A haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia

Hennah, William; Tuulio-Henriksson, A; Paunio, Tiina; Ekelund, Jesper; Varilo, Teppo; Partonen, Timo; Cannon, Tyrone D.; Lönnqvist, Jouko; Peltonen, Leena

doi:10.1038/sj.mp.4001731

Cited by 143 publications

(105 citation statements)

References 40 publications

(48 reference statements)

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“…21 Although originally reported as being undertransmitted to affected females, 21 it was later reported that in fact this haplotype is overtransmitted to affected males in this population. 22,23 Association of a haplotype overlapping HEP3 (called Hap 1) has further confirmed this finding in an independent study of North American schizoaffective patients. 24 However, in this population, the Hap 1 haplotype is reported to be undertransmitted to the affected individuals.…”

Section: Genetics Of Disc1 Discoverymentioning

confidence: 54%

“…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%

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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: Genetics Of Disc1 Discoverymentioning

confidence: 54%

Section: Disc1 Variation and Cognitive Abilitiesmentioning

confidence: 76%

The DISC locus in psychiatric illness

et al. 2007

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“…65 Interestingly, this protein also interacts with 14-3-3 gamma which has been implicated in schizophrenia previously 66,67 and which also interacts with the disrupted in schizophrenia 1 protein strongly implicated in the disease. 68,69 Postsynaptic density and glutamatergic system implicated by findings Several proteins that were differentially expressed in this investigation, namely PACSIN, NF-L, DYN-I and septin 5, are involved in the function of the pre-and/ or postsynaptic density, and through these in NMDAregulated glutamatergic neurotransmission, strongly implicated in the pathophysiology of schizophrenia. 70,71 In addition, many of the susceptibility genes for schizophrenia to date have been shown to play a role in glutamate function.…”

Section: Discussionmentioning

confidence: 75%

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder

et al. 2007

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There is evidence for both similarity and distinction in the presentation and molecular characterization of schizophrenia and bipolar disorder. In this study, we characterized protein abnormalities in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder using two-dimensional gel electrophoresis. Tissue samples were obtained from 35 individuals with schizophrenia, 35 with bipolar disorder and 35 controls. Eleven protein spots in schizophrenia and 48 in bipolar disorder were found to be differentially expressed (P < 0.01) in comparison to controls, with 7 additional spots found to be altered in both diseases. Using mass spectrometry, 15 schizophrenia-associated proteins and 51 bipolar disorder-associated proteins were identified. The functional groups most affected included synaptic proteins (7 of the 15) in schizophrenia and metabolic or mitochondrial-associated proteins (25 of the 51) in bipolar disorder. Six of seven synaptic-associated proteins abnormally expressed in bipolar disorder were isoforms of the septin family, while two septin protein spots were also significantly differentially expressed in schizophrenia. This finding represented the largest number of abnormalities from one protein family. All septin protein spots were upregulated in disease in comparison to controls. This study provides further characterization of the synaptic pathology present in schizophrenia and of the metabolic dysfunction observed in bipolar disorder. In addition, our study has provided strong evidence implicating the septin protein family of proteins in psychiatric disorders for the first time.

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“…Preliminary data show an association with DISC1 gene in families of schizophrenia probands (Hennah et al, 2005). Genome-wide data from 168 schizophrenia families suggested a locus for verbal learning and memory on 4q21.…”

Section: Yesmentioning

confidence: 87%