Case-control association study of Disrupted-in-Schizophrenia-1 (DISC1) gene and schizophrenia in the Chinese population

Chen, Qing-Ying; Chen, Qi; Gao, Feng; Lindpaintner, Klaus; Wang, Lijun; Chen, Zhengxiong; Gao, Zhe; Tang, Jisheng; Huang, Gang; He, Lin

doi:10.1016/j.jpsychires.2006.01.001

Cited by 51 publications

(36 citation statements)

References 45 publications

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“…28 Additional sex-specific associations for DISC1 have been reported within the Han-Chinese and Japanese populations, making this a common finding for the DISC locus in relation to its involvement in psychiatric illness. 27,29 A recent association study of Finnish autism and Asperger families detected sex-specific associations of DISC1 with autism spectrum disorders and Asperger syndrome in affected male subjects. 30 This study implicated a microsatellite within DISC1 intron 9, and a three-SNP haplotype, encompassing HEP3, both of which have previously displayed linkage or association to schizophrenia in the Finnish population.…”

Section: Genetics Of Disc1 Discoverymentioning

confidence: 99%

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: Genetics Of Disc1 Discoverymentioning

confidence: 99%

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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“…Independent linkage/ association studies now implicate DISC1 in schizophrenia, severe affective disorders and autistic spectrum disorders of diverse populations (Devon et al, 2001;Ekelund et al, 2001;Hennah et al, 2005Hennah et al, , 2008Sachs et al, 2005;Zhang et al, 2005;Chen et al, 2007;Kilpinen et al, 2008). However, robust evidence for functional variants is still lacking, and genetic heterogeneity is likely.…”

Section: Introductionmentioning

confidence: 99%

Schizophrenia-Related Neural and Behavioral Phenotypes in Transgenic Mice Expressing TruncatedDisc1

Shen¹,

Luo²,

Nakamoto³

et al. 2008

J. Neurosci.

239

204

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Disrupted-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.

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Case-control association study of Disrupted-in-Schizophrenia-1 (DISC1) gene and schizophrenia in the Chinese population

Cited by 51 publications

References 45 publications

The DISC locus in psychiatric illness

The DISC locus in psychiatric illness

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

Schizophrenia-Related Neural and Behavioral Phenotypes in Transgenic Mice Expressing TruncatedDisc1

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