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

Abstract

The Translin-associated factor X/Disrupted in Schizophrenia 1 (TRAX/DISC) region was first implicated as a susceptibility locus for schizophrenia by analysis of a large Scottish family in which a t(1;11) translocation cosegregates with schizophrenia, bipolar disorder and recurrent major depression. We now report evidence for association between bipolar disorder and schizophrenia and this locus in the general Scottish population. A systematic study of linkage disequilibrium in a representative sample of the Scottish population was undertaken across the 510 kb of TRAX and DISC1. SNPs representing each haplotype block were selected for case–control association studies of both schizophrenia and bipolar disorder. Significant association with bipolar disorder in women P=0.00026 (P=0.0016 in men and women combined) was detected in a region of DISC1. This same region also showed nominally significant association with schizophrenia in both men and women combined, P=0.0056. Two further regions, one in TRAX and the second in DISC1, showed weaker evidence for sex-specific associations of individual haplotypes with bipolar disorder in men and women respectively, P<0.01. Only the association between bipolar women and DISC1 remained significant after correction for multiple testing. This result provides further supporting evidence for DISC1 as a susceptibility factor for both bipolar disorder and schizophrenia, consistent with the diagnoses in the original Scottish translocation family.

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References

  1. Kendler KS, Pedersen N, Johnson L, Neale MC, Mathe AA . A pilot Swedish twin study of affective illness, including hospital- and population-ascertained subsamples. Arch Gen Psychiatry 1993; 50: 699–700.

    Article  CAS  Google Scholar 

  2. Sullivan PF, Kendler KS, Neale MC . Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003; 60: 1187–1192.

    Article  Google Scholar 

  3. St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 1990; 336: 13–16.

    Article  CAS  Google Scholar 

  4. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 2000; 9: 1415–1423.

    Article  CAS  Google Scholar 

  5. Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ . Schizophrenia and affective disorders—cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet 2001; 69: 428–433.

    Article  CAS  Google Scholar 

  6. Blackwood DH, Muir WJ . Clinical phenotypes associated with DISC1, a candidate gene for schizophrenia. Neurotox Res 2004; 6: 35–41.

    Article  CAS  Google Scholar 

  7. Millar JK, Christie S, Semple CA, Porteous DJ . Chromosomal location and genomic structure of the human translin-associated factor X gene (TRAX; TSNAX) revealed by intergenic splicing to DISC1, a gene disrupted by a translocation segregating with schizophrenia. Genomics 2000; 67: 69–77.

    Article  CAS  Google Scholar 

  8. Ekelund J, Hovatta I, Parker A, Paunio T, Varilo T, Martin R et al. Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet 2001; 10: 1611–1617.

    Article  CAS  Google Scholar 

  9. Hennah W, Varilo T, Kestila M, Paunio T, Arajarvi R, Haukka J et al. Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet 2003; 12: 3151–3159.

    Article  CAS  Google Scholar 

  10. Ekelund J, Hennah W, Hiekkalinna T, Parker A, Meyer J, Lonnqvist J et al. Replication of 1q42 linkage in Finnish schizophrenia pedigrees. Mol Psychiatry 2004; 9: 1037–1041.

    Article  CAS  Google Scholar 

  11. Hwu HG, Liu CM, Fann CS, Ou-Yang WC, Lee SF . Linkage of schizophrenia with chromosome 1q loci in Taiwanese families. Mol Psychiatry 2003; 8: 445–452.

    Article  CAS  Google Scholar 

  12. Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH et al. Disrupted in Schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet 2004; 75: 862–872.

    Article  CAS  Google Scholar 

  13. Harrison PJ, Weinberger DR . Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10: 40–68.

    Article  CAS  Google Scholar 

  14. Gejman PV, Martinez M, Cao Q, Friedman E, Berrettini WH, Goldin LR et al. Linkage analysis of fifty-seven microsatellite loci to bipolar disorder. Neuropsychopharmacology 1993; 9: 31–40.

    Article  CAS  Google Scholar 

  15. Curtis D, Kalsi G, Brynjolfsson J, McInnis M, O'Neill J, Smyth C et al. Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23–q24, and suggests the presence of additional loci on 1p and 1q. Psychiatr Genet 2003; 13: 77–84.

    Google Scholar 

  16. Macgregor S, Visscher PM, Knott SA, Thomson P, Porteous DJ, Millar JK et al. A genome scan and follow-up study identify a bipolar disorder susceptibility locus on chromosome 1q42. Mol Psychiatry 2004; 9: 1083–1090.

    Article  CAS  Google Scholar 

  17. Austin CP, Ma L, Ky B, Morris JA, Shughrue PJ . DISC1 (Disrupted in Schizophrenia-1) is expressed in limbic regions of the primate brain. Neuroreport 2003; 14: 951–954.

    Article  CAS  Google Scholar 

  18. Austin CP, Ky B, Ma L, Morris JA, Shughrue PJ . Expression of Disrupted-In-Schizophrenia-1, a schizophrenia-associated gene, is prominent in the mouse hippocampus throughout brain development. Neuroscience 2004; 124: 3–10.

    Article  CAS  Google Scholar 

  19. Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L, Fujii K et al. Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci USA 2003; 100: 289–294.

    Article  CAS  Google Scholar 

  20. Miyoshi K, Honda A, Baba K, Taniguchi M, Oono K, Fujita T et al. Disrupted-in-schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Mol Pyschiatry 2003; 8: 685–694.

    Article  CAS  Google Scholar 

  21. James R, Adams RR, Christie S, Buchanan SR, Porteous DJ, Millar JK . Disrupted in Schizophrenia 1 is a multi-compartmentalised protein that predominantly localises to mitochondria. Mol Cell Neurosci 2004; 26: 112–122.

    Article  CAS  Google Scholar 

  22. Honda A, Miyoshi K, Baba K, Taniguchi M, Koyama Y, Kuroda S et al. Expression of fasciculation and elongation protein zeta-1 (FEZ1) in the developing rat brain. Brain Res Mol Brain Res 2004; 122: 89–92.

    Article  CAS  Google Scholar 

  23. Morris JA, Kandpal G, Ma L, Austin CP . DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Hum Mol Genet 2003; 12: 1591–1608.

    Article  CAS  Google Scholar 

  24. Millar JK, Christie S, Porteous DJ . Yeast two-hybrid screens implicate DISC1 in brain development and function. Biochem Biophys Res Commun 2003; 311: 1019–1025.

    Article  CAS  Google Scholar 

  25. Brandon NJ, Handford EJ, Schurov I, Rain JC, Pelling M, Duran-Jimeniz B et al. Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Mol Cell Neurosci 2004; 25: 42–55.

    Article  CAS  Google Scholar 

  26. Millar JK, James R, Brandon NJ, Thomson PA . DISC1 and DISC2: discovering and dissecting molecular mechanisms underlying psychiatric illness. Ann Med 2004; 36: 367–378.

    Article  CAS  Google Scholar 

  27. Aoki K, Ishida R, Kasai M . Isolation and characterisation of a cDNA encoding a translin-like protein, TRAX. FEBS Lett 1997; 401: 109–112.

    Article  CAS  Google Scholar 

  28. Han JR, Gu W, Hecht NB . Testis-brain RNA-binding protein, a testicular translational regulatory RNA-binding protein, is present in the brain and binds to the 3′ untranslated regions of transported brain mRNAs. Biol Reprod 1995; 53: 707–717.

    Article  CAS  Google Scholar 

  29. Kobayashi S, Takashima A, Anzai K . The dendritic translocation of translin protein in the form of BC1 RNA protein particles in developing rat hippocampal neurons in primary culture. Biochem Biophys Res Commun 1998; 253: 448–453.

    Article  CAS  Google Scholar 

  30. Yang S, Cho YS, Chennathukuzhi VM, Underkoffler LA, Loomes K, Hecht NB . Translin-associated factor X is post-transcriptionally regulated by its partner protein TB-RBP, and both are essential for normal cell proliferation. J Biol Chem 2004; 279: 12605–12614.

    Article  CAS  Google Scholar 

  31. Chennathukuzhi V, Stein JM, Abel T, Donlon S, Yang S, Miller JP et al. Mice deficient for testis–brain RNA-binding protein exhibit a coordinate loss of TRAX, reduced fertility, altered gene expression in the brain, and behavioral changes. Mol Cell Biol 2003; 23: 6419–6434.

    Article  CAS  Google Scholar 

  32. Wilson-Annan JC, Blackwood DH, Muir W, Millar JK, Porteous DJ . An allelic association study of two polymorphic markers in close proximity to a balanced translocation t(1:11) that co-segregates with mental illness. Psychiatr Genet 1997; 7: 171–174.

    Article  CAS  Google Scholar 

  33. Devon RS, Anderson S, Teague PW, Burgess P, Kipari TM, Semple CA et al. Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder. Psychiatr Genet 2001; 11: 71–78.

    Article  CAS  Google Scholar 

  34. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. APA: Washington, DC, 1994.

  35. Endicott J, Spitzer RL . A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 1978; 35: 837–862.

    Article  CAS  Google Scholar 

  36. UCSC Human Genome Browser, http://genome.ucsc.edu/.

  37. NCBI Entrz SNP, http://www.ncbi.nlm.nih.gov/entrez.

  38. Clayton D 2002. Choosing a set of haplotype tagging SNPs from a larger set of diallelic loci. http://www.gene.cimr.cam.ac.uk/clayton/software/stata/htSNP/htsnp.pdf.

  39. Weale M, Goldstein D 2002. TagIT, Version 1.17. http://popgen.biol.ucl.ac.uk/software.html.

  40. Johnson GC, Esposito L, Barratt BJ, Smith AN, Heward J, Di Genova G et al. Haplotype tagging for the identification of common disease genes. Nat Genet 2001; 29: 233–237.

    Article  CAS  Google Scholar 

  41. http://www.hapmap.org/thehapmap.html.en.

  42. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  Google Scholar 

  43. Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–221. http://www.hgmp.mrc.ac.uk/~fdudbrid/software/unphased/.

    Article  Google Scholar 

  44. Miyoshi K, Asanuma M, Miyazaki I, Diaz-Corrales FJ, Katayama T, Tohyama M et al. DISC1 localizes to the centrosome by binding to kendrin. Biochem Biophys Res Commun 2004; 317: 1195–1199.

    Article  CAS  Google Scholar 

  45. Stefansson H, Steinthorsdottir V, Thorgeirsson TE, Gulcher JR, Stefansson K . Neuregulin 1 and schizophrenia. Ann Med 2004; 36: 62–71.

    Article  CAS  Google Scholar 

  46. Kirov G, Ivanov D, Williams NM, Preece A, Nikolov I, Milev R et al. Strong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia in 488 parent–offspring trios from Bulgaria. Biol Psychiatry 2004; 55: 971–975.

    Article  CAS  Google Scholar 

  47. Zhang X, Wei J, Yu YQ, Liu SZ, Shi JP, Liu LL et al. Is NOTCH4 associated with schizophrenia? Psychiatr Genet 2004; 14: 43–46.

    Article  Google Scholar 

  48. Zondervan KT, Cardon LR . The complex interplay among factors that influence allelic association. Nat Rev Genet 2004; 5: 89–100.

    Article  CAS  Google Scholar 

  49. Levinson DF, Holmans PA, Laurent C, Riley B, Pulver AE, Gejman PV et al. No major schizophrenia locus detected on chromosome 1q in a large multicenter sample. Science 2002; 296: 739–741.

    Article  CAS  Google Scholar 

  50. Macgregor S, Visscher PM, Knott S, Porteous D, Muir W, Millar K et al. Is schizophrenia linked to chromosome 1q? Science 2002; 298: 2277, author reply 2277.

    Article  Google Scholar 

  51. Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J et al. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 2003; 12: 205–216.

    Article  CAS  Google Scholar 

  52. Mukai J, Liu H, Burt RA, Swor DE, Lai WS, Karayiorgou M et al. Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia. Nat Genet 2004; 36: 725–731.

    Article  CAS  Google Scholar 

  53. Owen MJ, Williams NM, O'Donovan MC . Dysbindin-1 and schizophrenia: from genetics to neuropathology. J Clin Invest 2004; 113: 1255–1257.

    Article  CAS  Google Scholar 

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Acknowledgements

We are indebted to patients, their families and volunteers for their participation in this study. We thank Maura Walker and Margaret Van Beck for the collation of patient data. This work was funded by a collaborative research grant from the University of Edinburgh and by Organon Laboratories Ltd, Newhouse, Lanarkshire, UK; further supported by grants from the Chief Scientists Office, Scottish Executive; the Health Foundation, London and the Medical Research Council, UK.

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Correspondence to P A Thomson.

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Thomson, P., Wray, N., Millar, J. et al. Association between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population. Mol Psychiatry 10, 657–668 (2005). https://doi.org/10.1038/sj.mp.4001669

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