79
PMID21833500
TitlePhosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex.
AbstractAlteration of dopamine neurotransmission in the prefrontal cortex, especially hypofunction of dopamine D1 receptors, contributes to psychotic symptoms and cognitive deficit in schizophrenia. D1 receptors signal through the cAMP/PKA second messenger cascade, which is modulated by phosphodiesterase (PDE) enzymes that hydrolyze and inactivate cyclic nucleotides. Though several PDEs are expressed in cortical neurons, the PDE4 enzyme family (PDE4A-D) has been implicated in the control of cognitive function. The best studied isoform, PDE4B, interacts with a schizophrenia susceptibility factor, disrupted in schizophrenia 1 (DISC1).
We explore the control of mouse frontal cortex dopamine D1 receptor signaling and associated behavior by PDE4.
Inhibition of PDE4 by rolipram induced activation of cAMP/PKA signaling in cortical slices and in vivo, leading to the phosphorylation of DARPP-32 and other postsynaptic and presynaptic PKA-substrates. Rolipram also enhanced DARPP-32 phosphorylation invoked by D1 receptor activation. Immunohistochemical studies demonstrated PDE4A, PDE4B, and PDE4D expression in DARPP-32-positive neurons in layer VI of frontal cortex, most likely in D1 receptor-positive, glutamatergic corticothalamic pyramidal neurons. Furthermore, the ability of rolipram treatment to improve the performance of mice in a sensorimotor gating test was DARPP-32-dependent.
PDE4, which is co-expressed with DARPP-32 in D1 receptor-positive cortical pyramidal neurons in layer VI, modulates the level of D1 receptor signaling and DARPP-32 phosphorylation in the frontal cortex, likely influencing cognitive function. These biochemical and behavioral actions of PDE4 inhibitors may contribute to the hypothesized antipsychotic actions of this class of compounds.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
330Hum. Mol. Genet. 2012 Oct 21: 4406-18
PMID22798627
TitleProteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits.
Abstractschizophrenia is a chronic illness of heterogenous biological origin. We hypothesized that, similar to chronic progressive brain conditions, persistent functional disturbances of neurons would result in disturbed proteostasis in the brains of schizophrenia patients, leading to increased abundance of specific misfolded, insoluble proteins. Identification of such proteins would facilitate the elucidation of molecular processes underlying these devastating conditions. We therefore generated antibodies against pooled insoluble proteome of post-mortem brains from schizophrenia patients in order to identify unique, disease-specific epitopes. We successfully identified such an epitope to be present on collapsin-response mediator protein 1 (CRMP1) in biochemically purified, insoluble brain fractions. A genetic association analysis for the CRMP1 gene in a large Finnish population cohort (n = 4651) corroborated the association of physical and social anhedonia with the CRMP1 locus in a DISC1 (Disrupted-in-schizophrenia 1)-dependent manner. Physical and social anhedonia are heritable traits, present as chronic, negative symptoms of schizophrenia and severe major depression, thus constituting serious vulnerability factors for mental disease. Strikingly, lymphoblastoid cell lines derived from schizophrenia patients mirrored aberrant CRMP1 immunoreactivity by showing an increase of CRMP1 expression, suggesting its potential role as a blood-based diagnostic marker. CRMP1 is a novel candidate protein for schizophrenia traits at the intersection of the reelin and DISC1 pathways that directly and functionally interacts with DISC1. We demonstrate the impact of an interdisciplinary approach where the identification of a disease-associated epitope in post-mortem brains, powered by a genetic association study, is rapidly translated into a potential blood-based diagnostic marker.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
331Mol. Psychiatry 2012 Nov 17: 1093-102
PMID21876540
TitleStatistical epistasis and progressive brain change in schizophrenia: an approach for examining the relationships between multiple genes.
AbstractAlthough schizophrenia is generally considered to occur as a consequence of multiple genes that interact with one another, very few methods have been developed to model epistasis. Phenotype definition has also been a major challenge for research on the genetics of schizophrenia. In this report, we use novel statistical techniques to address the high dimensionality of genomic data, and we apply a refinement in phenotype definition by basing it on the occurrence of brain changes during the early course of the illness, as measured by repeated magnetic resonance scans (i.e., an 'intermediate phenotype.') The method combines a machine-learning algorithm, the ensemble method using stochastic gradient boosting, with traditional general linear model statistics. We began with 14 genes that are relevant to schizophrenia, based on association studies or their role in neurodevelopment, and then used statistical techniques to reduce them to five genes and 17 single nucleotide polymorphisms (SNPs) that had a significant statistical interaction: five for PDE4B, four for RELN, four for ERBB4, three for DISC1 and one for NRG1. Five of the SNPs involved in these interactions replicate previous research in that, these five SNPs have previously been identified as schizophrenia vulnerability markers or implicate cognitive processes relevant to schizophrenia. This ability to replicate previous work suggests that our method has potential for detecting a meaningful epistatic relationship among the genes that influence brain abnormalities in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
332PLoS Comput. Biol. 2012 -1 8: e1002587
PMID22792057
TitleNetwork-assisted investigation of combined causal signals from genome-wide association studies in schizophrenia.
AbstractWith the recent success of genome-wide association studies (GWAS), a wealth of association data has been accomplished for more than 200 complex diseases/traits, proposing a strong demand for data integration and interpretation. A combinatory analysis of multiple GWAS datasets, or an integrative analysis of GWAS data and other high-throughput data, has been particularly promising. In this study, we proposed an integrative analysis framework of multiple GWAS datasets by overlaying association signals onto the protein-protein interaction network, and demonstrated it using schizophrenia datasets. Building on a dense module search algorithm, we first searched for significantly enriched subnetworks for schizophrenia in each single GWAS dataset and then implemented a discovery-evaluation strategy to identify module genes with consistent association signals. We validated the module genes in an independent dataset, and also examined them through meta-analysis of the related SNPs using multiple GWAS datasets. As a result, we identified 205 module genes with a joint effect significantly associated with schizophrenia; these module genes included a number of well-studied candidate genes such as DISC1, GNA12, GNA13, GNAI1, GPR17, and GRIN2B. Further functional analysis suggested these genes are involved in neuronal related processes. Additionally, meta-analysis found that 18 SNPs in 9 module genes had P(meta)<1 10??, including the gene HLA-DQA1 located in the MHC region on chromosome 6, which was reported in previous studies using the largest cohort of schizophrenia patients to date. These results demonstrated our bi-directional network-based strategy is efficient for identifying disease-associated genes with modest signals in GWAS datasets. This approach can be applied to any other complex diseases/traits where multiple GWAS datasets are available.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
333Schizophr. Res. 2012 Sep 140: 175-84
PMID22804924
TitleMaternal immune activation alters behavior in adult offspring, with subtle changes in the cortical transcriptome and epigenome.
AbstractMaternal immune activation during prenatal development, including treatment with the viral RNA mimic, polyriboinosinic-polyribocytidilic acid (poly IC), serves as a widely used animal model to induce behavioral deficits reminiscent of schizophrenia and related disease. Here, we report that massive cytokine activation after a single dose of poly IC in the prenatal period is associated with lasting working memory deficits in adult offspring. To explore whether dysregulated gene expression in cerebral cortex, contributes to cognitive dysfunction, we profiled the cortical transcriptome, and in addition, mapped the genome-wide distribution of trimethylated histone H3-lysine 4 (H3K4me3), an epigenetic mark sharply regulated at the 5' end of transcriptional units. However, deep sequencing-based H3K4me3 mapping and mRNA profiling by microarray did not reveal significant alterations in mature cerebral cortex after poly IC exposure at embryonic days E17.5 or E12.5. At a small set of genes (including suppressor of cytokine signaling Socs3), H3K4me3 was sensitive to activation of cytokine signaling in primary cultures from fetal forebrain but adult cortex of saline- and poly IC-exposed mice did not show significant differences. A limited set of transcription start sites (TSS), including Disrupted-in-schizophrenia 1 (DISC1), a schizophrenia risk gene often implicated in gene-environment interaction models, showed altered H3K4me3 after prenatal poly IC but none of these differences survived after correcting for multiple comparisons. We conclude that prenatal poly IC is associated with cognitive deficits later in life, but without robust alterations in epigenetic regulation of gene expression in the cerebral cortex.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
334Front Psychiatry 2012 -1 3: 57
PMID22723785
TitleDISC1 and Striatal Volume: A Potential Risk Phenotype For mental Illness.
AbstractDisrupted-in-schizophrenia 1 was originally discovered in a large Scottish family with abnormally high rates of severe mental illness, including schizophrenia, bipolar disorder, and depression. An accumulating body of evidence from genetic, postmortem, and animal data supports a role for DISC1 in different forms of mental illness. DISC1 may play an important role in determining structure and function of several brain regions. One brain region of particular importance for several mental disorders is the striatum, and DISC1 mutant mice have demonstrated an increase in dopamine (D2) receptors in this structure. However, association between DISC1 functional polymorphisms and striatal structure have not been examined in humans. We, therefore hypothesized that there would be a relationship between human striatal volume and DISC1 genotype, specifically in the Leu607Phe (rs6675281) and Ser704Cys (rs821618) single nucleotide polymorphisms. We tested our hypothesis by automatically identifying the striatum in 54 healthy volunteers recruited for this study. We also performed an exploratory analysis of cortical thickness, cortical surface area, and structure volume. Our results demonstrate that Phe allele carriers have larger striatal volume bilaterally (left striatum: p?=?0.017; right striatum: p?=?0.016). From the exploratory analyses we found that the Phe carriers also had larger left hemisphere volumes (p?=?0.0074) and right occipital lobe surface area (p?=?0.014) compared to LeuLeu homozygotes. However, these exploratory findings do not survive a conservative correction for multiple comparisons. Our findings demonstrate that a functional DISC1 variant influences striatal volumes. Taken together with animal data that this gene influences D2 receptor levels in striatum, a key risk pathway for mental illnesses such as schizophrenia and bipolar disorder may be conferred via DISC1's effects on the striatum.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
335J. Neurosci. Res. 2012 Jul 90: 1445-53
PMID22388794
TitleDisruption of exploratory and habituation behavior in mice with mutation of DISC1: an ethologically based analysis.
AbstractDisrupted-in-schizophrenia-1 (DISC1) is a gene that has been functionally linked with neurodevelopmental processes and structural plasticity in the brain. Clinical genetic investigations have implicated DISC1 as a genetic risk factor for schizophrenia and related psychoses. Studies using mutant mouse models of DISC1 gene function have demonstrated schizophrenia-related anatomical and behavioral endophenotypes. In the present study, ethologically based assessment of exploratory and habituation behavior in the open field was conducted in DISC1 (L100P), wild-type (WT), heterozygous (HET), and homozygous (HOM) mutant mice of both sexes. Ethological assessment was conducted in an open-field environment to explore specific topographies of murine exploratory behavior across the extended course of interaction from initial exploration through subsequent habituation (the ethogram). During initial exploration, HET and HOM DISC1 mutants evidenced increased levels of locomotion and rearing to wall compared with WT. A HOM-specific increase in total rearing and a HET-specific increase in sifting behavior and reduction in rearing seated were also observed. Over subsequent habituation, locomotion, sniffing, total rearing, rearing to wall, rearing free, and rearing seated were increased in HET and HOM mutants vs. WT. Overall, grooming was increased in HOM relative to other genotypes. HET mice displayed a selective decrease in habituation of sifting behavior. These data demonstrate impairment in both initial exploratory and habituation of exploration in a novel environment in mice with mutation of DISC1. This is discussed in the context of the functional role of the gene vis vis a schizophrenia phenotype as well as the value of ethologically based approaches to behavioral phenotyping.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
336BMC Res Notes 2012 -1 5: 108
PMID22348257
TitleComprehensive behavioral analysis of ENU-induced Disc1-Q31L and -L100P mutant mice.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is considered to be a candidate susceptibility gene for psychiatric disorders, including schizophrenia, bipolar disorder, and major depression. A recent study reported that N-ethyl-N-nitrosourea (ENU)-induced mutations in exon 2 of the mouse DISC1 gene, which resulted in the amino acid exchange of Q31L and L100P, caused an increase in depression-like behavior in 31 L mutant mice and schizophrenia-like behavior in 100P mutant mice; thus, these are potential animal models of psychiatric disorders. However, remaining heterozygous mutations that possibly occur in flanking genes other than DISC1 itself might induce behavioral abnormalities in the mutant mice. Here, to confirm the effects of DISC1-Q31L and DISC1-L100P mutations on behavioral phenotypes and to investigate the behaviors of the mutant mice in more detail, the mutant lines were backcrossed to C57BL/6JJcl through an additional two generations and the behaviors were analyzed using a comprehensive behavioral test battery.
Contrary to expectations, 31 L mutant mice showed no significant behavioral differences when compared with wild-type control mice in any of the behavioral tests, including the Porsolt forced swim and tail suspension tests, commonly used tests for depression-like behavior. Also, 100P mutant mice exhibited no differences in almost all of the behavioral tests, including the prepulse inhibition test for measuring sensorimotor gating, which is known to be impaired in schizophrenia patients; however, 100P mutant mice showed higher locomotor activity compared with wild-type control mice in the light/dark transition test.
Although these results are partially consistent with the previous study in that there was hyperactivity in 100P mutant mice, the vast majority of the results are inconsistent with those of the previous study; this discrepancy may be explained by differences in the genetic background of the mice, the laboratory environment, experimental protocols, and more. Further behavioral studies under various experimental conditions are necessary to determine whether these DISC1 mutant mouse lines are suitable animal models of schizophrenia and major depression.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
337Mol. Psychiatry 2012 Jun 17: 634-41
PMID21483435
TitleMeta-analysis indicates that common variants at the DISC1 locus are not associated with schizophrenia.
AbstractSeveral polymorphisms in the Disrupted-in-schizophrenia-1 (DISC1) gene are reported to be associated with schizophrenia. However, to date, there has been little effort to evaluate the evidence for association systematically. We carried out an imputation-driven meta-analysis, the most comprehensive to date, using data collected from 10 candidate gene studies and three genome-wide association studies containing a total of 11?626 cases and 15?237 controls. We tested 1241 single-nucleotide polymorphisms in total, and estimated that our power to detect an effect from a variant with minor allele frequency >5% was 99% for an odds ratio of 1.5 and 51% for an odds ratio of 1.1. We find no evidence that common variants at the DISC1 locus are associated with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
338J Vis Exp 2012 -1 -1: e4132
PMID22952026
TitleGeneration, purification, and characterization of cell-invasive DISC1 protein species.
AbstractProtein aggregation is seen as a general hallmark of chronic, degenerative brain conditions like, for example, in the neurodegenerative diseases Alzheimer's disease (A?, tau), Parkinson's Disease (?-synuclein), Huntington's disease (polyglutamine, huntingtin), and others. Protein aggregation is thought to occur due to disturbed proteostasis, i.e. the imbalance between the arising and degradation of misfolded proteins. Of note, the same proteins are found aggregated in sporadic forms of these diseases that are mutant in rare variants of familial forms. schizophrenia is a chronic progressive brain condition that in many cases goes along with a permanent and irreversible cognitive deficit. In a candidate gene approach, we investigated whether Disrupted-in-schizophrenia 1 (DISC1), a gene cloned in a Scottish family with linkage to chronic mental disease, could be found as insoluble aggregates in the brain of sporadic cases of schizophrenia. Using the SMRI CC, we identified in approximately 20% of cases with CMD but not normal controls or patients with neurodegenerative diseases sarkosyl-insoluble DISC1 immunoreactivity after biochemical fractionation. Subsequent studies in vitro revealed that the aggregation propensity of DISC1 was influenced by disease-associated polymorphism S704C, and that DISC1 aggresomes generated in vitro were cell-invasive, similar to what had been shown for A?, tau, ?-synuclein, polyglutamine, or SOD1 aggregates. These findings prompted us to propose that at least a subset of cases with CMD, those with aggregated DISC1 might be protein conformational disorders. Here we describe how we generate DISC1 aggresomes in mammalian cells, purify them on a sucrose gradient and use them for cell-invasiveness studies. Similarly, we describe how we generate an exclusively multimeric C-terminal DISC1 fragment, label and purify it for cell invasiveness studies. Using the recombinant multimers of DISC1 we achieve similar cell invasiveness as for a similarly labeled synthetic ?-synuclein fragment. We also show that this fragment is taken up in vivo when stereotactically injected into the brain of recipient animals.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
339J. Hum. Genet. 2012 Aug 57: 523-30
PMID22673686
TitleGender-specific association of TSNAX/DISC1 locus for schizophrenia and bipolar affective disorder in South Indian population.
AbstractGenetic association studies have implicated the TSNAX/DISC1 (disrupted in schizophrenia 1) in schizophrenia (SCZ), bipolar affective disorder (BPAD) and major depression. This study was performed to assess the possible involvement of TSNAX/DISC1 locus in the aetiology of BPAD and SCZ in the Southern Indian population. We genotyped seven single nucleotide polymorphism (SNPs) from TSNAX/DISC1 region in 1252 individuals (419 BPAD patients, 408 SCZ patients and 425 controls). Binary logistic regression revealed a nominal association for rs821616 in DISC1 for BPAD and also combined cases of BPAD or SCZ, but after correcting for multiple testing, these results were non-significant. However, significant association was observed with BPAD, as well as combined cases of BPAD or SCZ, within the female subjects for the rs766288 after applying false discovery rate corrections at the 0.05 level. Two-locus analysis showed C-C (rs766288-rs2812393) as a risk combination in BPAD, and G-T (rs2812393-rs821616) as a protective combination in SCZ and combined cases of BPAD or SCZ. Female-specific associations were observed for rs766288-rs2812393, rs766288-rs821616 and rs8212393-rs821616 in two-locus analysis. Our results provide further evidence for sex-dependent effects of the TSNAX/DISC1 locus in the aetiology of SCZ and BPAD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
340Hum. Mol. Genet. 2012 Aug 21: 3374-86
PMID22547224
TitleA t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric DISC1 transcripts that encode structurally altered, deleterious mitochondrial proteins.
AbstractDisrupted-In-schizophrenia 1 (DISC1) was identified as a risk factor for psychiatric illness through its disruption by a balanced chromosomal translocation, t(1;11)(q42.1;q14.3), that co-segregates with schizophrenia, bipolar disorder and depression. We previously reported that the translocation reduces DISC1 expression, consistent with a haploinsufficiency disease model. Here we report that, in lymphoblastoid cell lines, the translocation additionally results in the production of abnormal transcripts due to the fusion of DISC1 with a disrupted gene on chromosome 11 (DISC1FP1/Boymaw). These chimeric transcripts encode abnormal proteins, designated CP1, CP60 and CP69, consisting of DISC1 amino acids 1-597 plus 1, 60 or 69 amino acids, respectively. The novel 69 amino acids in CP69 induce increased ?-helical content and formation of large stable protein assemblies. The same is predicted for CP60. Both CP60 and CP69 exhibit profoundly altered functional properties within cell lines and neurons. Both are predominantly targeted to mitochondria, where they induce clustering and loss of membrane potential, indicative of severe mitochondrial dysfunction. There is currently no access to neural material from translocation carriers to confirm these findings, but there is no reason to suppose that these chimeric transcripts will not also be expressed in the brain. There is thus potential for the production of abnormal chimeric proteins in the brains of translocation carriers, although at substantially lower levels than for native DISC1. The mechanism by which inheritance of the translocation increases risk of psychiatric illness may therefore involve both DISC1 haploinsufficiency and mitochondrial deficiency due to the effects of abnormal chimeric protein expression. GenBank accession numbers: DISC1FP1 (EU302123), Boymaw (GU134617), der 11 chimeric transcript DISC1FP1 exon 2 to DISC1 exon 9 (JQ650115), der 1 chimeric transcript DISC1 exon 4 to DISC1FP1 exon 4 (JQ650116), der 1 chimeric transcript DISC1 exon 6 to DISC1FP1 exon 3a (JQ650117).
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
341Hum. Mol. Genet. 2012 Jul 21: 2862-72
PMID22434823
TitleThe DISC1 promoter: characterization and regulation by FOXP2.
AbstractDisrupted in schizophrenia 1 (DISC1) is a leading candidate susceptibility gene for schizophrenia, bipolar disorder and recurrent major depression, which has been implicated in other psychiatric illnesses of neurodevelopmental origin, including autism. DISC1 was initially identified at the breakpoint of a balanced chromosomal translocation, t(1;11) (q42.1;14.3), in a family with a high incidence of psychiatric illness. Carriers of the translocation show a 50% reduction in DISC1 protein levels, suggesting altered DISC1 expression as a pathogenic mechanism in psychiatric illness. Altered DISC1 expression in the post-mortem brains of individuals with psychiatric illness and the frequent implication of non-coding regions of the gene by association analysis further support this assertion. Here, we provide the first characterization of the DISC1 promoter region. Using dual luciferase assays, we demonstrate that a region -300 to -177 bp relative to the transcription start site (TSS) contributes positively to DISC1 promoter activity, while a region -982 to -301 bp relative to the TSS confers a repressive effect. We further demonstrate inhibition of DISC1 promoter activity and protein expression by forkhead-box P2 (FOXP2), a transcription factor implicated in speech and language function. This inhibition is diminished by two distinct FOXP2 point mutations, R553H and R328X, which were previously found in families affected by developmental verbal dyspraxia. Our work identifies an intriguing mechanistic link between neurodevelopmental disorders that have traditionally been viewed as diagnostically distinct but which do share varying degrees of phenotypic overlap.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
342J. Biol. Chem. 2012 Sep 287: 32381-93
PMID22843697
TitleThe mitosis and neurodevelopment proteins NDE1 and NDEL1 form dimers, tetramers, and polymers with a folded back structure in solution.
AbstractParalogs NDE1 (nuclear distribution element 1) and NDEL1 (NDE-like 1) are essential for mitosis and neurodevelopment. Both proteins are predicted to have similar structures, based upon high sequence similarity, and they co-complex in mammalian cells. X-ray diffraction studies and homology modeling suggest that their N-terminal regions (residues 8-167) adopt continuous, extended ?-helical coiled-coil structures, but no experimentally derived information on the structure of their C-terminal regions or the architecture of the full-length proteins is available. In the case of NDE1, no biophysical data exists. Here we characterize the structural architecture of both full-length proteins utilizing negative stain electron microscopy along with our established paradigm of chemical cross-linking followed by tryptic digestion, mass spectrometry, and database searching, which we enhance using isotope labeling for mixed NDE1-NDEL1. We determined that full-length NDE1 forms needle-like dimers and tetramers in solution, similar to crystal structures of NDEL1, as well as chain-like end-to-end polymers. The C-terminal domain of each protein, required for interaction with key protein partners dynein and DISC1 (disrupted-in-schizophrenia 1), includes a predicted disordered region that allows a bent back structure. This facilitates interaction of the C-terminal region with the N-terminal coiled-coil domain and is in agreement with previous results showing N- and C-terminal regions of NDEL1 and NDE1 cooperating in dynein interaction. It sheds light on recently identified mutations in the NDE1 gene that cause truncation of the encoded protein. Additionally, analysis of mixed NDE1-NDEL1 complexes demonstrates that NDE1 and NDEL1 can interact directly.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
343Front Psychiatry 2012 -1 3: 25
PMID22461775
TitleDISC1 Pathway in Brain Development: Exploring Therapeutic Targets for Major Psychiatric Disorders.
AbstractGenetic risk factors for major psychiatric disorders play key roles in neurodevelopment. Thus, exploring the molecular pathways of risk genes is important not only for understanding the molecular mechanisms underlying brain development, but also to decipher how genetic disturbances affect brain maturation and functioning relevant to major mental illnesses. During the last decade, there has been significant progress in determining the mechanisms whereby risk genes impact brain development. Nonetheless, given that the majority of psychiatric disorders have etiological complexities encompassing multiple risk genes and environmental factors, the biological mechanisms of these diseases remain poorly understood. How can we move forward to our research for discovery of the biological markers and novel therapeutic targets for major mental disorders? Here we review recent progress in the neurobiology of disrupted in schizophrenia 1 (DISC1), a major risk gene for major mental disorders, with a particular focus on its roles in cerebral cortex development. Convergent findings implicate DISC1 as part of a large, multi-step pathway implicated in various cellular processes and signal transduction. We discuss links between the DISC1 pathway and environmental factors, such as immune/inflammatory responses, which may suggest novel therapeutic targets. Existing treatments for major mental disorders are hampered by a limited number of pharmacological targets. Consequently, elucidation of the DISC1 pathway, and its association with neuropsychiatric disorders, may offer hope for novel treatment interventions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
344Genes Brain Behav. 2012 Oct 11: 859-63
PMID22891933
TitleAnalysis of the DISC1 translocation partner (11q14.3) in genetic risk of schizophrenia.
AbstractThe Disrupted-in-schizophrenia 1 (DISC1) locus on human chromosome 1 was identified as a consequence of its involvement in a balanced translocation (1;11)(q42.1;q14.3) segregating with major psychiatric disorders in a Scottish family. Recently a comprehensive meta-analysis of genome-wide association scan data found no evidence that common variants of DISC1 (1q42.1) are associated with schizophrenia. Our aim was to test for association of variants in the 11q14.3 translocation region with schizophrenia. The 11q14.3 region was examined by meta-analysis of genome-wide scan data made available by the Genetic Association Information Network (GAIN) and other investigators (non-GAIN) through dbGap. P-values were adjusted for multiple testing using the false discovery rate (FDR) approach. There were no single-nucleotide polymorphisms (SNPs) significant (P < 0.05) after correction for multiple testing in the combined schizophrenia dataset. However, one SNP (rs2509382) was significantly associated in the male-only analysis with P(FDR) ?=?0.024. Whilst the relevance of the (1;11)(q42.1;q14.3) translocation to psychiatric disorders is currently specific to the Scottish family, genetic material in the chromosome 11 region may contain risk variants for psychiatric disorders in the wider population. The association found in this region does warrant follow-up analysis in further sample sets.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
345Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Sep 159B: 722-30
PMID22815203
TitleEffect of DISC1 SNPs on brain structure in healthy controls and patients with a history of psychosis.
AbstractDisrupted-in-schizophrenia-1 (DISC1) has been suggested as a susceptibility locus for a broad spectrum of psychiatric disorders. Risk variants have been associated with brain structural changes, which overlap alterations reported in schizophrenia and bipolar disorder patients. We used genome-wide genotyping data for a Norwegian sample of healthy controls (n = 171) and patients with a history of psychosis (n = 184), to investigate 61 SNPs in the DISC1 region for putative association with structural magnetic resonance imaging (sMRI) measures (hippocampal volume; mean cortical thickness; and total surface area, as well as cortical thickness and area divided into four lobar measures). SNP rs821589 was associated with mean temporal and total brain cortical thickness in controls (P(adjusted) = 0.009 and 0.02, respectively), but not in patients. SNPs rs11122319 and rs1417584 were associated with mean temporal cortical thickness in patients (P(adjusted) = 0.04 and 0.03, respectively), but not in controls, and both SNPs have previously been highly associated with DISC1 gene expression. There were significant genotype?? case-control interactions. There was no significant association between SNPs and cortical area or hippocampal volume in controls, or with any of the structural measures in cases, after correction for multiple comparisons. In conclusion, DISC1 SNPs might impact brain structural variation, possibly differently in psychosis patients versus controls, but independent replication will be needed to confirm our findings.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
346Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Apr 159B: 343-53
PMID22337479
TitleEffects of a mis-sense DISC1 variant on brain activation in two cohorts at high risk of bipolar disorder or schizophrenia.
AbstractBipolar disorder and schizophrenia share a number of clinical features and genetic risk variants of small effect, suggesting overlapping pathogenic mechanisms. The effect of single genetic risk variants on brain function is likely to differ in people at high familial risk versus controls as these individuals have a higher overall genetic loading and are therefore closer to crossing a threshold of disease liability. Therefore, whilst the effects of genetic risk variants on brain function may be similar across individuals at risk of both disorders, they are hypothesized to differ compared to that seen in control subjects. We sought to examine the effects of the DISC1 Leu(607) Phe polymorphism on brain activation in young healthy individuals at familial risk of bipolar disorder (n?=?84), in a group of controls (n?=?78), and in a group at familial risk of schizophrenia (n?=?47), performing a language task. We assessed whether genotype effects on brain activation differed according to risk status. There was a significant genotype??group interaction in a cluster centered on the left pre/postcentral gyrus, extending to the inferior frontal gyrus. The origin of this genotype??group effect originated from a significant effect of the presumed risk variant (Phe) on brain activation in the control group, which was absent in both high-risk groups. Differential effects of this polymorphism in controls compared to the two familial groups suggests a commonality of effect across individuals at high-risk of the disorders, which is likely to be dependant upon existing genetic background.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
347Neuropharmacology 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, schizophrenias
348Neuropharmacology 2012 Mar 62: 1252-62
PMID21376063
TitleSynergistic interactions between PDE4B and GSK-3: DISC1 mutant mice.
AbstractDisrupted-In-schizophrenia-1 (DISC1) is a strong genetic risk factor associated with psychiatric disorders. Two distinct mutations in the second exon of the DISC1 gene (Q31L and L100P) lead to either depression- or schizophrenia-like behavior in mice. Both phosphodiesterase-4B (PDE4B) and glycogen synthase kinase-3 (GSK-3) have common binding sites on N-terminal region of DISC1 and are implicated into etiology of schizophrenia and depression. It is not known if PDE4B and GSK-3 could converge signals in the cell via DISC1 at the same time. The purpose of the present study was to assess whether rolipram (PDE4 inhibitor) might synergize with TDZD-8 (GSK-3 blocker) to produce antipsychotic effects at low doses on the DISC1-L100P genetic model. Indeed, combined treatment of DISC1-L100P mice with rolipram (0.1 mg/kg) and TDZD-8 (2.5 mg/kg) in sub-threshold doses corrected their Pre-Pulse Inhibition (PPI) deficit and hyperactivity, without any side effects at these doses. We have suggested that rolipram-induced increase of cAMP level might influence GSK-3 function and, hence the efficacy of TDZD-8. Our second goal was to estimate how DISC1-Q31L with reduced PDE4B activity, and therefore mimicking rolipram-induced conditions, could alter pharmacological response to TDZD-8, GSK-3 activity and its interaction with DISC1. DISC1-Q31L mutants showed increased sensitivity to GSK-3 inhibitor compare to DISC1-L100P mice. TDZD-8 (2.5 mg/kg) was able to correct PPI deficit, reduce immobility in the forced swim test (FST) and increased social motivation/novelty. In parallel, biochemical analysis revealed significantly reduced binding of GSK-3 to the mutated DISC1-Q31L and increased enzymatic activity of GSK-3. Taken together, genetic variations in DISC1 influence formation of biochemical complex with PDE4 and GSK-3 and strength the possibility of synergistic interactions between these proteins.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
349Neuropharmacology 2012 Mar 62: 1242-51
PMID21315744
TitleMutant DISC1 affects methamphetamine-induced sensitization and conditioned place preference: a comorbidity model.
AbstractGenetic factors involved in neuroplasticity have been implicated in major psychiatric illnesses such as schizophrenia, depression, and substance abuse. Given its extended interactome, variants in the Disrupted-In-schizophrenia-1 (DISC1) gene could contribute to drug addiction and psychiatric diseases. Thus, we evaluated how dominant-negative mutant DISC1 influenced the neurobehavioral and molecular effects of methamphetamine (METH). Control and mutant DISC1 mice were studied before or after treatment with non-toxic escalating dose (ED) of METH. In nave mice, we assessed METH-induced conditioned place preference (CPP), dopamine (DA) D2 receptor density and the basal and METH-induced activity of DISC1 partners, AKT and GSK-3? in the ventral striatum. In ED-treated mice, 4 weeks after METH treatment, we evaluated fear conditioning, depression-like responses in forced swim test, and the basal and METH-induced activity of AKT and GSK-3? in the ventral striatum. We found impairment in METH-induced CPP, decreased DA D2 receptor density and altered METH-induced phosphorylation of AKT and GSK-3? in nave DISC1 female mice. The ED regimen was not neurotoxic as evidenced by unaltered brain regional monoamine tissue content. Mutant DISC1 significantly delayed METH ED-produced sensitization and affected drug-induced phosphorylation of AKT and GSK-3? in female mice. Our results suggest that perturbations in DISC1 functions in the ventral striatum may impact the molecular mechanisms of reward and sensitization, contributing to comorbidity between drug abuse and major mental diseases.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
350J Psychiatry Neurosci 2012 Jan 37: 7-16
PMID21711983
TitleA role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health.
AbstractMental illnesses, such as bipolar disorder, attention-deficit/hyperactivity disorder, depression and schizophrenia are a major public health concern worldwide. Several pharmacologic agents acting on monoamine neurotransmission are used for the management of these disorders. However, there is still little understanding of the ultimate molecular mechanisms responsible for the therapeutic effects of these drugs or their relations with disease etiology. Here I provide an overview of recent advances on the involvement of the signalling molecules Akt and glycogen synthase kinase-3 (GSK3) in the regulation of behaviour by the monoamine neurotransmitters dopamine (DA) and serotonin (5-HT). I examine the possible participation of these signalling molecules to the effects of antidepressants, lithium and antipsychotics, as well as their possible contribution to mental disorders. Regulation of Akt and GSK3 may constitute an important signalling hub in the subcellular integration of 5-HT and DA neurotransmission. It may also provide a link between the action of these neurotransmitters and gene products, like disrupted in schizophrenia 1 (DISC1) and neuregulin (NRG), that are associated with increased risk for mental disorders. However, changes in Akt and GSK3 signalling are not restricted to a single disorder, and their contribution to specific behavioural symptoms or therapeutic effects may be modulated by broader changes in biologic contexts or signalling landscapes. Understanding these interactions may provide a better understanding of mental illnesses, leading to better efficacy of new therapeutic approaches.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
351J. Neurosci. 2012 Jan 32: 738-45
PMID22238109
TitleDisrupted-in-Schizophrenia 1 (DISC1) is necessary for the correct migration of cortical interneurons.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a prominent susceptibility gene for major psychiatric disorders. Previous work indicated that DISC1 plays an important role during neuronal proliferation and differentiation in the cerebral cortex and that it affects the positioning of radial migrating pyramidal neurons. Here we show that in mice, DISC1 is necessary for the migration of the cortical interneurons generated in the medial ganglionic eminence (MGE). RT-PCR, in situ hybridizations, and immunocytochemical data revealed expression of DISC1 transcripts and protein in MGE-derived cells. To study the possible functional role of DISC1 during tangential migration, we performed in utero and ex utero electroporation to suppress DISC1 in the MGE in vivo and in vitro. Results indicate that after DISC1 knockdown, the proportion of tangentially migrating MGE neurons that reached their cortical target was strongly reduced. In addition, there were profound alterations in the morphology of DISC1-deficient neurons, which exhibited longer and less branched leading processes than control cells. These findings provide a possible link between clinical studies reporting alterations of cortical interneurons in schizophrenic patients and the current notion of schizophrenia as a neurodevelopmental disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
352Neurosci. Lett. 2012 May 517: 21-4
PMID22516458
TitleThe effect of DISC1 on regional gray matter density of schizophrenia in Han Chinese population.
Abstractschizophrenia is thought to arise in part from abnormal gray matter (GM), which are partly shared by the relatives of the probands. DISC1 is one of the most promising susceptibility genes of schizophrenia and a SNP rs821597 (A) in the gene was associated with schizophrenia in Han Chinese population. In this study, 61 healthy controls and 72 with schizophrenic patients were genotyped at rs821597, and underwent T1-weighted MRI for the density of GM. The results showed that the risk allele (A) carriers had higher GM density in regional left parahippocampal gyrus and right orbitofrontal cortex in schizophrenic patients, but had reduced GM density of these brain regions in healthy controls. The DISC1 variant rs821597 may confer risk for schizophrenia by its effects on the regional GM in left parahippocampal gyrus and right orbitofrontal cortex with other risk factors for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
353Mol. Psychiatry 2013 Oct 18: 1050-2
PMID24056909
TitleQuestions about DISC1 as a genetic risk factor for schizophrenia.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
354Front Biol (Beijing) 2013 Oct 8: -1
PMID24285940
TitleNovel functions of GABA signaling in adult neurogenesis.
AbstractNeurotransmitter gamma-aminobutiric acid (GABA) through ionotropic GABAA and metabotropic GABAB receptors plays key roles in modulating the development, plasticity and function of neuronal networks. GABA is inhibitory in mature neurons but excitatory in immature neurons, neuroblasts and neural stem/progenitor cells (NSCs/NPCs). The switch from excitatory to inhibitory occurs following the development of glutamatergic synaptic input and results from the dynamic changes in the expression of Na(+)/K(+)/2Cl(-) co-transporter NKCC1 driving Cl(-) influx and neuron-specific K(+)/Cl(-) co-transporter KCC2 driving Cl(-) efflux. The developmental transition of KCC2 expression is regulated by Disrupted-in-schizophrenia 1 (DISC1) and brain-derived neurotrophic factor (BDNF) signaling. The excitatory GABA signaling during early neurogenesis is important to the activity/experience-induced regulation of NSC quiescence, NPC proliferation, neuroblast migration and newborn neuronal maturation/functional integration. The inhibitory GABA signaling allows for the sparse and static functional networking essential for learning/memory development and maintenance.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
355Neuropsychiatr 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, schizophrenias
356J. Chem. Neuroanat. 2013 Nov 53: 1-10
PMID23912123
TitleDBZ (DISC1-binding zinc finger protein)-deficient mice display abnormalities in basket cells in the somatosensory cortices.
AbstractDisrupted-in-schizophrenia 1 (DISC1)-binding zinc finger protein (DBZ) is a DISC1-interacting molecule and the interaction between DBZ and DISC1 is involved in neurite outgrowth in vitro. DBZ is highly expressed in brain, especially in the cortex. However, the physiological roles of DBZ in vivo have not been clarified. Here, we show that development of basket cells, a morphologically defined class of parvalbumin (PV)-containing interneurons, is disturbed in DBZ knockout (KO) mice. DBZ mRNA was highly expressed in the ventral area of the subventricular zone of the medial ganglionic eminence, where PV-containing cortical interneurons were generated, at embryonic 14.5 days (E14.5). Although the expression level for PV and the number of PV-containing interneurons were not altered in the cortices of DBZ KO mice, basket cells were less branched and had shorter processes in the somatosensory cortices of DBZ KO mice compared with those in the cortices of WT mice. Furthermore, in the somatosensory cortices of DBZ KO mice, the level of mRNAs for the gamma-aminobutyric acid-synthesizing enzymes GAD67 was decreased. These findings show that DBZ is involved in the morphogenesis of basket cells.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
357Mol. Psychiatry 2013 Aug 18: 898-908
PMID23587879
TitleDISC1-ATF4 transcriptional repression complex: dual regulation of the cAMP-PDE4 cascade by DISC1.
AbstractDisrupted-In-schizophrenia 1 (DISC1), a risk factor for major mental illnesses, has been studied extensively in the context of neurodevelopment. However, the role of DISC1 in neuronal signaling, particularly in conjunction with intracellular cascades that occur in response to dopamine, a neurotransmitter implicated in numerous psychiatric disorders, remains elusive. Previous data suggest that DISC1 interacts with numerous proteins that impact neuronal function, including activating transcription factor 4 (ATF4). In this study, we identify a novel DISC1 and ATF4 binding region in the genomic locus of phosphodiesterase 4D (PDE4D), a gene implicated in psychiatric disorders. We found that the loss of function of either DISC1 or ATF4 increases PDE4D9 transcription, and that the association of DISC1 with the PDE4D9 locus requires ATF4. We also show that PDE4D9 is increased by D1-type dopamine receptor dopaminergic stimulation. We demonstrate that the mechanism for this increase is due to DISC1 dissociation from the PDE4D locus in mouse brain. We further characterize the interaction of DISC1 with ATF4 to show that it is regulated via protein kinase A-mediated phosphorylation of DISC1 serine-58. Our results suggest that the release of DISC1-mediated transcriptional repression of PDE4D9 acts as feedback inhibition to regulate dopaminergic signaling. Furthermore, as DISC1 loss-of-function leads to a specific increase in PDE4D9, PDE4D9 itself may represent an attractive target for therapeutic approaches in psychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
358Genet Test Mol Biomarkers 2013 May 17: 407-11
PMID23581481
TitleAssociation study of three microsatellite polymorphisms located in introns 1, 8, and 9 of DISC1 with schizophrenia in the Chinese Han population.
AbstractThis study explores more polymorphisms in Disrupted-in-schizophrenia-1 (DISC1) for schizophrenia, which confer risk of developing the disorder.
We report three short tandem repeat (STR) loci ((ATCC)n1, D1S1621, and (ATCC)n2) in DISC1 that showed a significant association with schizophrenia in a set of Chinese Han individuals, including 310 schizophrenics and 400 controls. The STRs in DISC1 associated with schizophrenia occur in intronic sequences in the vicinity of a critical splice junction that gives rise to the expression of DISC1 isoforms. The frequencies of allele 12 of (ATCC)n1, alleles 11 and 12, allele 13 and allele 15 of D1S1621, and allele 10 of (ATCC)n2 were significantly higher in schizophrenia patients than in controls. In contrast, the frequencies of alleles 9 and 10 of (ATCC)n1 and allele 16 and alleles17 and 18 of D1S1621 were significantly lower in schizophrenia patients than in controls.
Our results provide further evidence for an effect of the DISC1 gene on the etiology of schizophrenia and suggest that STRs in the DISC1 gene may be genetic risk factors for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
359Ann. Hum. Genet. 2013 Nov 77: 504-12
PMID23909765
TitleRole of DISC1 interacting proteins in schizophrenia risk from genome-wide analysis of missense SNPs.
AbstractA balanced translocation affecting DISC1 cosegregates with several psychiatric disorders, including schizophrenia, in a Scottish family. DISC1 is a hub protein of a network of protein-protein interactions involved in multiple developmental pathways within the brain. Gene set-based analysis has been proposed as an alternative to individual analysis of single nucleotide polymorphisms (SNPs) to get information from genome-wide association studies. In this work, we tested for an overrepresentation of the DISC1 interacting proteins within the top results of our ranked list of genes based on our previous genome-wide association study of missense SNPs in schizophrenia. Our data set consisted of 5100 common missense SNPs genotyped in 476 schizophrenic patients and 447 control subjects from Galicia, NW Spain. We used a modification of the Gene Set Enrichment Analysis adapted for SNPs, as implemented in the GenGen software. The analysis detected an overrepresentation of the DISC1 interacting proteins (permuted P-value=0.0158), indicative of the role of this gene set in schizophrenia risk. We identified seven leading-edge genes, MACF1, UTRN, DST, DISC1, KIF3A, SYNE1, and AKAP9, responsible for the overrepresentation. These genes are involved in neuronal cytoskeleton organization and intracellular transport through the microtubule cytoskeleton, suggesting that these processes may be impaired in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
360J. Clin. Invest. 2013 Jul 123: 2961-4
PMID23921125
TitleDISC1 and SLC12A2 interaction affects human hippocampal function and connectivity.
AbstractHippocampal development is coordinated by both extracellular factors like GABA neurotransmission and intracellular components like DISC1. We previously reported that SLC12A2-dependent GABA depolarization and DISC1 coregulate hippocampal neuronal development, and 2 SNPs in these genes linked to mRNA expression interactively increase schizophrenia risk. Using functional MRI, we now confirm this biological interaction in vivo by showing in 2 independent samples of healthy individuals (total N = 349) that subjects homozygous for both risk alleles evince dramatically decreased hippocampal area activation (Cohen's d = 0.78)and connectivity (d = 0.57) during a recognition memory task. These data highlight the importance of epistatic models in understanding genetic association with complex brain phenotypes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
361Transl Psychiatry 2013 -1 3: e328
PMID24301646
TitleRole of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction.
AbstractRecent genetic studies have linked mental illness to alterations in disrupted in schizophrenia 1 (DISC1), a multifunctional scaffolding protein that regulates cyclic adenosine monophosphate (cAMP) signaling via interactions with phosphodiesterase 4 (PDE4). High levels of cAMP during stress exposure impair function of the prefrontal cortex (PFC), a region gravely afflicted in mental illness. As stress can aggravate mental illness, genetic insults to DISC1 may worsen symptoms by increasing cAMP levels. The current study examined whether viral knockdown (KD) of the DISC1 gene in rat PFC increases susceptibility to stress-induced PFC dysfunction. Rats were trained in a spatial working memory task before receiving infusions of (a) an active viral construct that knocked down DISC1 in PFC (DISC1 KD group), (b) a 'scrambled' construct that had no effect on DISC1 (Scrambled group), or (c) an active construct that reduced DISC1 expression dorsal to PFC (Anatomical Control group). Data were compared with an unoperated Control group. Cognitive performance was assessed following mild restraint stress that had no effect on normal animals. DISC1 KD rats were impaired by 1??h restraint stress, whereas Scrambled, Control, and Anatomical Control groups were unaffected. Thus, knocking down DISC1 in PFC reduced the threshold for stress-induced cognitive dysfunction, possibly through disinhibited cAMP signaling at neuronal network synapses. These findings may explain why patients with DISC1 mutations may be especially vulnerable to the effects of stress.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
362Prog. 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, schizophrenias
363PLoS ONE 2013 -1 8: e60099
PMID23555897
TitleThe DAO gene is associated with schizophrenia and interacts with other genes in the Taiwan Han Chinese population.
Abstractschizophrenia is a highly heritable disease with a polygenic mode of inheritance. Many studies have contributed to our understanding of the genetic underpinnings of schizophrenia, but little is known about how interactions among genes affect the risk of schizophrenia. This study aimed to assess the associations and interactions among genes that confer vulnerability to schizophrenia and to examine the moderating effect of neuropsychological impairment.
We analyzed 99 SNPs from 10 candidate genes in 1,512 subject samples. The permutation-based single-locus, multi-locus association tests, and a gene-based multifactorial dimension reduction procedure were used to examine genetic associations and interactions to schizophrenia.
We found that no single SNP was significantly associated with schizophrenia. However, a risk haplotype, namely A-T-C of the SNP triplet rsDAO7-rsDAO8-rsDAO13 of the DAO gene, was strongly associated with schizophrenia. Interaction analyses identified multiple between-gene and within-gene interactions. Between-gene interactions including DAO*DISC1 , DAO*NRG1 and DAO*RASD2 and a within-gene interaction for CACNG2 were found among schizophrenia subjects with severe sustained attention deficits, suggesting a modifying effect of impaired neuropsychological functioning. Other interactions such as the within-gene interaction of DAO and the between-gene interaction of DAO and PTK2B were consistently identified regardless of stratification by neuropsychological dysfunction. Importantly, except for the within-gene interaction of CACNG2, all of the identified risk haplotypes and interactions involved SNPs from DAO.
These results suggest that DAO, which is involved in the N-methyl-d-aspartate receptor regulation, signaling and glutamate metabolism, is the master gene of the genetic associations and interactions underlying schizophrenia. Besides, the interaction between DAO and RASD2 has provided an insight in integrating the glutamate and dopamine hypotheses of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
364Neuroscience 2013 Sep 248: 670-80
PMID23811072
TitleA neuregulin 1 transmembrane domain mutation causes imbalanced glutamatergic and dopaminergic receptor expression in mice.
AbstractThe neuregulin 1 gene has repeatedly been identified as a susceptibility gene for schizophrenia, thus mice with genetic mutations in this gene offer a valuable tool for studying the role of neuregulin 1 in schizophrenia-related neurotransmission. In this study, slide-based receptor autoradiography was used to quantify glutamatergic N-methyl-d-aspartate (NMDA), dopaminergic D2, cannabinoid CB1 and acetylcholine M1/4 receptor levels in the brains of male heterozygous transmembrane domain neuregulin 1 mutant (Nrg1(+/-)) mice at two ages. Mutant mice expressed small but significant increases in NMDA receptor levels in the cingulate cortex (7%, p=0.044), sensory cortex (8%, p=0.024), and motor cortex (8%, p=0.047), effects that were independent of age. In the nucleus accumbens and thalamus Nrg1(+/-) mice exhibited age-dependent alterations in NMDA receptors. Nrg1(+/-) mice showed a statistically significant increase in NMDA receptor levels in the nucleus accumbens of 14-week-old Nrg1(+/-) mice compared to control littermates of the same age (12%, p=0.026), an effect that was not seen in 20-week-old mice. In contrast, NMDA receptor levels in the thalamus, while initially unchanged in 14-week-old mice, were then decreased in the 20-week-old Nrg1(+/-) mice compared to control littermates of the same age (14%, p=0.011). Nrg1(+/-) mutant mice expressed a significant reduction in D2 receptor levels (13-16%) in the striatum compared to controls, independent of age. While there was a borderline significant increase (6%, p=0.058) in cannabinoid CB1 receptor levels in the substantia nigra of Nrg1(+/-) mice compared to controls, CB1 as well as acetylcholine M1/4 receptors showed no change in Nrg1(+/-) mice in any other brain region examined. These data indicate that a Nrg1 transmembrane mutation produces selective imbalances in glutamatergic and dopaminergic neurotransmission, which are two key systems believed to contribute to schizophrenia pathogenesis. While the effects on these systems are subtle, they may underlie the susceptibility of these mutants to further impacts.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
365Proc. Natl. Acad. Sci. U.S.A. 2013 Jul 110: 12462-7
PMID23840059
TitleCognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness.
AbstractGuided by features of molecular, cellular, and circuit dysfunction affecting the prefrontal cortex in clinical investigations, we targeted prefrontal cortex in studies of a model for neuropsychiatric illness using transgenic mice expressing a putative dominant-negative disrupted in schizophrenia 1 (DN-DISC1). We detected marked augmentation of GAPDH-seven in absentia homolog Siah protein binding in the DISC1 mice, a major hallmark of a nuclear GAPDH cascade that is activated in response to oxidative stress. Furthermore, deficits were observed in well-defined tests for the cognitive control of adaptive behavior using reversal learning and reinforcer devaluation paradigms. These deficits occurred even though DN-DISC1 mice showed intact performance in simple associative learning and normal responses in consumption of reward. In an additional series of assessments, motivational functions also were impoverished in DN-DISC1 mice, including tests of the dynamic modulation of reward value by effortful action, progressive ratio performance, and social behavior. Augmentation of an oxidative stress-associated cascade (e.g., a nuclear GAPDH cascade) points to an underlying condition that may contribute to the profile of cognitive and motivational impairments in DN-DISC1 mice by affecting the functional integrity of the prefrontal cortex and dysfunction within its connected networks. As such, this model should be useful for further preclinical research and drug discovery efforts relevant to the burden of prefrontal dysfunction in neuropsychiatric illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
366Biol. Chem. 2013 Nov 394: 1425-37
PMID23832957
TitleRevisiting disrupted-in-schizophrenia 1 as a scaffold protein.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a widely-accepted genetic risk factor for schizophrenia and many other major mental illnesses. Traditionally DISC1 has been referred to as a 'scaffold protein' because of its ability to bind to a wide array of other proteins, including those of importance for neurodevelopment. Here, we review the characteristic properties shared between established scaffold proteins and DISC1. We find DISC1 to have many, but not all, of the characteristics of a scaffold protein, as it affects a considerable number of different, but related, signaling pathways, in most cases through inhibition of key enzymes. Using threading algorithms, the C-terminal portion of DISC1 could be mapped to extended helical structures, yet it may not closely resemble any of the known tertiary folds. While not completely fitting the classification of a classical scaffold protein, DISC1 does appear to be a tightly regulated and multi-faceted inhibitor of a wide range of enzymes from interrelated signaling cascades (Diverse Inhibitor of Signaling Cascades), which together contribute to neurodevelopment and synaptic homeostasis. Consequently, disruption of this complex regulation would be expected to lead to the range of major mental illnesses in which the DISC1 gene has been implicated.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
367Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Oct -1: -1
PMID24513021
TitleIncreased Stability of Microtubules in Cultured Olfactory Neuroepithelial Cells from Individuals with Schizophrenia.
AbstractMicrotubules (MTs) are essential components of the cytoskeleton that play critical roles in neurodevelopment and adaptive central nervous system functioning. MTs are essential to growth cone advance and ultrastructural events integral to synaptic plasticity; these functions figure significantly into current pathophysiologic conceptualizations of schizophrenia. To date, no study has directly investigated MT dynamics in humans with schizophrenia. We therefore compared the stability of MTs in olfactory neuroepithelial (OE) cells between schizophrenia cases and matched nonpsychiatric comparison subjects. For this purpose, we applied nocodazole (Nz) to cultured OE cells obtained from tissue biopsies from seven living schizophrenia patients and seven matched comparison subjects; all schizophrenia cases were on antipsychotic medications. Nz allows MT depolymerization to be followed but prevents repolymerization, so that in living cells treated for varying time intervals, the MTs that are stable for a given treatment interval remain. Our readout of MT stability was the time at which fewer than 10 MTs per cell could be distinguished by anti-?-tubulin immunofluorescence. The percentage of cells with >10 intact MTs at specified intervals following Nz treatment was estimated by systematic uniform random sampling with Visiopharm software. These analyses showed that the mean percentages of OE cells with intact MTs were significantly greater for schizophrenia cases than for the matched comparison subjects at 10, 15, and 30minutes following Nz treatment indicating increased MT stability in OE cells from schizophrenia patients (p=.0007 at 10minutes; p=.0008 at 15minutes; p=.036 at 30minutes). In conclusion, we have demonstrated increased MT stability in nearly all cultures of OE cells from individuals with schizophrenia who received several antipsychotic treatments, versus comparison subjects matched for age and sex. While we cannot rule out a possible confounding effect of antipsychotic medications, these findings may reflect analogous neurobiological events in at least a subset of immature neurons or other cell types during gestation, or newly generated cells destined for the olfactory bulb or hippocampus, suggesting a mechanism that underlies findings of postmortem and neuroimaging investigations of schizophrenia. Future studies aimed at replicating these findings, including samples of medication-nave subjects with schizophrenia, and reconciling the results with other studies, will be necessary. Although the observed abnormalities may suggest one of a number of putative pathophysiologic anomalies in schizophrenia, this work may ultimately have implications for an improved understanding of pathogenic processes related to this disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
368Neurosci Biobehav Rev 2013 Jun 37: 896-910
PMID23567519
TitleUsing rodents to model schizophrenia and substance use comorbidity.
Abstractschizophrenia and substance use disorders (SUD) often occur together, yet it is unclear why this is the case or how best to manage dual diagnosis. Rodent models are well suited to study how genes and environment interact to impact neurodevelopment, brain function and behaviors relevant to dual diagnosis. Indeed a variety of rodent models for schizophrenia display behavioral and physiological features relevant to SUD including: neurodevelopmental models, models of a rare variant (DISC1), to models of common variants (neurexin, dysbindin and neuregulin), and models of various gene-drug interactions. Thus it may be worthwhile to probe models of schizophrenia for insights relevant to SUD and dual diagnosis. However, future studies on dual diagnosis should involve characterization beyond measuring locomotor responses to self-administration tasks, include drug classes other than psychostimulants, and dissect the neuroadaptations that underlie risk for dual diagnosis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
369Expert Rev Neurother 2013 Jan 13: 37-47
PMID23253390
TitleProgress in imaging the effects of psychosis susceptibility gene variants.
AbstractGenetic imaging has become an increasingly popular tool that utilizes neuroimaging techniques to investigate the impact of genetic variation on the structure, function and connectivity of the brain. Combining genetic and neuroimaging domains is a promising approach to further the understanding of the neural mechanisms involved in mediating the effect of genetic variants on psychosis risk, with the potential to explore individual vulnerability to psychiatric illness. Imaging genetics approaches have successfully been applied to a wide range of risk genes for schizophrenia. This article reviews the recent literature on genetic imaging in schizophrenia, using two key susceptibility genes for psychosis, DISC1 and NRG1, as examples. The authors explore challenges and future perspectives in the field, including the need for future research to focus on epistatic effects of multiple common variants, account for the complexity of gene-environment interactions, characterize rare high-risk structural variants and identify more effective neuroimaging paradigms that reach a higher threshold of heritability. Ultimately, this review highlights that genetic imaging remains a research technique, and further progress and integration with other techniques will be required before we can predict the onset and development of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
370Mol. Cell. Neurosci. 2013 May 54: 84-92
PMID23396153
TitleA Disc1 mutation differentially affects neurites and spines in hippocampal and cortical neurons.
AbstractA balanced chromosomal translocation segregating with schizophrenia and affective disorders in a large Scottish family disrupting DISC1 implicated this gene as a susceptibility gene for major mental illness. Here we study neurons derived from a genetically engineered mouse strain with a truncating lesion disrupting the endogenous DISC1 ortholog. We provide a detailed account of the consequences of this mutation on axonal and dendritic morphogenesis as well as dendritic spine development in cultured hippocampal and cortical neurons. We show that the mutation has distinct effects on these two types of neurons, supporting a cell-type specific role of DISC1 in establishing structural connections among neurons. Moreover, using a validated antibody we provide evidence indicating that DISC1 localizes primarily to Golgi apparatus-related vesicles. Our results support the notion that in vitro cultures derived from DISC1(Tm1Kara) mice provide a valuable model for future mechanistic analysis of the cellular and biochemical effects of this mutation, and can thus serve as a platform for drug discovery efforts.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
371Exp Neurobiol 2013 Dec 22: 235-43
PMID24465138
TitleInvolvement of genetic and environmental factors in the onset of depression.
AbstractFirst, this article provides a brief overview of the previous hypotheses regarding depression and then focuses on involvement of genetic and environmental factors in development of depression. According to epidemiological research, 30~40% of occurrences of bipolar disorder involve a genetic factor. Therefore, environmental factors play a more important role in development of depression. Resilience and resistance to stress are common; therefore, although a certain extent of stress might be received during the embryonic or perinatal period, having a genetic predisposition to mental disorders does not imply that a mental disorder will develop. However, having a genetic predisposition to disorders does weaken resistance to stresses received during puberty, and without the ability to recover, a mental disorder is triggered. The importance of epigenetics in maintaining normal development and biology is reflected by the observation that development of many diseases occurs when the wrong type of epigenetic marks are introduced or are added at the wrong time or in the wrong place. Involvement of genetic and environmental factors in the onset of depression was investigated in relation to epigenetics. When mice with the disrupted in schizophrenia 1 (DISC1) abnormal gene received isolated rearing stress, depression-like abnormal behaviors and decreased gene expression of tyrosine hydroxylase in the frontal cortex by epigenetical suppression via DNA methylation were observed. Decrease of dopamine in the frontal cortex triggers behavioral disorders. Administration of a glucocorticoid receptor antagonist resulted in full recovery from neurological and behavioral disorders. These results suggest a new therapeutic approach to depression.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
372J. Neurosci. 2013 May 33: 7654-66
PMID23637159
TitleMaternal immune activation during gestation interacts with Disc1 point mutation to exacerbate schizophrenia-related behaviors in mice.
Abstractschizophrenia is thought to result from interactions between susceptible genotypes and environmental risk factors. DISC1 is an important gene for schizophrenia and mood disorders based on both human and animal studies. In the present study we sought to investigate interactions between two distinct point mutations in the mouse DISC1 gene (L100P and Q31L) and maternal immune activation (MIA) during pregnancy with polyinosinic:polycytidylic acid (polyI:C). PolyI:C given at 5 mg/kg impaired cognitive and social behavior in both wild-type (WT) and DISC1-Q31L(+/-) offspring, and reduced prepulse inhibition at 16 but not 8 weeks of age. DISC1-L100P(+/-) mutants were more sensitive to MIA than WT or DISC1-Q31L(+/-) mice. Interleukin-6 (IL-6) is a critical cytokine for mediating the behavioral and transcriptional effects of polyI:C. We found a more pronounced increase of IL-6 in response to polyI:C in fetal brain in DISC1-L100P(+/-) mice compared with WT or DISC1-Q31L(+/-) mice. Coadministration of an anti-IL-6 antibody with polyI:C reversed schizophrenia-related behavioral phenotypes in DISC1-L100P(+/-) mice. In summary, we found specific interactions between discrete genetic (DISC1-L100P(+/-)) and environmental factors (MIA) that exacerbate schizophrenia-related phenotypes. IL-6 may be important in the pathophysiology of this interaction.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
373Neuroscience 2013 Oct 251: 90-107
PMID22546337
TitleDendritic spine pathology in schizophrenia.
Abstractschizophrenia is a neurodevelopmental disorder whose clinical features include impairments in perception, cognition and motivation. These impairments reflect alterations in neuronal circuitry within and across multiple brain regions that are due, at least in part, to deficits in dendritic spines, the site of most excitatory synaptic connections. Dendritic spine alterations have been identified in multiple brain regions in schizophrenia, but are best characterized in layer 3 of the neocortex, where pyramidal cell spine density is lower. These spine deficits appear to arise during development, and thus are likely the result of disturbances in the molecular mechanisms that underlie spine formation, pruning, and/or maintenance. Each of these mechanisms may provide insight into novel therapeutic targets for preventing or repairing the alterations in neural circuitry that mediate the debilitating symptoms of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
374Mol Brain 2013 -1 6: 20
PMID23631734
TitleAbnormal interneuron development in disrupted-in-schizophrenia-1 L100P mutant mice.
AbstractInterneuron deficits are one of the most consistent findings in post-mortem studies of schizophrenia patients and are likely important in the cognitive deficits associated with schizophrenia. Disrupted-in-schizophrenia 1 (DISC1), a strong susceptibility gene for schizophrenia and other mental illnesses, is involved in neurodevelopment, including that of interneurons. However, the mechanism by which DISC1 regulates interneuron development remains unknown. In this study, we analyzed interneuron histology in the DISC1-L100P single point mutation mouse, that was previously shown to have behavioral abnormalities and cortical developmental defects related to schizophrenia.
We sought to determine whether a DISC1-L100P point mutation in the mouse would alter interneuron density and location. First, we examined interneuron position in the developing mouse cortex during embryonic days 14-16 as an indicator of interneuron tangential migration, and found striking migration deficits in DISC1-L100P mutants. Further analysis of adult brains revealed that the DISC1-L100P mutants have selective alterations of calbindin- and parvalbumin-expressing interneurons in the cortex and hippocampus, decreased GAD67/PV co-localization and mis-positioned interneurons across the neocortex when compared to wild-type littermates.
Our results are consistent with the anomalies seen in post-mortem schizophrenia studies and other DISC1 mutant mouse models. Future research is required to determine the specific mechanisms underlying these cellular deficits. Overall, these findings provide further evidence that DISC1 participates in interneuron development and add to our understanding of how DISC1 variants can affect susceptibility to psychiatric illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
375Front Biol (Beijing) 2013 Feb 8: 1-31
PMID23550053
TitleDISC1 genetics, biology and psychiatric illness.
AbstractPsychiatric disorders are highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points towards DISC1 being one of the genes that influence risk of schizophrenia, bipolar disorder and depression, and functional studies of DISC1 consequently have the potential to reveal much about the pathways that lead to major mental illness. Here, we review the evidence that DISC1 influences disease risk through effects upon multiple critical pathways in the developing and adult brain.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
376Psychiatry Res 2013 Jul 208: 189-90
PMID23497821
TitleLack of association between DISC1 polymorphisms and risk of schizophrenia in a Korean population.
AbstractThe DISC1 gene is considered to be a strong candidate gene for the development of schizophrenia. This study examines the association of DISC1 polymorphisms with schizophrenia in a Korean population. Although we fail to discover convincing evidence that DISC1 affects schizophrenia development, our findings may be useful for further genetic studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
377Gene 2013 Apr 518: 223-30
PMID23353011
TitleDISC1-related signaling pathways in adult neurogenesis of the hippocampus.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a multifunctional scaffold protein which plays an important role in neurogenesis and neural development in the adult brain, especially in the dentate gyrus (DG) of the hippocampus. Accumulated research has unveiled the role of DISC1 in several aspects of neural development and neurogenesis, such as neuronal maturation, proliferation, migration, positioning, differentiation, dendritic growth, axonal outgrowth, and synaptic plasticity. Studies on the function of this protein have explored multiple facets, including variants and missense mutants in genetics, proteins interactivity and signaling pathways in molecular biology, and pathogenesis and treatment targets of major mental illness, and more. In this review, we present several signaling pathways discussed in recent research, such as the AKT signaling pathway, GABA signaling pathway, GSK3? signaling pathway, Wnt signaling pathway, and NMDA-R signaling pathway. DISC1 interacts, directly or indirectly, with these signaling pathways and they co-regulate the process of adult neurogenesis in the hippocampus.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
378Neuroscientist 2013 Oct 19: 451-64
PMID23300216
TitleDISC1: a key lead in studying cortical development and associated brain disorders.
AbstractFor the past decade, DISC1 has been studied as a promising lead to understand the biology underlying major mental illnesses, such as schizophrenia. Consequently, many review articles on DISC1 have been published. In this article, rather than repeating comprehensive overviews of research articles, we will introduce the utility of DISC1 in the study of cortical development in association with a wide range of developmental brain disorders. Cortical development involves cell autonomous and cell nonautonomous mechanisms as well as host responses to environmental factors, all of which involve DISC1 function. Thus, we will discuss the significance of DISC1 in forming an overall understanding of multiple mechanisms that orchestrate corticogenesis and can serve as therapeutic targets in diseases caused by abnormal cortical development.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
379J Psychiatr Res 2013 Feb 47: 188-96
PMID23140672
TitleDISC1 (disrupted-in-schizophrenia 1) is associated with cortical grey matter volumes in the human brain: a voxel-based morphometry (VBM) study.
AbstractDISC1 (Disrupted-In-schizophrenia 1), one of the top candidate genes for schizophrenia, has been associated with a range of major mental illnesses over the last two decades. DISC1 is crucially involved in neurodevelopmental processes of the human brain. Several haplotypes and single nucleotide polymorphisms of DISC1 have been associated with changes of grey matter volumes in brain regions known to be altered in schizophrenia and other psychiatric disorders. The aim of the present study was to investigate the effects of two single nucleotide polymorphisms (SNPs) of DISC1 on grey matter volumes in human subjects using voxel-based morphometry (VBM). 114/113 participating subjects (psychiatric patients and healthy controls) were genotyped with respect to two at-risk SNPs of DISC1, rs6675281 and rs821616. All participants underwent structural magnetic resonance imaging (MRI). MRI data was statistically analyzed using voxel-based morphometry. We found significant alterations of grey matter volumes in prefrontal and temporal brain regions in association with rs6675281 and rs821616. These effects of DISC1 polymorphisms on brain morphology provide further support for an involvement of DISC1 in the neurobiology of major psychiatric disorders such as schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
380Schizophr. Res. 2013 Jun 147: 1-13
PMID23602339
TitleHuman brain imaging studies of DISC1 in schizophrenia, bipolar disorder and depression: a systematic review.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a well researched candidate gene for schizophrenia and affective disorders with a range of functions relating to neurodevelopment. Several human brain imaging studies investigating correlations between common and rare variants in DISC1 and brain structure and function have shown conflicting results. A meta-analysis of case/control data showed no association between schizophrenia and any common SNP in DISC1. Therefore it is timely to review the literature to plan the direction of future studies. Twenty-two human brain imaging studies have examined the influence of DISC1 variants in health, schizophrenia, bipolar disorder or depression. The most studied common SNPs are Ser704Cys (rs821616) and Leu607Phe (rs6675281). Some imaging-genomic studies report effects on frontal, temporal and hippocampal structural indices in health and illness and a volumetric longitudinal study supports a putative role for these common SNPs in neurodevelopment. Callosal agenesis is described in association with rare deletions at 1q42 which include DISC1 and rare sequence variants at DISC1 itself. DISC1 interactions with translin-associated factor X (TRAX) and neuregulin have been shown to influence several regional volumes. In the first study involving neonates, a role for Ser704Cys (rs821616) has been highlighted in prenatal brain development with large clusters of reduced grey matter reported in the frontal lobes. Functional MRI studies examining associations between Ser704Cys (rs821616) and Leu607Phe (rs6675281) with prefrontal and hippocampal activation have also given inconsistent results. Prefrontal function was reported to be associated with interaction between DISC1 and CITRON (CIT) in health. Preliminary magnetic resonance spectroscopy and diffusion tensor data support the influence of Ser704Cys (rs821616) status on grey and white matter integrity. The glutamate system remains uninvestigated. Associations between rare sequence variants and structural changes in brain regions including the corpus callosum and effects of gene-gene interactions on brain structure and function are promising areas for future study.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
381Front Behav Neurosci 2013 -1 7: 113
PMID24027503
TitleDISC1 mouse models as a tool to decipher gene-environment interactions in psychiatric disorders.
AbstractDISC1 was discovered in a Scottish pedigree in which a chromosomal translocation that breaks this gene segregates with psychiatric disorders, mainly depression and schizophrenia. Linkage and association studies in diverse populations support DISC1 as a susceptibility gene to a variety of neuropsychiatric disorders. Many DISC1 mouse models have been generated to study its neuronal functions. These mouse models display variable phenotypes, some of them relevant to schizophrenia, others to depression. The DISC1 mouse models are popular genetic models for studying gene-environment interactions in schizophrenia. Five different DISC1 models have been combined with environmental factors. The environmental stressors employed can be classified as either early immune activation or later social paradigms. These studies cover major time points along the neurodevelopmental trajectory: prenatal, early postnatal, adolescence, and adulthood. Various combinations of molecular, anatomical and behavioral methods have been used to assess the outcomes. Additionally, three of the studies sought to rescue the resulting abnormalities. Here we provide background on the environmental paradigms used, summarize the results of these studies combining DISC1 mouse models with environmental stressors and discuss what we can learn and how to proceed. A major question is how the genetic and environmental factors determine which psychiatric disorder will be clinically manifested. To address this we can take advantage of the many DISC1 models available and expose them to the same environmental stressor. The complementary experiment would be to expose the same model to different environmental stressors. DISC1 is an ideal gene for this approach, since in the Scottish pedigree the same chromosomal translocation results in different psychiatric conditions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
382Neurosci. Res. 2013 Dec 77: 222-7
PMID24013095
TitleAssociation analysis of the DISC1 gene with schizophrenia in the Japanese population and DISC1 immunoreactivity in the postmortem brain.
AbstractThe Disrupted-in-schizophrenia 1 (DISC1) gene plays a role in the regulation of neural development. Previous evidence from genetic association and biological studies implicates the DISC1 gene as having a role in the pathophysiology of schizophrenia. In the present study, we explored the association between DISC1 missense mutation rs821616 (Ser704Cys) single nucleotide polymorphism (SNP) and four other SNPs (rs1772702, rs1754603, rs821621, rs821624) in the related haplotype block and schizophrenia in the Japanese population. We could not find a significant association of selected SNPs with schizophrenia after correction for multiple testing. We performed a meta-analysis of the Ser704Cys variant in schizophrenia using data from the present study and five previous Japanese population studies, and found no association with schizophrenia. We also examined DISC1 immunoreactivity in postmortem prefrontal cortex specimens of schizophrenia patients compared to control samples. The immunoreactivity revealed a significant decrease of DISC1 protein expression in the schizophrenia samples after ruling out potential confounding factors. However, the Ser704Cys variant did not show effects on DISC1 immunoreactivity. These results provide evidence that this functional genetic variation of DISC1 do not underlie the pathophysiology of schizophrenia in the Japanese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
383Int. J. Neuropsychopharmacol. 2013 Aug 16: 1483-503
PMID23442539
TitleGene expression profiling in treatment-naive schizophrenia patients identifies abnormalities in biological pathways involving AKT1 that are corrected by antipsychotic medication.
AbstractDistinct gene expression profiles can be detected in peripheral blood mononuclear cells (PBMCs) in patients with schizophrenia; however, little is known about the effects of antipsychotic medication. This study compared gene expression profiles in PMBCs from treatment-naive patients with schizophrenia before and after antipsychotic drug treatment. PBMCs were obtained from 10 treatment-naive schizophrenia patients before and 6 wk after initiating antipsychotic drug treatment and compared to PMBCs collected from 11 healthy community volunteers. Genome-wide expression profiling was conducted using Illumina HumanHT-12 expression bead arrays and analysed using significance analysis of microarrays. This analysis identified 624 genes with altered expression (208 up-regulated, 416 down-regulated) prior to antipsychotic treatment (p<0.05) including schizophrenia-associated genes AKT1, DISC1 and DGCR6. After 6-8 wk treatment of patients with risperidone or risperidone in combination with haloperidol, only 106 genes were altered, suggesting that the treatment corrected the expression of a large proportion of genes back to control levels. However, 67 genes continued to show the same directional change in expression after treatment. Ingenuity pathway analysis and gene set enrichment analysis implicated dysregulation of biological functions and pathways related to inflammation and immunity in patients with schizophrenia. A number of the top canonical pathways dysregulated in treatment-naive patients signal through AKT1 that was up-regulated. After treatment, AKT1 returned to control levels and less dysregulation of these canonical pathways was observed. This study supports immune dysfunction and pathways involving AKT1 in the aetiopathophysiology of schizophrenia and their response to antipsychotic medication.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
384Anal. Biochem. 2013 Jun 437: 164-71
PMID23481915
TitleDesign and interpretation of microRNA-reporter gene activity.
AbstractMicroRNAs (miRNAs) are small noncoding RNA molecules that act as sequence specificity guides to direct post-transcriptional gene silencing. In doing so, miRNAs regulate many critical developmental processes, including cellular proliferation, differentiation, migration, and apoptosis, as well as more specialized biological functions such as dendritic spine development and synaptogenesis. Interactions between miRNAs and their miRNA recognition elements occur via partial complementarity, rendering tremendous redundancy in targeting such that miRNAs are predicted to regulate 60% of the genome, with each miRNA estimated to regulate more than 200 genes. Because these predictions are prone to false positives and false negatives, there is an ever present need to provide material support to these assertions to firmly establish the biological function of specific miRNAs in both normal and pathophysiological contexts. Using schizophrenia-associated miR-181b as an example, we present detailed guidelines and novel insights for the rapid establishment of a streamlined miRNA-reporter gene assay and explore various design concepts for miRNA-reporter gene applications, including bidirectional miRNA modulation. In exemplifying this approach, we report seven novel miR-181b target sites for five schizophrenia candidate genes (DISC1, BDNF, ENKUR, GRIA1, and GRIK1) and dissect a number of vital concepts regarding future developments for miRNA-reporter gene assays and the interpretation of their results.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
385Schizophr 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, schizophrenias
386Neuropsychopharmacology 2013 Feb 38: 423-36
PMID23011268
TitleDisrupted-in-schizophrenia-1 Gln31Leu polymorphism results in social anhedonia associated with monoaminergic imbalance and reduction of CREB and ?-arrestin-1,2 in the nucleus accumbens in a mouse model of depression.
AbstractDisrupted-in-schizophrenia-1 (DISC1) is associated with mental disorders, including major depression. We previously showed that DISC1-Q31L mutant mice have depression-like behaviors and can therefore be used to study neurobiological mechanisms of depression and antidepressant (AD) medication action. First, we found reduced levels of dopamine, serotonin and norepinephrine in the nucleus accumbens (NAC) of DISC1-Q31L mutants. Next, we assessed social-conditioned place preference as a reward-dependent task and the capacity of distinct ADs to correct impaired social behavior in DISC1-Q31L mice. Bupropion, but not fluoxetine or desipramine, was able to correct deficient social facilitation, social reward, and social novelty in DISC1-Q31L mutants, whereas all three ADs were able to improve social motivation and behavioral despair in DISC1-Q31L mutants. Furthermore, we sought to correlate social anhedonia with molecular and cellular features including dendritic spine density, ?-arrestin-1,2, and cAMP-response-element-binding protein (CREB) in the NAC as biomarkers related to depression and the DISC1 pathway. DISC1-Q31L mutants showed reduced levels of ?-arrestin-1,2, CREB, and spine density in the NAC, further supporting the construct validity of the genetic model. Bupropion induced the greatest effect on CREB in DISC1-Q31L mutants, whereas all studied ADs corrected the reduced levels of ?-arrestin-1,2 and modestly ameliorated deficient spine density in this brain region. Overall, we find neurobiological changes accompanying social anhedonia in the NAC of DISC1-Q31L mutant mice, consistent with a role for DISC1 in regulating social reward as an endophenotype of depression.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
387Cereb. Cortex 2013 Jul 23: 1643-54
PMID22693343
TitleConstellation of HCN channels and cAMP regulating proteins in dendritic spines of the primate prefrontal cortex: potential substrate for working memory deficits in schizophrenia.
Abstractschizophrenia associates with impaired prefrontal cortical (PFC) function and alterations in cyclic AMP (cAMP) signaling pathways. These include genetic insults to disrupted-in-schizophrenia (DISC1) and phosphodiesterases (PDE4s) regulating cAMP hydrolysis, and increased dopamine D1 receptor (D1R) expression that elevates cAMP. We used immunoelectron microscopy to localize DISC1, PDE4A, PDE4B, and D1R in monkey PFC and to view spatial interactions with hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that gate network inputs when opened by cAMP. Physiological interactions between PDE4s and HCN channels were tested in recordings of PFC neurons in monkeys performing a spatial working memory task. The study reveals a constellation of cAMP-related proteins (DISC1, PDE4A, and D1R) and HCN channels next to excitatory synapses and the spine neck in thin spines of superficial PFC, where working memory microcircuits interconnect and spine loss is most evident in schizophrenia. In contrast, channels in dendrites were distant from synapses and cAMP-related proteins, and were associated with endosomal trafficking. The data suggest that a cAMP signalplex is selectively positioned in the spines to gate PFC pyramidal cell microcircuits. Single-unit recordings confirmed physiological interactions between cAMP and HCN channels, consistent with gating actions. These data may explain why PFC networks are especially vulnerable to genetic insults that dysregulate cAMP signaling.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
388Brain Behav. Immun. 2013 May 30: 168-75
PMID23402795
TitleEpigenetic changes at gene promoters in response to immune activation in utero.
AbstractIncreasing evidence suggests that maternal infection increases the risk of psychiatric disorders, such as schizophrenia and autism in offspring. However, the molecular mechanisms associated with these effects are unclear. Here, we have studied epigenetic gene regulation in mice exposed to non-specific immune activation elicited by polyI:C injection to pregnant dams. Using Western blot analysis, we detected global hypoacetylation of histone H3, at lysine residues 9 and 14, and histone H4, at lysine residue 8, in the cortex from juvenile (?24days of age) offspring exposed to polyI:C in utero, but not from adult (3months of age) offspring, which exhibit significant behavioral abnormalities. Accordingly, we detected robust deficits in the expression of genes associated with neuronal development, synaptic transmission and immune signaling in the cortex of polyI:C-exposed juvenile mice. In particular, we found that several genes in the glutamate receptor signaling pathway, including Gria1 and Slc17a7, showed decreases in promoter-specific histone acetylation, and corresponding gene expression deficits, in polyI:C-exposed offspring at both juvenile and adult ages. In contrast, the expression of these same genes, in addition to DISC1 and Ntrk3, was elevated in the hippocampus of juvenile mice, in concordance with elevated levels of promoter-specific histone acetylation. We suggest that these early epigenetic changes contribute to the delayed behavioral abnormalities that are observed in adult animals after exposure to polyI:C, and which resemble symptoms seen in schizophrenia and related disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
389J. Pharmacol. Sci. 2013 -1 121: 185-91
PMID23449491
TitleBehavioral phenotypes in schizophrenic animal models with multiple combinations of genetic and environmental factors.
Abstractschizophrenia is a multifactorial psychiatric disorder in which both genetic and environmental factors play a role. Genetic [e.g., Disrupted-in-schizophrenia 1 (DISC1), Neuregulin-1 (NRG1)] and environmental factors (e.g., maternal viral infection, obstetric complications, social stress) may act during the developmental period to increase the incidence of schizophrenia. In animal models, interactions between susceptibility genes and the environment can be controlled in ways not possible in humans; therefore, such models are useful for investigating interactions between or within factors in the pathogenesis and pathophysiology of schizophrenia. We provide an overview of schizophrenic animal models investigating interactions between or within factors. First, we reviewed gene-environment interaction animal models, in which schizophrenic candidate gene mutant mice were subjected to perinatal immune activation or adolescent stress. Next, environment-environment interaction animal models, in which mice were subjected to a combination of perinatal immune activation and adolescent administration of drugs, were described. These animal models showed interaction between or within factors; behavioral changes, which were obscured by each factor, were marked by interaction of factors and vice versa. Appropriate behavioral approaches with such models will be invaluable for translational research on novel compounds, and also for providing insight into the pathogenesis and pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
390Schizophr. Res. 2013 May 146: 264-72
PMID23481583
TitleFrontal cortical synaptic communication is abnormal in Disc1 genetic mouse models of schizophrenia.
AbstractMouse models carrying DISC1 mutations may provide insights into how DISC1 genetic variations contribute to schizophrenia (SZ) susceptibility. DISC1 mutant mice show behavioral and cognitive disturbances reminiscent of SZ. To dissect the synaptic mechanisms underlying these phenotypes, we examined electrophysiological properties of cortical neurons from two mouse models, the first expressing a truncated mouse DISC1 (mDISC1) protein throughout the entire brain, and the second expressing a truncated human DISC1 (hDISC1) protein in forebrain regions. We obtained whole-cell patch clamp recordings to examine how altered expression of DISC1 protein changes excitatory and inhibitory synaptic transmissions onto cortical pyramidal neurons in the medial prefrontal cortex in 4-7 month-old mDISC1 and hDISC1 mice. In both mDISC1 and hDISC1 mice, the frequency of spontaneous EPSCs was greater than in wild-type littermate controls. Male mice from both lines were more affected by the DISC1 mutation than were females, exhibiting increases in the ratio of excitatory to inhibitory events. Changes in spontaneous IPSCs were only observed in the mDISC1 model and were sex-specific, with diminished cortical GABAergic neurotransmission, a well-documented characteristic of SZ, occurring only in male mDISC1 mice. In contrast, female mDISC1 mice showed an increase in the frequency of small-amplitude sIPSCs. These findings indicate that truncations of DISC1 alter glutamatergic and GABAergic neurotransmission both commonly and differently in the models and some of the effects are sex-specific, revealing how altered DISC1 expression may contribute to behavioral disruptions and cognitive deficits of SZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
391Mol. Psychiatry 2013 May 18: 557-67
PMID22801410
TitlePathogenic disruption of DISC1-serine racemase binding elicits schizophrenia-like behavior via D-serine depletion.
AbstractPerturbation of Disrupted-In-schizophrenia-1 (DISC1) and D-serine/NMDA receptor hypofunction have both been implicated in the pathophysiology of schizophrenia and other psychiatric disorders. In the present study, we demonstrate that these two pathways intersect with behavioral consequences. DISC1 binds to and stabilizes serine racemase (SR), the enzyme that generates D-serine, an endogenous co-agonist of the NMDA receptor. Mutant DISC1 fails to bind to SR, facilitating ubiquitination and degradation of SR and a decrease in D-serine production. To elucidate DISC1-SR interactions in vivo, we generated a mouse model of selective and inducible expression of mutant DISC1 in astrocytes, the main source of D-serine in the brain. Expression of mutant DISC1 downregulates endogenous DISC1 and decreases protein but not mRNA levels of SR, resulting in diminished production of D-serine. In contrast, mutant DISC1 does not alter levels of ALDH1L1, connexins, GLT-1 or binding partners of DISC1 and SR, LIS1 or PICK1. Adult male and female mice with lifelong expression of mutant DISC1 exhibit behavioral abnormalities consistent with hypofunction of NMDA neurotransmission. Specifically, mutant mice display greater responses to an NMDA antagonist, MK-801, in open field and pre-pulse inhibition of the acoustic startle tests and are significantly more sensitive to the ameliorative effects of D-serine. These findings support a model wherein mutant DISC1 leads to SR degradation via dominant negative effects, resulting in D-serine deficiency that diminishes NMDA neurotransmission thus linking DISC1 and NMDA pathophysiological mechanisms in mental illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
392Neuropharmacology 2013 Jan 64: 205-14
PMID22749842
TitleDual inhibitor of PDE7 and GSK-3-VP1.15 acts as antipsychotic and cognitive enhancer in C57BL/6J mice.
AbstractCognitive deficit is a core of schizophrenia and it is not effectively treated by the available antipsychotic drugs, hence new and more effective therapy is needed. schizophrenia is considered as a pathway disorder where Disrupted-In-schizophrenia-1 (DISC1) is important molecular player that regulates multiple cellular cascades. We recently reported synergistic action between phosphodiesterase-4 (PDE4) and glycogen synthase kinase-3 (GSK-3) as DISC1 interacting proteins. In the current study we characterized behavioural effects of a newly developed compound, VP1.15 that inhibits both PDE7 and GSK-3 with main focus on its antipsychotic and cognitive capacities. VP1.15 reduced ambulation in C57BL/6J mice in a dose-dependent manner (7.5 mg/kg and 3 mg/kg, respectively) and, hence, lower dose was chosen for the further analysis. VP1.1.5 facilitated pre-pulse inhibition (PPI), reversed amphetamine- but not MK-801-induced PPI deficit. The drug was able to ameliorate the disrupted latent inhibition (LI) induced by the increased number of conditioning trials and reversed amphetamine-induced LI deficit, supporting further its antipsychotic effects. The drug also significantly improved episodic memory in the spatial object recognition test, facilitated working memory in Y-maze and enhanced cued fear memory, but had no effect on executive function in the Puzzle box and contextual fear conditioning. Taken together, VP1.15 elicited antipsychotic effects and also facilitated cognitive domains in mice, suggesting that multitarget drugs, affecting molecular substrates from the same pathway, perhaps could be antipsychotics of new-generation that open a new possibilities in drug discoveries. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
393Cell. Mol. Life Sci. 2013 May 70: 1663-72
PMID23233134
TitleInteraction of DISC1 with the PTB domain of Tensin2.
AbstractThe gene for Disrupted-in-schizophrenia 1 (DISC1) is amongst the most significant risk genes for schizophrenia. The DISC1 protein is an intracellular scaffolding molecule thought to act an important hub for protein interactions involved in signalling for neural cell differentiation and function. Tensin2 is an intracellular actin-binding protein that bridges the intracellular portion of transmembrane receptors to the cytoskeleton, thereby regulating signalling for cell shape and motility. In this study, we probed in molecular detail a novel interaction between DISC1 and Tensin2. Western blot and confocal microscopic analyses revealed widespread expression of both DISC1 and Tensin2 proteins throughout the mouse brain. Furthermore, we have developed novel anti-DISC1 antibodies that verified the predominant expression of a 105-kDa isoform of DISC1 in the rodent brain as well as in human cells. In the mouse brain, both proteins showed region-specific expression patterns, including strong expression in the pyramidal cell layer of the hippocampus and dentate gyrus. DISC1-Tensin2 colocalisation was most clearly observed in the Purkinje cells of the mouse cerebellum. Biochemical coimmunoprecipitation experiments revealed an interaction between endogenous DISC1 and Tensin2 proteins in the mouse brain. Further pulldown studies in human cells using Myc-tagged Tensin2 constructs revealed that DISC1 specifically interacts with the C-terminal PTB domain of Tensin2 in a phosphorylation-independent manner. This new knowledge on the DISC1-Tensin2 interaction, as part of the wider DISC1 interactome, should further elucidate the signalling pathways that are perturbed in schizophrenia and other mental disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
394J Psychiatr Res 2013 May 47: 657-63
PMID23388542
TitlePlasma Ndel1 enzyme activity is reduced in patients with schizophrenia--a potential biomarker?
AbstractNdel1 oligopeptidase interacts with schizophrenia (SCZ) risk gene product DISC1 and mediates several functions related to neurite outgrowth and neuronal migration. Ndel1 also hydrolyzes neuropeptides previously implicated in SCZ, namely neurotensin and bradykinin. Herein, we compared the plasma Ndel1 enzyme activity of 92 SCZ patients and 96 healthy controls (HCs). Ndel1 enzyme activity was determined by fluorimetric measurements of the FRET peptide substrate Abz-GFSPFRQ-EDDnp hydrolysis rate. A 31% lower mean value for Ndel1 activity was observed in SCZ patients compared to HCs (Student's t = 4.36; p < 0.001; Cohen's d = 0.64). The area under the curve (AUC) for the Receiver Operating Characteristic (ROC) curve for Ndel1 enzyme activity and SCZ/HCs status as outcome was 0.70. Treatment-resistant (TR) SCZ patients were shown to present a significantly lower Ndel1 activity compared to non-TR (NTR) patients by t-test analysis (t = 2.25; p = 0.027). A lower enzymatic activity was significantly associated with both NTR (p = 0.002; B = 1.19; OR = 3.29; CI 95% 1.57-6.88) and TR patients (p < 0.001; B = 2.27; OR = 9.64; CI 95% 4.12-22.54). No correlation between Ndel1 enzyme activity and antipsychotic dose, nicotine dependence, and body mass index was observed. This study is the first to show differences in Ndel1 activity in SCZ patients compared to HCs, besides with a significant lower activity for TR patients compared to NTR patients. Our findings support the Ndel1 enzyme activity implications to clinical practice in terms of diagnosis and drug treatment of SCZ.
To compare the Ndel1 enzyme activity levels of schizophrenia (SCZ) patients and healthy controls (HCs) and to correlate these values with the clinical profile and response to treatment by measuring the Ndel1 enzyme activity in human plasma.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
395DNA Cell Biol. 2013 Feb 32: 73-80
PMID23347445
TitleEffects of the adverse life events and Disrupted in Schizophrenia-1 (DISC1) gene polymorphisms on acute symptoms of schizophrenia.
AbstractThe aim of this study was to evaluate the effects of traumatic childhood events and recent adverse life events, as well as the Disrupted in schizophrenia-1 (DISC1) gene polymorphisms on types of last acute symptoms of patients with schizophrenia. Hundred patients with schizophrenia were given the Childhood Trauma Questionnaire, the Social Readjustment Rating Scale, Scale for Assessment of Positive Symptoms (SAPS), Scale for Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), and Calgary Depression Scale for schizophrenia (CDSS). The patients' and healthy controls' DISC1 gene was evaluated for the -274G>C, c.791G>A, and c.2110A>T polymorphisms. There was no statistically significant difference with regard to the DISC1 gene polymorphisms between patient and healthy control groups. No significant relationship was found between the -274G>C, c.791G>A, and c.2110A>T haplotypes and development of different acute symptoms of schizophrenia. Having a recent stressful life event significantly affected SAPS (95% confidence interval [CI]=-67.547, -21.473; p=0.00) and BPRS-1 scores (95% CI=-51.405, -6.885; p=0.01), whereas emotional abuse at childhood significantly affected SANS scores (95% CI=-37.300, -10.401; p=0.00). This study shows that features of acute symptoms in schizophrenia are not influenced by the polymorphisms on the DISC1 gene, but are influenced by recent adverse life events and emotional abuse at childhood.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
396Schizophr Bull 2013 Jan 39: 161-7
PMID21878470
TitleEffect of DISC1 on the P300 waveform in psychosis.
AbstractAbnormalities in the neurophysiological measures P300 amplitude and latency constitute endophenotypes for psychosis. Disrupted-in-schizophrenia-1 (DISC1) has been proposed as a promising susceptibility gene for schizophrenia, and a previous study has suggested that it is associated with P300 deficits in schizophrenia.
We examined the role of variation in DISC1 polymorphisms on the P300 endophenotype in a large sample of patients with schizophrenia or psychotic bipolar disorder (n = 149), their unaffected relatives (n = 130), and unrelated healthy controls (n = 208) using linear regression and haplotype analysis.
Significant associations between P300 amplitude and latency and DISC1 polymorphisms/haplotypes were found. Those homozygous for the A allele of single-nucleotide polymorphism (SNP) rs821597 displayed significantly reduced P300 amplitudes in comparison with homozygous for the G allele (P = .009) and the heterozygous group (P = .018). Haplotype analysis showed a significant association for DISC1 haplotypes (rs3738401|rs6675281|rs821597|rs821616|rs967244|rs980989) and P300 latency. Haplotype GCGTCG and ACGTTT were associated with shorter latencies.
The P300 waveform appears to be modulated by variation in individual SNPs and haplotypes of DISC1. Because DISC1 is involved in neurodevelopment, one hypothesis is that disruption in neural connectivity impairs cognitive processes illustrated by P300 deficits observed in this sample.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
397Front Cell Neurosci 2013 -1 7: 31
PMID23543703
TitleNMDA hypofunction as a convergence point for progression and symptoms of schizophrenia.
Abstractschizophrenia is a disabling mental illness that is now recognized as a neurodevelopmental disorder. It is likely that genetic risk factors interact with environmental perturbations to affect normal brain development and that this altered trajectory results in a combination of positive, negative, and cognitive symptoms. Although the exact pathophysiology of schizophrenia is unknown, the N-methyl-D-aspartate receptor (NMDAR), a major glutamate receptor subtype, has received great attention. Proper expression and regulation of NMDARs in the brain is critical for learning and memory processes as well as cortical plasticity and maturation. Evidence from both animal models and human studies implicates a dysfunction of NMDARs both in disease progression and symptoms of schizophrenia. Furthermore, mutations in many of the known genetic risk factors for schizophrenia suggest that NMDAR hypofunction is a convergence point for schizophrenia. In this review, we discuss how disrupted NMDAR function leads to altered neurodevelopment that may contribute to the progression and development of symptoms for schizophrenia, particularly cognitive deficits. We review the shared signaling pathways among the schizophrenia susceptibility genes DISC1, neuregulin1, and dysbindin, focusing on the AKT/GSK3? pathway, and how their mutations and interactions can lead to NMDAR dysfunction during development. Additionally, we explore what open questions remain and suggest where schizophrenia research needs to move in order to provide mechanistic insight into the cause of NMDAR dysfunction, as well as generate possible new avenues for therapeutic intervention.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
398Am. J. Med. Genet. B Neuropsychiatr. Genet. 2013 Apr 162B: 227-34
PMID23389941
TitleDISC1 in adult ADHD patients: an association study in two European samples.
AbstractThe DISC1 gene was named after its discovery in a Scottish pedigree with schizophrenia (SCZ) patients. However, subsequent studies have shown association of DISC1 variants with a range of different neurocognitive phenotypes and psychiatric disorders, including bipolar disorder (BPD), and major depression. Attention-deficit/hyperactivity disorder (ADHD) shares some symptoms with BPD and ADHD patients often suffer from comorbid affective disorders. We wanted to examine the role of DISC1 in ADHD, and with comorbid symptoms of mood disorders. Eleven single nucleotide polymorphisms (SNPs) previously implicated in SCZ and BPD, and a DISC1 duplication involving exon 1, were genotyped in 561 adult ADHD cases and 713 controls of Norwegian ancestry. The intronic SNP rs1538979 was associated with ADHD in the Norwegian sample [odds ratio (OR): 1.33, 95% confidence interval (CI) 1.03-1.73, P = 0.03] and replicated in a Spanish adult ADHD sample of 694 cases and 735 controls, using the tagging SNP rs11122330 (meta-analysis: P = 0.008, OR 1.25, 95% CI 1.06-1.47). In the Norwegian ADHD sample we also observed an association between the Phe607-variant of rs6675281 and a positive score on the Mood Disorder Questionnaire (MDQ; OR = 1.44, 95% CI 1.08-1.93, P = 0.01). To our knowledge, this is the first study to show an association between DISC1 variants and ADHD. Our study suggests that further studies are warranted to resolve if DISC1 variation is involved in several common neurodevelopmental disorders including ADHD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
399Cereb. Cortex 2013 Jul 23: 1715-23
PMID22693340
TitleLess efficient information transfer in Cys-allele carriers of DISC1: a brain network study based on diffusion MRI.
AbstractPrevious neuroimaging studies of brain networks have revealed less efficient information transfer in patients with schizophrenia. However, the underlying genetic basis remains largely unexplored. In this study, we investigated the brain anatomical networks of 278 healthy volunteers with different genotypes in the common missense variant (Ser704Cys) of the Disrupted-in-schizophrenia-1 (DISC1) gene, which is one of the main susceptibility genes of schizophrenia and other psychiatric disorders. The anatomical brain network for each individual was constructed using fiber tractography technique based on diffusion magnetic resonance imaging (dMRI). The properties of this network were then calculated using graph theory. This revealed that Cys-allele carriers showed significantly lower global efficiency of their brain networks than Ser homozygotes, thereby supporting our hypothesis that genetic variation in DISC1 may relate to the risk of schizophrenia by affecting the efficiency of brain network. Additional dMRI analyses were also performed at different levels, with a convergent trend towards decreased white matter integrity being consistently observed in Cys-allele carriers. Together these findings not only provide new clues for understanding DISC1 function, but also suggest that network analyses based on graph theory combined with neuroimaging techniques may reveal structural disruptions related to genetic risk in the brains of healthy individuals.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
400Genet Test Mol Biomarkers 2013 May 17: 407-11
PMID23581481
TitleAssociation study of three microsatellite polymorphisms located in introns 1, 8, and 9 of DISC1 with schizophrenia in the Chinese Han population.
AbstractThis study explores more polymorphisms in Disrupted-in-schizophrenia-1 (DISC1) for schizophrenia, which confer risk of developing the disorder.
We report three short tandem repeat (STR) loci ((ATCC)n1, D1S1621, and (ATCC)n2) in DISC1 that showed a significant association with schizophrenia in a set of Chinese Han individuals, including 310 schizophrenics and 400 controls. The STRs in DISC1 associated with schizophrenia occur in intronic sequences in the vicinity of a critical splice junction that gives rise to the expression of DISC1 isoforms. The frequencies of allele 12 of (ATCC)n1, alleles 11 and 12, allele 13 and allele 15 of D1S1621, and allele 10 of (ATCC)n2 were significantly higher in schizophrenia patients than in controls. In contrast, the frequencies of alleles 9 and 10 of (ATCC)n1 and allele 16 and alleles17 and 18 of D1S1621 were significantly lower in schizophrenia patients than in controls.
Our results provide further evidence for an effect of the DISC1 gene on the etiology of schizophrenia and suggest that STRs in the DISC1 gene may be genetic risk factors for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
401Ann. Hum. Genet. 2013 Nov 77: 504-12
PMID23909765
TitleRole of DISC1 interacting proteins in schizophrenia risk from genome-wide analysis of missense SNPs.
AbstractA balanced translocation affecting DISC1 cosegregates with several psychiatric disorders, including schizophrenia, in a Scottish family. DISC1 is a hub protein of a network of protein-protein interactions involved in multiple developmental pathways within the brain. Gene set-based analysis has been proposed as an alternative to individual analysis of single nucleotide polymorphisms (SNPs) to get information from genome-wide association studies. In this work, we tested for an overrepresentation of the DISC1 interacting proteins within the top results of our ranked list of genes based on our previous genome-wide association study of missense SNPs in schizophrenia. Our data set consisted of 5100 common missense SNPs genotyped in 476 schizophrenic patients and 447 control subjects from Galicia, NW Spain. We used a modification of the Gene Set Enrichment Analysis adapted for SNPs, as implemented in the GenGen software. The analysis detected an overrepresentation of the DISC1 interacting proteins (permuted P-value=0.0158), indicative of the role of this gene set in schizophrenia risk. We identified seven leading-edge genes, MACF1, UTRN, DST, DISC1, KIF3A, SYNE1, and AKAP9, responsible for the overrepresentation. These genes are involved in neuronal cytoskeleton organization and intracellular transport through the microtubule cytoskeleton, suggesting that these processes may be impaired in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
402J. Pharmacol. Sci. 2013 -1 121: 185-91
PMID23449491
TitleBehavioral phenotypes in schizophrenic animal models with multiple combinations of genetic and environmental factors.
Abstractschizophrenia is a multifactorial psychiatric disorder in which both genetic and environmental factors play a role. Genetic [e.g., Disrupted-in-schizophrenia 1 (DISC1), Neuregulin-1 (NRG1)] and environmental factors (e.g., maternal viral infection, obstetric complications, social stress) may act during the developmental period to increase the incidence of schizophrenia. In animal models, interactions between susceptibility genes and the environment can be controlled in ways not possible in humans; therefore, such models are useful for investigating interactions between or within factors in the pathogenesis and pathophysiology of schizophrenia. We provide an overview of schizophrenic animal models investigating interactions between or within factors. First, we reviewed gene-environment interaction animal models, in which schizophrenic candidate gene mutant mice were subjected to perinatal immune activation or adolescent stress. Next, environment-environment interaction animal models, in which mice were subjected to a combination of perinatal immune activation and adolescent administration of drugs, were described. These animal models showed interaction between or within factors; behavioral changes, which were obscured by each factor, were marked by interaction of factors and vice versa. Appropriate behavioral approaches with such models will be invaluable for translational research on novel compounds, and also for providing insight into the pathogenesis and pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
403Sheng Li Ke Xue Jin Zhan 2014 Dec 45: 442-7
PMID25872352
Title[Research progress on structure and function of schizophrenia-associated gene Disc1 and its encoding protein].
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
404Psychiatr. Genet. 2014 Jun 24: 120-1
PMID24770450
TitleDISC1 loci not associated with anhedonia in individuals with genetic liability for schizophrenia.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
405Mol. Psychiatry 2014 Feb 19: 141-3
PMID24457522
TitleDISC1 as a genetic risk factor for schizophrenia and related major mental illness: response to Sullivan.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
406Seishin Shinkeigaku Zasshi 2014 -1 116: 842-58
PMID25672211
Title[Role of oxidative stress in the pathophysiology of neuropsychiatric disorders].
AbstractThe brain is particularly vulnerable to oxidative damage because of its high rate of oxygen consumption, abundant lipid content, and relative paucity of antioxidant enzymes compared with other organs. It has been well established that oxidative stress (OS) is involved in the pathogenesis of age-associated neurodegenerative disorders such as Alzheimer's disease (AD). Indeed, a large number of genetic and environmental factors of neurodegenerative disorders are associated with OS. Of note, studies on the levels of oxidative damage in patients with the prodromal stage of AD, transgenic animal models of AD, and induced pluripotent stem (iPS) cells derived from AD patients support the early-stage involvement of OS in the pathological cascade of the disorder. Recently, a growing body of evidence suggests that a considerable number of genetic and environmental factors of psychiatric disorders such as schizophrenia (SZ), bipolar disorders, and depression are associated with OS. Not only genetic polymorphisms in genes encoding antioxidant enzymes but also several known susceptible genes for psychiatric disorders, i. e., Disrupted-in-schizophrenia-1 (DISC1), Neuregulin 1 (NRG1), proline dehydrogenase (PRODH), and G72, are all associated with increased levels of OS or decreased antioxidant capacities. Moreover, environmental factors such as infection, hypoxia, malnutrition, illicit substance use, and psychosocial stress are possibly associated with OS. In fact, increased levels of oxidized nucleic acids, proteins, and lipids have been described in the postmortem brains of patients with SZ and bipolar disorders, and decreased antioxidant capacities have been described in blood samples obtained from patients with first-episode psychosis. In concordance, iPS cells from SZ patients show an increased level of OS. Of particular interest is a conditional gene knockout mouse model of SZ with the functional elimination of NMDA receptors specifically from cortical interneurons. The NMDA receptor knockout mouse shows behavioral phenotypes resembling symptoms of human SZ. Importantly, a marked increase of OS, particularly in the cortical parvalbumin-positive interneurons, is rapidly exacerbated by post-weaning social isolation, but treatment with antioxidants abolishes OS and partially alleviates the SZ-like behavioral phenotypes. Therefore, it is suggested that OS is a convergence point for genetic and environmental susceptibilities to not only neurodegenerative but also psychiatric disorders. In other words, OS potentially plays a central role in the pathomechanisms that integrate gene-environment interactions in neuropsychiatric disorders. Further investigations into the development of useful OS biomarkers and efficacious OS-targeting interventions may shed light on a promising approach for establishing preemptive strategies against neuropsychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
407Front Pharmacol 2014 -1 5: 277
PMID25566074
TitleThe effect of deficient muscarinic signaling on commonly reported biochemical effects in schizophrenia and convergence with genetic susceptibility loci in explaining symptom dimensions of psychosis.
AbstractWith the advent of DSM 5 criticism has generally centered on a lack of biological validity of the diagnostic criteria. Part of the problem in describing a nosology of psychosis is the tacit assumption of multiple genetic causes each with an incremental loading on the clinical picture that fails to differentiate a clear underlying pathophysiology of high impact. The aim of this paper is to consolidate a primary theory of deficient muscarinic signaling underlying key clinical features of schizophrenia and its regulation by several important genetic associations including neuregulin, DISC and dysbindin. Secondary reductions in markers for GABAergic function and changes in the levels of interneuron calcium binding proteins parvalbumin and calbindin can be attributed to dysfunctional muscarinic transduction. A parallel association exists for cytokine production. The convergent pathway hypothesis is likewise used to model dopaminergic and glutamatergic theories of schizophrenia. The negative symptom dimension is correlated with dysfunction of Akt and ERK transduction, a major point of convergence. The present paradigm predicts the importance of a recent finding of a deletion in a copy number variant of PLCB1 and its potential use if replicated, as one of the first testable biological markers differentiating schizophrenia from bipolar disorder and further subtyping of schizophrenia into deficit and non-deficit. Potential limitations of PLCB1 as a prospective marker are also discussed.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
408Cell Rep 2014 Apr 7: 552-64
PMID24726361
TitleDendrite development regulated by the schizophrenia-associated gene FEZ1 involves the ubiquitin proteasome system.
AbstractDownregulation of the schizophrenia-associated gene DISC1 and its interacting protein FEZ1 positively regulates dendrite growth in young neurons. However, little is known about the mechanism that controls these molecules during neuronal development. Here, we identify several components of the ubiquitin proteasome system and the cell-cycle machinery that act upstream of FEZ1. We demonstrate that the ubiquitin ligase cell division cycle 20/anaphase-promoting complex (Cdc20/APC) controls dendrite growth by regulating the degradation of FEZ1. Furthermore, dendrite growth is modulated by BubR1, whose known function so far has been restricted to control Cdc20/APC activity during the cell cycle. The modulatory function of BubR1 is dependent on its acetylation status. We show that BubR1 is deacetylated by Hdac11, thereby disinhibiting the Cdc20/APC complex. Because dendrite growth is affected both in hippocampal dentate granule cells and olfactory bulb neurons upon modifying expression of these genes, we conclude that the proposed mechanism governs neuronal development in a general fashion.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
409World J. Biol. Psychiatry 2014 Jan 15: 76-82
PMID24219803
TitleDominant negative DISC1 mutant mice display specific social behaviour deficits and aberration in BDNF and cannabinoid receptor expression.
AbstractOBJECTIVES. Disrupted in schizophrenia 1 (DISC1) is considered the most prominent candidate gene for schizophrenia. In this study, we aimed to characterize behavioural and brain biochemical traits in a mouse expressing a dominant negative DISC1mutant (DN-DISC1).
DN-DISC1 mice underwent behavioural tests to evaluate object recognition, social preference and social novelty seeking. ELISA was conducted on brain tissue to evaluate BDNF levels. Western blot was employed to measure BDNF receptor (TrkB) and cannabinoid receptor CB1.
The mutant DISC1 mice displayed deficits in preference to social novelty while both social preference and object recognition were intact. Biochemical analysis of prefrontal cortex and hippocampus revealed a modest reduction in cortical TrkB protein levels of male mice while no differences in BDNF levels were observed. We found sex dependent differences in the expression of cannabinoid-1 receptors.
We describe novel behavioural and biochemical abnormalities in the DN-DISC1 mouse model of schizophrenia. The data shows for the first time a possible link between DISC1 mutation and the cannabinoid system.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
410Mol. Psychiatry 2014 Apr 19: 486-94
PMID23628989
TitleThe long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing.
Abstractschizophrenia (SZ) is a complex disease characterized by impaired neuronal functioning. Although defective alternative splicing has been linked to SZ, the molecular mechanisms responsible are unknown. Additionally, there is limited understanding of the early transcriptomic responses to neuronal activation. Here, we profile these transcriptomic responses and show that long non-coding RNAs (lncRNAs) are dynamically regulated by neuronal activation, including acute downregulation of the lncRNA Gomafu, previously implicated in brain and retinal development. Moreover, we demonstrate that Gomafu binds directly to the splicing factors QKI and SRSF1 (serine/arginine-rich splicing factor 1) and dysregulation of Gomafu leads to alternative splicing patterns that resemble those observed in SZ for the archetypal SZ-associated genes DISC1 and ERBB4. Finally, we show that Gomafu is downregulated in post-mortem cortical gray matter from the superior temporal gyrus in SZ. These results functionally link activity-regulated lncRNAs and alternative splicing in neuronal function and suggest that their dysregulation may contribute to neurological disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
411Neuron 2014 Dec 84: 1302-16
PMID25433637
TitleA dopamine D2 receptor-DISC1 protein complex may contribute to antipsychotic-like effects.
AbstractCurrent antipsychotic drugs primarily target dopamine D2 receptors (D2Rs), in conjunction with other receptors such as those for serotonin. However, these drugs have serious side effects such as extrapyramidal symptoms (EPS) and diabetes. Identifying a specific D2R signaling pathway that could be targeted for antipsychotic effects, without inducing EPS, would be a significant improvement in the treatment of schizophrenia. We report here that the D2R forms a protein complex with Disrupted in schizophrenia 1 (DISC1) that facilitates D2R-mediated glycogen synthase kinase (GSK)-3 signaling and inhibits agonist-induced D2R internalization. D2R-DISC1 complex levels are increased in conjunction with decreased GSK-3?/? (Ser21/9) phosphorylation in both postmortem brain tissue from schizophrenia patients and in DISC1-L100P mutant mice, an animal model with behavioral abnormalities related to schizophrenia. Administration of an interfering peptide that disrupts the D2R-DISC1 complex successfully reverses behaviors relevant to schizophrenia but does not induce catalepsy, a strong predictor of EPS in humans.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
412PLoS ONE 2014 -1 9: e108088
PMID25272038
TitleDisc1 variation leads to specific alterations in adult neurogenesis.
AbstractDisrupted in schizophrenia 1 (DISC1) is a risk factor for a spectrum of neuropsychiatric illnesses including schizophrenia, bipolar disorder, and major depressive disorder. Here we use two missense DISC1 mouse mutants, described previously with distinct behavioural phenotypes, to demonstrate that DISC1 variation exerts differing effects on the formation of newly generated neurons in the adult hippocampus. DISC1 mice carrying a homozygous Q31L mutation, and displaying depressive-like phenotypes, have fewer proliferating cells while DISC1 mice with a homozygous L100P mutation that induces schizophrenia-like phenotypes, show changes in the generation, placement and maturation of newly generated neurons in the hippocampal dentate gyrus. Our results demonstrate DISC1 allele specific effects in the adult hippocampus, and suggest that the divergence in behavioural phenotypes may in part stem from changes in specific cell populations in the brain.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
413J. Neurosci. Res. 2014 Dec 92: 1659-68
PMID25131692
TitleMutant disrupted-in-schizophrenia 1 in astrocytes: focus on glutamate metabolism.
AbstractDisrupted-in-schizophrenia 1 (DISC1) is a genetic risk factor that has been implicated in major mental disorders. DISC1 binds to and stabilizes serine racemase to regulate production of D-serine by astrocytes, contributing to glutamate (GLU) neurotransmission. However, the possible involvement of astrocytic DISC1 in synthesis, metabolism, reuptake, or secretion of GLU remains unexplored. Therefore, we studied the effects of dominant-negative mutant DISC1 on various aspects of GLU metabolism by using primary astrocyte cultures and hippocampal tissue from transgenic mice with astrocyte-restricted expression of mutant DISC1. Although mutant DISC1 had no significant effects on astrocyte proliferation, GLU reuptake, glutaminase, or glutamate carboxypeptidase II activity, expression of mutant DISC1 was associated with increased levels of alanine-serine-cysteine transporter 2, vesicular glutamate transporters 1 and 3 in primary astrocytes and in the hippocampus, and elevated expression of the NR1 subunit and diminished expression of the NR2A subunit of N-methyl-D-aspartate (NMDA) receptors in the hippocampus, at postnatal day 21. Our findings indicate that decreased D-serine production by astrocytic mutant DISC1 might lead to compensatory changes in levels of the amino acid transporters and NMDA receptors in the context of tripartite synapse.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
414Front Behav Neurosci 2014 -1 8: 253
PMID25126062
TitleMice with a naturally occurring DISC1 mutation display a broad spectrum of behaviors associated to psychiatric disorders.
AbstractDisrupted in schizophrenia-1 (DISC1) gene is associated with several neuropsychiatric disorders as it is disrupted by a balanced translocation involving chromosomes 1 and 11 in a large Scottish pedigree with high prevalence of schizophrenia, bipolar disorder and major depression. Since its identification, several mouse models with DISC1 genetic modifications have been generated using different approaches. Interestingly, a natural deletion of 25bp in the 129 mouse strain alters the DISC1 gene reading frame leading to a premature stop codon very close to the gene breakpoint in the mutant allele of the Scottish family. In the present study we confirmed that the 129DISC1(Del) mutation results in reduced level of full length DISC1 in hippocampus of heterozygous mice and we have characterized the behavioral consequences of heterozygous 129DISC1(Del) mutation in a mixed B6129 genetic background. We found alterations in spontaneous locomotor activity (hyperactivity in males and hypoactivity in females), deficits in pre-pulse inhibition (PPI) and also increased despair behavior in heterozygous 129DISC1(Del) mice, thus reproducing typical behaviors associated to psychiatric disorders. Since this mouse strain is widely and commercially available, we propose it as an amenable tool to study DISC1-related biochemical alterations and psychiatric behaviors.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
415Cell. Signal. 2014 Sep 26: 1958-74
PMID24815749
TitleMitotic activation of the DISC1-inducible cyclic AMP phosphodiesterase-4D9 (PDE4D9), through multi-site phosphorylation, influences cell cycle progression.
AbstractIn Rat-1 cells, the dramatic decrease in the levels of both intracellular cyclic 3'5' adenosine monophosphate (cyclic AMP; cAMP) and in the activity of cAMP-activated protein kinase A (PKA) observed in mitosis was paralleled by a profound increase in cAMP hydrolyzing phosphodiesterase-4 (PDE4) activity. The decrease in PKA activity, which occurs during mitosis, was attributable to PDE4 activation as the PDE4 selective inhibitor, rolipram, but not the phosphodiesterase-3 (PDE3) inhibitor, cilostamide, specifically ablated this cell cycle-dependent effect. PDE4 inhibition caused Rat-1 cells to move from S phase into G2/M more rapidly, to transit through G2/M more quickly and to remain in G1 for a longer period. Inhibition of PDE3 elicited no observable effects on cell cycle dynamics. Selective immunopurification of each of the four PDE4 sub-families identified PDE4D as being selectively activated in mitosis. Subsequent analysis uncovered PDE4D9, an isoform whose expression can be regulated by Disrupted-In-schizophrenia 1 (DISC1)/activating transcription factor 4 (ATF4) complex, as the sole PDE4 species activated during mitosis in Rat-1 cells. PDE4D9 becomes activated in mitosis through dual phosphorylation at Ser585 and Ser245, involving the combined action of ERK and an unidentified 'switch' kinase that has previously been shown to be activated by H2O2. Additionally, in mitosis, PDE4D9 also becomes phosphorylated at Ser67 and Ser81, through the action of MK2 (MAPKAPK2) and AMP kinase (AMPK), respectively. The multisite phosphorylation of PDE4D9 by all four of these protein kinases leads to decreased mobility (band-shift) of PDE4D9 on SDS-PAGE. PDE4D9 is predominantly concentrated in the perinuclear region of Rat-1 cells but with a fraction distributed asymmetrically at the cell margins. Our investigations demonstrate that the diminished levels of cAMP and PKA activity that characterise mitosis are due to enhanced cAMP degradation by PDE4D9. PDE4D9, was found to locate primarily not only in the perinuclear region of Rat-1 cells but also at the cell margins. We propose that the sequestration of PDE4D9 in a specific complex together with AMPK, ERK, MK2 and the H2O2-activatable 'switch' kinase allows for its selective multi-site phosphorylation, activation and regulation in mitosis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
416Eur. J. Neurosci. 2014 Apr 39: 1074-90
PMID24712988
TitleNeurophysiological modification of CA1 pyramidal neurons in a transgenic mouse expressing a truncated form of disrupted-in-schizophrenia 1.
AbstractA t(1;11) balanced chromosomal translocation transects the DISC1 gene in a large Scottish family and produces genome-wide linkage to schizophrenia and recurrent major depressive disorder. This study describes our in vitro investigations into neurophysiological function in hippocampal area CA1 of a transgenic mouse (DISC1tr ) that expresses a truncated version of DISC1 designed to reproduce aspects of the genetic situation in the Scottish t(1;11) pedigree. We employed both patch-clamp and extracellular recording methods in vitro to compare intrinsic properties and synaptic function and plasticity between DISC1tr animals and wild-type littermates. Patch-clamp analysis of CA1 pyramidal neurons (CA1-PNs) revealed no genotype dependence in multiple subthreshold parameters, including resting potential, input resistance, hyperpolarization-activated 'sag' and resonance properties. Suprathreshold stimuli revealed no alteration to action potential (AP) waveform, although the initial rate of AP production was higher in DISC1tr mice. No difference was observed in afterhyperpolarizing potentials following trains of 5-25 APs at 50Hz. Patch-clamp analysis of synaptic responses in the Schaffer collateral commissural (SC) pathway indicated no genotype-dependence of paired pulse facilitation, excitatory postsynaptic potential summation or AMPA/NMDA ratio. Extracellular recordings also revealed an absence of changes to SC synaptic responses and indicated input-output and short-term plasticity were also unaltered in the temporoammonic (TA) input. However, in DISC1tr mice theta burst-induced long-term potentiation was enhanced in the SC pathway but completely lost in the TA pathway. These data demonstrate that expressing a truncated form of DISC1 affects intrinsic properties of CA1-PNs and produces pathway-specific effects on long-term synaptic plasticity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
417Carcinogenesis 2014 Dec 35: 2687-97
PMID25239642
TitleIdentification of chimeric TSNAX-DISC1 resulting from intergenic splicing in endometrial carcinoma through high-throughput RNA sequencing.
AbstractGene fusion is among the primary processes that generate new genes and has been well characterized as potent pathway of oncogenesis. Here, by high-throughput RNA sequencing in nine paired human endometrial carcinoma (EC) and matched non-cancerous tissues, we obtained that chimeric translin-associated factor X-disrupted-in-schizophrenia 1 (TSNAX-DISC1) occurred significantly upregulated in multiple EC samples. Experimental investigation showed that TSNAX-DISC1 appears to be formed by splicing without chromosomal rearrangement. The chimera expression inversely correlated with the binding of CCCTC-binding factor (CTCF) to the insulators. Subsequent investigations indicate that long intergenic non-coding RNA lincRNA-NR_034037, separating TSNAX from DISC1, regulates TSNAX -DISC1 production and TSNAX/DISC1 expression levels by extricating CTCF from insulators. Dysregulation of TSNAX influences steroidogenic factor-1-stimulated transcription on the StAR promoter, altering progesterone actions, implying the association with cancer. Together, these results advance our understanding of the mechanism in which lincRNA-NR_034037 regulates TSNAX-DISC1 formation programs that tightly regulate EC development.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
418Biol. Psychiatry 2014 Sep 76: 476-85
PMID24560582
TitleDisrupted in schizophrenia 1 modulates medial prefrontal cortex pyramidal neuron activity through cAMP regulation of transient receptor potential C and small-conductance K+ channels.
AbstractDisrupted in schizophrenia 1 (DISC1) is a protein implicated in schizophrenia, bipolar disorder, major depressive disorder, and autism. To date, most of research examining DISC1 function has focused on its role in neurodevelopment, despite its presence throughout life. DISC1 also regulates cyclic adenosine monophosphate (cAMP) signaling by increasing type 4 phosphodiesterase catabolism of cAMP when cAMP concentrations are high. In this study, we tested the hypothesis that DISC1, through its regulation of cAMP, modulates I-SK and I-TRPC channel-mediated ionic currents that we have shown previously to regulate the activity of mature prefrontal cortical pyramidal neurons.
We used patch-clamp recordings in prefrontal cortical slices from adult rats in which DISC1 function was reduced in vivo by short hairpin RNA viral knockdown or in vitro by dialysis of DISC1 antibodies.
We found that DISC1 disruption resulted in an increase of metabotropic glutamate receptor-induced intracellular calcium (Ca2+) waves, small-conductance K+ (SK)-mediated hyperpolarization and a decrease of transient receptor potential C (TRPC)-mediated sustained depolarization. Consistent with a role for DISC1 in regulation of cAMP signaling, forskolin-induced cAMP production also increased intracellular Ca2+ waves, I-SK and decreased I-TRPC. Lastly, inhibiting cAMP generation with guanfacine, an ?2A-noradrenergic agonist, normalized the function of SK and TRPC channels.
Based on our findings, we propose that diminished DISC1 function, such as occurs in some mental disorders, can lead to the disruption of normal patterns of prefrontal cortex activity through the loss of cAMP regulation of metabotropic glutamate receptor-mediated intracellular Ca2+ waves, SK and TRPC channel activity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
419Hum. Mol. Genet. 2014 Nov 23: 5859-65
PMID24934694
TitleNeuropeptide precursor VGF is genetically associated with social anhedonia and underrepresented in the brain of major mental illness: its downregulation by DISC1.
AbstractIn a large Scottish pedigree, disruption of the gene coding for DISC1 clearly segregates with major depression, schizophrenia and related mental conditions. Thus, study of DISC1 may provide a clue to understand the biology of major mental illness. A neuropeptide precursor VGF has potent antidepressant effects and has been reportedly associated with bipolar disorder. Here we show that DISC1 knockdown leads to a reduction of VGF, in neurons. VGF is also downregulated in the cortices from sporadic cases with major mental disease. A positive correlation of VGF single-nucleotide polymorphisms (SNPs) with social anhedonia was also observed. We now propose that VGF participates in a common pathophysiology of major mental disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
420Neuroscience 2014 May 268: 276-83
PMID24680936
TitleNDEL1 was decreased in the CA3 region but increased in the hippocampal blood vessel network during the spontaneous seizure period after pilocarpine-induced status epilepticus.
AbstractNuclear distribution factor E homolog like 1 (NDEL1) plays an important role in mitosis, neuronal migration, and microtubule organization during brain development by binding to disrupted-in-schizophrenia-1 (DISC1) or lissencephaly (LIS1). Although some evidence has suggested that DISC1 expression is altered in epilepsy, few studies have reported the relationship between NDEL1 and the etiology of epilepsy. In present study, we first investigated the expression of NDEL1 and its binding protein DISC1 after pilocarpine-induced epilepsy in male C57BL/6 mice. Data revealed that the mRNA and protein expression of NDEL1 and DISC1 in the whole hippocampus increased during the spontaneous seizure period after status epilepticus (SE). Interestingly, however, the expression of NDEL1 was decreased in the cornu ammonis 3 (CA3) and dentate gyrus (DG) regions. Moreover, SE also increased the number of blood vessels that fed the CA3 and DG regions of the hippocampus and increased the incidence of abnormalities in capillary network formation where NDEL1 protein was expressed positively. Meanwhile, the expression of phosphorylated ERK (p-ERK) was also increased during the spontaneous seizure period, with a similar expression pattern as NDEL1 and DISC1. Based on these results, we hypothesize that NDEL1 might interact with DISC1 to activate ERK signaling and function as a potential protective factor during the spontaneous seizure period after pilocarpine-induced SE.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
421Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jun 51: 166-71
PMID24561237
TitleThe polymorphism of YWHAE, a gene encoding 14-3-3epsilon, and orbitofrontal sulcogyral pattern in patients with schizophrenia and healthy subjects.
AbstractAn altered sulcogyral pattern in the orbitofrontal cortex (OFC) has been implicated in schizophrenia as a possible marker of abnormal neurodevelopment, while its genetic mechanism remains unknown. This magnetic resonance imaging study investigated the relationship between the polymorphism of YWHAE (rs28365859), a gene encoding 14-3-3epsilon that is a Disrupted-in-schizophrenia 1 (DISC1)-interacting molecule associated with neuronal development, and the OFC subtypes of the 'H-shaped' sulcus (Types I, II, and III) in a Japanese sample of 72 schizophrenia patients and 86 healthy controls. The schizophrenia patients had significantly increased Type III (p = 0.004) and decreased Type I (p = 0.013) expression on the right hemisphere compared to the controls. The subjects carrying the protective C allele showed a decrease in Type III (p = 0.005) and an increase in Type I (p = 0.017) compared to the G allele homozygotes, especially for the healthy subjects in the left hemisphere. These results suggest a possible role for the YWHAE genotype in the early development of the OFC sulcogyral pattern, but its effect alone is not likely to explain the altered sulcogyral pattern in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
422Clin. Genet. 2014 Nov 86: 401-11
PMID25142969
TitleNovel treatment strategies for schizophrenia from improved understanding of genetic risk.
AbstractRecent years have seen significant advances in our understanding of the genetic basis of schizophrenia. In particular, genome-wide approaches have suggested the involvement of many common genetic variants of small effect, together with a few rare variants exerting relatively large effects. While unequivocal identification of the relevant genes has, for the most part, remained elusive, the genes revealed as potential candidates can in many cases be clustered into functionally related groups which are potentially open to therapeutic intervention. In this review, we summarise this information, focusing on the accumulating evidence that genetic dysfunction at glutamatergic synapses and post-synaptic signalling complexes contributes to the aetiology of the disease. In particular, there is converging support for involvement of post-synaptic JNK pathways in disease aetiology. An expansion of our neurobiological knowledge of the basis of schizophrenia is urgently needed, yet some promising novel pharmacological targets can already be discerned.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
423Neurosci Biobehav Rev 2014 Sep 45: 271-94
PMID25016072
TitleDisrupted-In-Schizophrenia-1 (DISC1) interactome and mental disorders: impact of mouse models.
AbstractDisrupted-In-schizophrenia-1 (DISC1) has captured much attention because it predisposes individuals to a wide range of mental illnesses. Notably, a number of genes encoding proteins interacting with DISC1 are also considered to be relevant risk factors of mental disorders. We reasoned that the understanding of DISC1-associated mental disorders in the context of network principles will help to address fundamental properties of DISC1 as a disease gene. Systematic integration of behavioural phenotypes of genetic mouse lines carrying perturbation in DISC1 interacting proteins would contribute to a better resolution of neurobiological mechanisms of mental disorders associated with the impaired DISC1 interactome and lead to a development of network medicine. This review also makes specific recommendations of how to assess DISC1 associated mental disorders in mouse models and discuss future directions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizophrenias
424PLoS ONE 2014 -1 9: e111196
PMID25333879
TitleAggregation of the protein TRIOBP-1 and its potential relevance to schizophrenia.
AbstractWe have previously proposed that specific proteins may form insoluble aggregates as a response to an illness-specific proteostatic dysbalance in a subset of brains from individuals with mental illness, as is the case for other chronic brain conditions. So far, established risk factors DISC1 and dysbindin were seen to specifically aggregate in a subset of such patient