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J K Millar - One of the best experts on this subject based on the ideXlab platform.
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The DISC locus in psychiatric illness
Molecular Psychiatry, 2008Co-Authors: J E Chubb, N J Bradshaw, D C Soares, D J Porteous, J K MillarAbstract:The 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.
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Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia
Molecular Psychiatry, 2001Co-Authors: J K Millar, S Christie, S Anderson, D Lawson, D Hsiao-wei Loh, R S Devon, B Arveiler, W J Muir, D H R Blackwood, D J PorteousAbstract:Two 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.
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Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder.
Psychiatric genetics, 2001Co-Authors: Rebecca S Devon, J K Millar, Colin A Semple, Susan Anderson, Walter J Muir, P. W. Teague, Paul Burgess, Tiina Kipari, V. Murray, Anthony J. PelosiAbstract:We have undertaken a search for polymorphic sequence variation within Disrupted in Schizophrenia I 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. Psychiatr Genet 11:71-78 (C) 2001 Lippincott Williams & Wilkins.
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Identification and Analysis of Genes Disrupted by a Translocation Segregating with Schizophrenia
Biochemical Society Transactions, 2000Co-Authors: J K Millar, Sheila Christie, Rachel James, Susan Anderson, Rebecca S Devon, Walter J Muir, Taylor, Cam Semple, J. C. Wilson-annan, D H R BlackwoodAbstract:Schizophrenia is a devastating disease affecting approximately 1 % of the population worldwide and there is substantial evidence pointing to a genetic contribution. However, the probable multifactorial nature of the disease, together with diagnostic difficulties and likely environmental contributions, has hampered attempts to identify the genes involved. We are studying a family in which a balanced translocation (1;l l)(q42.l;q14.3) segregates with schizophrenia and related major mental illness, with a maximum LOD score of 6.0. We hypothesise that the translocation has affected expression of a gene, or genes, leading to the psychiatric disorders within this family. We have identified two overlapping candidate genes, DISCl and DISC2, which are directly disrupted by the translocation on chromosome 1. DISCl also participates in intergenic splicing with an upstream gene, TSNAX. DISC2 is apparently an RNA gene that may regulate expression of DISCl. The translocation breakpoint is therefore located within a complex transcription unit. We are currently studying all three genes in order to identify their normal cellular function, assess them as candidate susceptibility genes and elucidate the mechanism of their likely contribution to the psychiatric illness suffered by translocation carriers.
Daryl A Scott - One of the best experts on this subject based on the ideXlab platform.
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A 1q42 deletion involving DISC1, DISC2, and TSNAX in an autism spectrum disorder.
American journal of medical genetics. Part A, 2009Co-Authors: Jaime M Williams, Tyler F Beck, David M Pearson, Monica B Proud, Sau Wai Cheung, Daryl A ScottAbstract:Individuals with autism spectrum disorders have impairments in social, communicative, and behavior development that are often accompanied by abnormalities in cognitive functioning, learning, attention, and sensory processing. In this report, we describe a 3-year-old male child with an autism spectrum disorder who carries a 2 Mb deletion of chromosome 1q42. Array comparative genome hybridization revealed that this deletion involves at least three genes-DISC1, DISC2, and TSNAX-which have been found to be associated with neuropsychiatric disorders and are likely to play key roles in normal CNS development. Further studies revealed that the deletion was inherited from his unaffected mother. This suggests that other genetic and/or environmental factors, some of which may be sex specific, may modify the phenotypic effects of this deletion. While this case provides evidence for the potential role of DISC1, DISC2, and TSNAX in the development of autism spectrum disorders, it is equally clear that caution must be taken when providing families with prognostic information and genetic counseling regarding such deletions.
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A 1q42 deletion involving DISC1, DISC2, and TSNAX in an autism spectrum disorder.
American Journal of Medical Genetics Part A, 2009Co-Authors: Jaime M Williams, Tyler F Beck, David M Pearson, Sau Wai Cheung, Monica Proud, Daryl A ScottAbstract:Individuals with autism spectrum disorders have impairments in social, communicative, and behavior development that are often accompanied by abnormalities in cognitive functioning, learning, attention, and sensory processing. In this report, we describe a 3-year-old male child with an autism spectrum disorder who carries a 2 Mb deletion of chromosome 1q42. Array comparative genome hybridization revealed that this deletion involves at least three genes—DISC1, DISC2, and TSNAX—which have been found to be associated with neuropsychiatric disorders and are likely to play key roles in normal CNS development. Further studies revealed that the deletion was inherited from his unaffected mother. This suggests that other genetic and/or environmental factors, some of which may be sex specific, may modify the phenotypic effects of this deletion. While this case provides evidence for the potential role of DISC1, DISC2, and TSNAX in the development of autism spectrum disorders, it is equally clear that caution must be taken when providing families with prognostic information and genetic counseling regarding such deletions. © 2009 Wiley-Liss, Inc.
Rebecca S Devon - One of the best experts on this subject based on the ideXlab platform.
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Evolutionary constraints on the Disrupted in Schizophrenia locus.
Genomics, 2003Co-Authors: Martin S Taylor, J. Kirsty Millar, Rebecca S Devon, David J PorteousAbstract:Abstract The 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.
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Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder.
Psychiatric genetics, 2001Co-Authors: Rebecca S Devon, J K Millar, Colin A Semple, Susan Anderson, Walter J Muir, P. W. Teague, Paul Burgess, Tiina Kipari, V. Murray, Anthony J. PelosiAbstract:We have undertaken a search for polymorphic sequence variation within Disrupted in Schizophrenia I 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. Psychiatr Genet 11:71-78 (C) 2001 Lippincott Williams & Wilkins.
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Identification and Analysis of Genes Disrupted by a Translocation Segregating with Schizophrenia
Biochemical Society Transactions, 2000Co-Authors: J K Millar, Sheila Christie, Rachel James, Susan Anderson, Rebecca S Devon, Walter J Muir, Taylor, Cam Semple, J. C. Wilson-annan, D H R BlackwoodAbstract:Schizophrenia is a devastating disease affecting approximately 1 % of the population worldwide and there is substantial evidence pointing to a genetic contribution. However, the probable multifactorial nature of the disease, together with diagnostic difficulties and likely environmental contributions, has hampered attempts to identify the genes involved. We are studying a family in which a balanced translocation (1;l l)(q42.l;q14.3) segregates with schizophrenia and related major mental illness, with a maximum LOD score of 6.0. We hypothesise that the translocation has affected expression of a gene, or genes, leading to the psychiatric disorders within this family. We have identified two overlapping candidate genes, DISCl and DISC2, which are directly disrupted by the translocation on chromosome 1. DISCl also participates in intergenic splicing with an upstream gene, TSNAX. DISC2 is apparently an RNA gene that may regulate expression of DISCl. The translocation breakpoint is therefore located within a complex transcription unit. We are currently studying all three genes in order to identify their normal cellular function, assess them as candidate susceptibility genes and elucidate the mechanism of their likely contribution to the psychiatric illness suffered by translocation carriers.
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disruption of two novel genes by a translocation co segregating with schizophrenia
Human Molecular Genetics, 2000Co-Authors: Kirsty J Millar, Sheila Christie, Colin A Semple, Julie C Wilsonannan, Susan Anderson, Martin S Taylor, Rebecca S Devon, David St Clair, Walter J Muir, Douglas BlackwoodAbstract:A 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.
D J Porteous - One of the best experts on this subject based on the ideXlab platform.
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The DISC locus in psychiatric illness
Molecular Psychiatry, 2008Co-Authors: J E Chubb, N J Bradshaw, D C Soares, D J Porteous, J K MillarAbstract:The 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.
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Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia
Molecular Psychiatry, 2001Co-Authors: J K Millar, S Christie, S Anderson, D Lawson, D Hsiao-wei Loh, R S Devon, B Arveiler, W J Muir, D H R Blackwood, D J PorteousAbstract:Two 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.
Leena Peltonen - One of the best experts on this subject based on the ideXlab platform.
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Association of DISC1 with autism and Asperger syndrome.
Molecular psychiatry, 2007Co-Authors: Helena Kilpinen, Tero Ylisaukko-oja, William Hennah, O M Palo, Teppo Varilo, Raija Vanhala, T. Nieminen-von Wendt, L. Von Wendt, Tiina Paunio, Leena PeltonenAbstract:The 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, naffected=138) and Asperger syndrome (29 families, naffected=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.
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a haplotype within the disc1 gene is associated with visual memory functions in families with a high density of schizophrenia
Molecular Psychiatry, 2005Co-Authors: William Hennah, Teppo Varilo, Tiina Paunio, Leena Peltonen, Timo Partonen, Annamari Tuuliohenriksson, Jesper Ekelund, Tyrone D Cannon, Jouko LonnqvistAbstract:We 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.