| 1 | Hum. Mol. Genet. 2007 Oct 16: 2517-28 |
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| PMID | 17673452 |
| Title | Association of distinct allelic haplotypes of DISC1 with psychotic and bipolar spectrum disorders and with underlying cognitive impairments. |
| Abstract | Bipolar disorder (BPD) and schizophrenia (SCZ) have at least a partially convergent aetiology and thus may share genetic susceptibility loci. Multiple lines of evidence emphasize the role of disrupted-in-schizophrenia-1 (DISC1) gene in psychotic disorders such as SCZ. We monitored the association of allelic variants of translin-associated factor X (TSNAX)/DISC1 gene cluster using 13 single-nucleotide polymorphisms (SNPs) in 723 members of 179 Finnish BPD families. Consistent with an earlier finding in Finnish SCZ families, the haplotype T-A of rs751229 and rs3738401 at the 5' end of DISC1 was over-transmitted to males with psychotic disorder (P = 0.008; for an extended haplotype P = 0.0007 with both genders). Haplotypes at the 3' end of DISC1 associated with bipolar spectrum disorder (P = 0.0002 for an under-transmitted haplotype T-T of rs821616 and rs1411771, for an extended haplotype P = 0.0001), as did a two-SNP risk haplotype at the 5' end of TSNAX (P = 0.007). The risk haplotype for psychotic disorder also associated to perseverations (P = 0.035; for rs751229 alone P = 0.0012), and a protective haplotype G-T-G with rs1655285 in addition to auditory attention (P = 0.0059). The 3' end variants associated with several cognitive traits, with the most robust signal for rs821616 and verbal fluency and rs980989 and psychomotor processing speed (P = 0.011 for both). These results support involvement of DISC1 in the genetic aetiology of BPD and suggest that its distinct variants contribute to variation in the dimensional features of psychotic and bipolar spectrum disorders. Finding of alternative associating haplotypes in the same set of BPD families gives evidence for allelic heterogeneity within DISC1, eventually leading to heterogeneity in the clinical outcome as well. |
| SCZ Keywords | schizophrenia |
| 2 | Mol. Psychiatry 2010 Aug 15: 844-9 |
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| PMID | 19255581 |
| Title | Association of DISC1 and TSNAX genes and affective disorders in the depression case-control (DeCC) and bipolar affective case-control (BACCS) studies. |
| Abstract | The gene known as Disrupted-in-schizophrenia-1, DISC1, was originally discovered in a large family, in which it also co-segregated with bipolar affective disorder (BD) and with major depressive disorder (MDD). The TSNAX (Translin-associated factor X) gene, located immediately upstream of DISC1, has also been suggested as a candidate gene in relation to psychiatric illness, as one transcript resulting from intergenic splicing encodes a novel TSNAX-DISC1 fusion protein. We explored the TSNAX-DISC1 gene region for an association with BD and MDD in a sample of 1984 patients (1469 MDD, 515 BD) and 1376 ethnically matched controls. Eight single nucleotide polymorphisms (SNPs) within the TSNAX-DISC1 region (rs766288, rs3738401, rs2492367, rs6675281, rs12133766, rs1000731, rs7546310 and rs821597) were investigated using the SNPlex Genotyping System. We found a significant allelic and genotypic association of the TSNAX-DISC1 gene region with BD, whereas a haplotypic association was found for both BD and MDD. Therefore, our results suggest an association between the TSNAX-DISC1 region and both forms of affective disorders, and support the hypothesis that a portion of the genotypic overlap between schizophrenia and affective disorders is attributable to this gene. |
| SCZ Keywords | schizophrenia |
| 3 | J. Hum. Genet. 2012 Aug 57: 475-6 |
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| PMID | 22763722 |
| Title | A commentary on the gender-specific association of TSNAX/DISC1 locus for schizophrenia and bipolar affective disorder in South Indian population. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia |
| 4 | J. Hum. Genet. 2012 Aug 57: 523-30 |
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| PMID | 22673686 |
| Title | Gender-specific association of TSNAX/DISC1 locus for schizophrenia and bipolar affective disorder in South Indian population. |
| Abstract | Genetic association studies have implicated the TSNAX/DISC1 (disrupted in schizophrenia 1) in schizophrenia (SCZ), bipolar affective disorder (BPAD) and major depression. This study was performed to assess the possible involvement of TSNAX/DISC1 locus in the aetiology of BPAD and SCZ in the Southern Indian population. We genotyped seven single nucleotide polymorphism (SNPs) from TSNAX/DISC1 region in 1252 individuals (419 BPAD patients, 408 SCZ patients and 425 controls). Binary logistic regression revealed a nominal association for rs821616 in DISC1 for BPAD and also combined cases of BPAD or SCZ, but after correcting for multiple testing, these results were non-significant. However, significant association was observed with BPAD, as well as combined cases of BPAD or SCZ, within the female subjects for the rs766288 after applying false discovery rate corrections at the 0.05 level. Two-locus analysis showed C-C (rs766288-rs2812393) as a risk combination in BPAD, and G-T (rs2812393-rs821616) as a protective combination in SCZ and combined cases of BPAD or SCZ. Female-specific associations were observed for rs766288-rs2812393, rs766288-rs821616 and rs8212393-rs821616 in two-locus analysis. Our results provide further evidence for sex-dependent effects of the TSNAX/DISC1 locus in the aetiology of SCZ and BPAD. |
| SCZ Keywords | schizophrenia |
| 5 | Carcinogenesis 2014 Dec 35: 2687-97 |
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| PMID | 25239642 |
| Title | Identification of chimeric TSNAX-DISC1 resulting from intergenic splicing in endometrial carcinoma through high-throughput RNA sequencing. |
| Abstract | Gene fusion is among the primary processes that generate new genes and has been well characterized as potent pathway of oncogenesis. Here, by high-throughput RNA sequencing in nine paired human endometrial carcinoma (EC) and matched non-cancerous tissues, we obtained that chimeric translin-associated factor X-disrupted-in-schizophrenia 1 (TSNAX-DISC1) occurred significantly upregulated in multiple EC samples. Experimental investigation showed that TSNAX-DISC1 appears to be formed by splicing without chromosomal rearrangement. The chimera expression inversely correlated with the binding of CCCTC-binding factor (CTCF) to the insulators. Subsequent investigations indicate that long intergenic non-coding RNA lincRNA-NR_034037, separating TSNAX from DISC1, regulates TSNAX -DISC1 production and TSNAX/DISC1 expression levels by extricating CTCF from insulators. Dysregulation of TSNAX influences steroidogenic factor-1-stimulated transcription on the StAR promoter, altering progesterone actions, implying the association with cancer. Together, these results advance our understanding of the mechanism in which lincRNA-NR_034037 regulates TSNAX-DISC1 formation programs that tightly regulate EC development. |
| SCZ Keywords | schizophrenia |