Association of DISC1/TRAX Haplotypes With Schizophrenia, Reduced Prefrontal Gray Matter, and Impaired Short- and Long-term Memory

Cannon, Tyrone D.; Hennah, William; Erp, Theo G.M. van; Thompson, Paul M.; Lönnqvist, Jouko; Huttunen, Matti; Gasperoni, Timothy L.; Tuulio‐Henriksson, Annamari; Pirkola, Tia; Toga, Arthur W.; Kaprio, Jaakko; Mazziotta, John C.; Peltonen, Leena

doi:10.1001/archpsyc.62.11.1205

Cited by 312 publications

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“…2 A number of studies have since reported evidence of linkage or association between the DISC1 locus and impaired cognitive function in both schizophrenic and normal individuals (Table 1b, Figure 1a). 22,25,[35][36][37][38][39][40] These deficits are consistent with dysfunction in the dorsolateral prefrontal cortex (PFC) and the hippocampus.…”

Section: Disc1 Variation and Cognitive Abilitiesmentioning

confidence: 76%

“…25 A similar trend towards decreased hippocampal volume has also been reported in the Finnish population for the DISC1-associated haplotype HEP1. 36 In contrast to these studies, Hashimoto et al 27 did not find decreases in hippocampal volume associated with the Ser704Cys polymorphism in their Japanese control sample; however, they did report decreases in the grey matter of the cingulate cortex, cingulate gyrus and the posterior gyrus, and abnormalities in prefrontal white matter, in carriers of the Cys704 allele. Therefore, while this study supports the idea that the Ser704Cys polymorphism is associated with reductions in brain tissue volume, the regions of volume reduction differ and the allele associated with the reductions differs also.…”

Section: Disc1 Variation and Cognitive Abilitiesmentioning

confidence: 81%

“…9 Although genetic evidence for the DISC locus is strong, with many positive linkage and association peaks across the length of the gene (Table 1), these studies do not discriminate between DISC1 and DISC2 in terms of positive linkage and association; furthermore, many studies report markers that are within the DISC2 gene region. 13,14,24,36 Therefore, DISC2 may represent an important schizophrenia candidate gene in its own right.…”

Section: Disrupted-in-schizophrenia-2 (Disc2)mentioning

confidence: 99%

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The DISC locus in psychiatric illness

et al. 2007

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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. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Section: Disc1 Variation and Cognitive Abilitiesmentioning

confidence: 76%

Section: Disc1 Variation and Cognitive Abilitiesmentioning

confidence: 81%

Section: Disrupted-in-schizophrenia-2 (Disc2)mentioning

confidence: 99%

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The DISC locus in psychiatric illness

et al. 2007

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“…The translocation disrupts a gene termed disrupted-in-schizophrenia 1 (DISC1) on chromosome 1. 5,7,9 Linkage and association at the DISC1 locus have been demonstrated for psychiatric illness in several populations, [10][11][12][13][14][15][16][17] suggesting wider relevance of DISC1.…”

Section: Introductionmentioning

confidence: 99%

Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

et al. 2007

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A strong candidate gene for schizophrenia and major mental disorders, disrupted-inschizophrenia 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.

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“…The potential contributions of DISC1/2 and a nearby TRAX gene to the pathogenesis of schizophrenia were subsequently supported by a number of, but not all, genetic association studies in the general population, including those with different ethnic genetic backgrounds. 2 However, the odds ratios are modest for DISC1 as a susceptibility gene and functional mutations have not been identified. In contrast, the t(1; 11) translocation in the Scottish family appears to be the causal genetic lesion with 70% penetrance for major mental illness.…”

mentioning

confidence: 99%