Association between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population

Thomson, Pippa A.; Wray, Naomi R.; Millar, J. Kirsty; Evans, Kathryn; Hellard, Stéphanie Le; Condie, Alison; Muir, Walter; Blackwood, Douglas; Porteous, David J.

doi:10.1038/sj.mp.4001699

Cited by 61 publications

(81 citation statements)

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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: 79%

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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Section: Discussionmentioning

confidence: 79%

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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“…50 It is interesting that two of the most promising candidate genes for susceptibility to psychiatric illness are associated with these disorders within the same sample set. In the future, we plan to test for interactions between these and other genes in an independent replication set.…”

Section: Discussionmentioning

confidence: 99%

Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population

et al. 2006

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Neuregulin 1 (NRG1) is a strong candidate for involvement in the aetiology of schizophrenia. A haplotype, initially identified as showing association in the Icelandic and Scottish populations, has shown a consistent effect size in multiple European populations. Additionally, NRG1 has been implicated in susceptibility to bipolar disorder. In this first study to select markers systematically on the basis of linkage disequilibrium across the entire NRG1 gene, we used haplotype-tagging single-nucleotide polymorphisms to identify single markers and haplotypes associated with schizophrenia and bipolar disorder in an independently ascertained Scottish population. Haplotypes in two regions met an experiment-wide significance threshold of P = 0.0016 (Nyholt's SpD) and were permuted to correct for multiple testing. Region A overlaps with the Icelandic haplotype and shows nominal association with schizophrenia (P = 0.00032), bipolar disorder (P = 0.0011), and the combined case group (P = 0.0017). This region includes the 5 0 exon of the NRG1 GGF2 isoform and overlaps the expressed sequence tag (EST) cluster Hs.97362. However, no haplotype in Region A remains significant after permutation analysis (P > 0.05). Region B contains a haplotype associated with both schizophrenia (P = 0.00014), and the combined case group (P = 0.000062), although it does not meet Nyholt's threshold in bipolar disorder alone (P = 0.0022). This haplotype remained significant after permutation analysis in both the schizophrenia and combined case groups (P = 0.024 and P = 0.016, respectively). It spans a B136 kb region that includes the coding sequence of the sensory and motor neuron derived factor (SMDF) isoform and 3 0 exons of all other known NRG1 isoforms. Our study identifies a new of NRG1 region involved in schizophrenia and bipolar disorder in the Scottish population.

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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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Association between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population

Abstract: Linkage disequilibrium maps of the TRAX/DISC region. Maps were generated using Haploview v2.05 (http:// www.broad.mit.edu/mpg/haploview/) under the analysis criteria solid spine of LD40.

Cited by 61 publications

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

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

Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population

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

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