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Identification of candidate genes for psychosis in rat models, and possible association between schizophrenia and the 14-3-3η gene

Molecular Psychiatry volume 8, pages 156–166 (2003)Cite this article

Abstract

Although the genetic contribution to schizophrenia is substantial, positive findings in whole-genome linkage scans have not been consistently replicated. We analyzed gene expression in various rat conditions to identify novel candidate genes for schizophrenia. Suppression subtraction hybridization (SSH), with polyA mRNA from temporal and frontal cortex of rats, was used to identify differentially expressed genes. Expression of mRNA was compared between adult Lewis and Fischer 344 (F344) rats, adult and postnatal day 6 (d6) F344, and adult F344 treated with haloperidol or control vehicle. These groups were chosen because each highlights a particular aspect of schizophrenia: differences in strain vulnerability to behavioral analogs of psychosis; factors that may relate to disease onset in relation to CNS development; and improvement of symptoms by haloperidol. The 14-3-3 gene family, as represented by 14-3-3γ and 14-3-3ζ isoforms in the SSH study, and SNAP-25 were among the candidate genes. Genetic association between schizophrenia and the 14-3-3η gene, positioned close to a genomic locus implicated in schizophrenia, and SNAP-25 genes was analyzed in 168 schizophrenia probands and their families. These findings address three different genes in the 14-3-3 family. We find a significant association with schizophrenia for two polymorphisms in the 14-3-3η gene: a 7 bp variable number of tandem repeats in the 5′ noncoding region (P=0.036, 1 df), and a 3′ untranslated region SNP (753G/A) that is an RFLP visualized with Ava II (P=0.028). There was no significant genetic association with SNAP-25. The candidate genes identified may be of functional importance in the etiology, pathophysiology or treatment response of schizophrenia or psychotic symptoms. This is to our knowledge the first report of a significant association between the 14-3-3η-chain gene and schizophrenia in a family-based sample, strengthening prior association reports in case–control studies and microarray gene expression studies.

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References

  1. Jablensky A . Epidemiology of schizophrenia: the global burden of disease and disability. Eur Arch Psychiatry Clin Neurosci 2000; 250: 274–285.

    Article  CAS  PubMed  Google Scholar 

  2. Sartorius N, Jablensky A, Korten A . Early manifestations and first contact incidence of schizophrenia in different cultures: a preliminary report on the inital evaluation phase of the WHO collaborative study on determinants of outcome of severe mental disorders. Psychol Med 1986; 16: 909–928.

    Article  CAS  PubMed  Google Scholar 

  3. Brzustowicz LM, Hodgkinson KA, Chow EW, Honer WG, Bassett AS . Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21–q22. Science 2000; 288: 678–682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Riley BP, McGuffin P . Linkage and associated studies of schizophrenia. Am J Med Genet 2000; 97: 23–44.

    Article  CAS  PubMed  Google Scholar 

  5. Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.

    Article  CAS  PubMed  Google Scholar 

  6. Risch N . Linkage strategies for genetically complex traits. II. The power of affected relative pairs. Am J Hum Genet 1990; 46: 229–241.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Risch N . Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet 1990; 46: 222–228.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Lipska BK, Jaskiw GE, Weinberger DR . Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic damage: a potential animal model of schizophrenia. Neuropsychopharmacology 1993; 9: 67–75.

    Article  CAS  PubMed  Google Scholar 

  9. Lipska BK, Swerdlow NR, Geyer MA, Jaskiw GE, Braff DL, Weinberger DR . Neonatal excitotoxic hippocampal damage in rats causes post-pubertal changes in prepulse inhibition of startle and its disruption by apomorphine. Psychopharmacology 1995; 122: 35–43.

    Article  CAS  PubMed  Google Scholar 

  10. Lipska BK, Jaskiw GE, Braun AR, Weinberger DR . Profrontal cortical and hippocampal modulation of haloperidol-induced catalepsy and apomorphine-induced stereotypic behaviours in the rat. Biol Psychiatry 1995; 38: 255–262.

    Article  CAS  PubMed  Google Scholar 

  11. Swerdlow NR, Lipska BK, Weinberger DR, Braff DL, Jaskiw GE, Geyer MA . Increased sensitivity to the sensorimotor gating-disruptive effects of apomorphine after lesions of medial prefrontal cortex or ventral hippocampus in rats. Psychopharmacology 1995; 122: 27–34.

    Article  CAS  PubMed  Google Scholar 

  12. Chambers RA, Moore J, McEvoy JP, Levin ED . Cognitive effects of neonatal hippocampal lesions in a rat model of schizophrenia. Neuropsychopharmacology 1996; 15: 587–594.

    Article  CAS  PubMed  Google Scholar 

  13. Lillrank SM, Lipska BK, Kolachana BS, Weinberger DR . Attenuated extracellular dopamine levels after stress and amphetamine in the nucleus accumbens of rats with neonatal ventral hippocampal damage. J Neural Transm 1999; 106: 183–196.

    Article  CAS  PubMed  Google Scholar 

  14. Lipska BK, Weinberger DR . Genetic variation in vulnerability to the behavioural effects of neonatal hippocampal damage in rats. Proc Natl Acad Sci 1995; 92: 8906–8910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lipska BK, Weinberger DR . To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 2000; 23: 223–239.

    Article  CAS  PubMed  Google Scholar 

  16. Harrison PJ . The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999; 122(Part 4): 593–624.

    Article  PubMed  Google Scholar 

  17. Weinberger D . Neurodevelopmental perspectives on schizophrenia. In: Bloom F, Kupfer D (eds). Psychopharmacology: The Fourth Generation of Progress. Raven Press Ltd: New York, 1995, pp 1171–1183.

    Google Scholar 

  18. Diatchenko L et al. Suppression subtractive hybridization: a method for generating differentially regulated or tissue-specific cDNA probes or libraries. Proc Natl Acad Sci 1996; 93: 6025–6030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. DSM-IV TFo. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association: Washington, DC, 1994.

  20. Nurnberger Jr JI, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J et al. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch Gen Psychiatry 1994; 51: 849–859; discussion 863-4.

    Article  PubMed  Google Scholar 

  21. Lahiri DK, Nurnberger Jr JI . A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 1991; 19: 5444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bell R, Munro J, Russ C, Powell JF, Bruinvels A, Kerwin RW et al. Systematic screening of the 14-3-3 eta (eta) chain gene for polymorphic variants and case-control analysis in schizophrenia. Am J Med Genet 2000; 96: 736–743.

    Article  CAS  PubMed  Google Scholar 

  23. Barr CL, Feng Y, Wigg K, Bloom S, Roberts W, Malone M et al. Identification of DNA variants in the SNAP-25 gene and linkage study of these polymorphisms and attention-deficit hyperactivity disorder. Mol Psychiatry 2000; 5: 405–409.

    Article  CAS  PubMed  Google Scholar 

  24. Spielman RS, Ewens WJ . A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am J Hum Genet 1998; 62: 450–458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Laird NM, Horvath S, Xu X . Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000; 19 (Suppl 1): S36–S42.

    Article  PubMed  Google Scholar 

  26. Hess EJ, Collins KA, Wilson MC . Mouse model of hyperkinesis implicates SNAP-25 in behavioral regulation. J Neurosci 1996; 16: 3104–3111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Young CE, Arima K, Xie J, Hu L, Beach TG, Falkai P et al. SNAP-25 deficit and hippocampal connectivity in schizophrenia. Cereb Cortex 1998; 8: 261–268.

    Article  CAS  PubMed  Google Scholar 

  28. Pulver AE, Karayiorgou M, Lasseter VK, Wolyniec P, Kasch L, Antonarakis S et al. Follow-up of a report of a potential linkage for schizophrenia on chromosome 22q12-q13.1: Part 2. Am J Med Genet 1994; 54: 44–50.

    Article  CAS  PubMed  Google Scholar 

  29. Murphy KC, Jones LA, Owen MJ . High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 1999; 56: 940–945.

    Article  CAS  PubMed  Google Scholar 

  30. Vawter MP, Barrett T, Cheadle C, Sokolov BP, Wood 3rd WH, Donovan DM et al. Application of cDNA microarrays to examine gene expression differences in schizophrenia. Brain Res Bull 2001; 55: 641–650.

    Article  CAS  PubMed  Google Scholar 

  31. Toyooka K, Muratake T, Tanaka T, Igarashi S, Watanabe H, Takeuchi H et al. 14-3-3 protein eta chain gene (YWHAH) polymorphism and its genetic association with schizophrenia. Am J Med Genet 1999; 88: 164–167.

    Article  CAS  PubMed  Google Scholar 

  32. Risch N . Searching for genes in complex diseases: lessons from systemic lupus erythematosus. J Clin Invest 2000; 105: 1503–1506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cavelier L, Jazin EE, Eriksson I, Prince J, Bave U, Oreland L et al. Decreased cytochrome-c oxidase activity and lack of age-related accumulation of mitochondrial DNA deletions in the brains of schizophrenics. Genomics 1995; 29: 217–224.

    Article  CAS  PubMed  Google Scholar 

  34. Kung L, Roberts RC . Mitochondrial pathology in human schizophrenic striatum: a postmortem ultrastructural study. Synapse 1999; 31: 67–75.

    Article  CAS  PubMed  Google Scholar 

  35. Whatley SA, Curti D, Marchbanks RM . Mitochondrial involvement in schizophrenia and other functional psychoses. Neurochem Res 1996; 21: 995–1004.

    Article  CAS  PubMed  Google Scholar 

  36. Whatley SA, Curti D, Das Gupta F, Ferrier IN, Jones S, Taylor C et al. Superoxide, neuroleptics and the ubiquinone and cytochrome b5 reductases in brain and lymphocytes from normals and schizophrenic patients. Mol Psychiatry 1998; 3: 227–237.

    Article  CAS  PubMed  Google Scholar 

  37. Prince JA, Yassin MS, Oreland L . Normalization of cytochrome-c oxidase activity in the rat brain by neuroleptics after chronic treatment with PCP or methamphetamine. Neuropharmacology 1997; 36: 1665–1678.

    Article  CAS  PubMed  Google Scholar 

  38. Ferre S . Adenosine-dopamine interactions in the ventral striatum Implications for the treatment of schizophrenia. Psychopharmacology (Berl) 1997; 133: 107–120.

    Article  CAS  PubMed  Google Scholar 

  39. Dixon DA, Fenix LA, Kim DM, Raffa RB . Indirect modulation of dopamine D2 receptors as potential pharmacotherapy for schizophrenia: I. Adenosine agonists. Ann Pharmacother 1999; 33: 480–488.

    Article  CAS  PubMed  Google Scholar 

  40. Deckert J, Nothen MM, Bryant SP, Schuffenhauer S, Schofield PR, Spurr NK et al. Mapping of the human adenosine A2a receptor gene: relationship to potential schizophrenia loci on chromosome 22q and exclusion from the CATCH 22 region. Hum Genet 1997; 99: 326–328.

    Article  CAS  PubMed  Google Scholar 

  41. Schwab SG, Wildenauer DB . Chromosome 22 workshop report. Am J Med Genet 1999; 88: 276–278.

    Article  CAS  PubMed  Google Scholar 

  42. Wilson MC, Mehta PP, Hess EJ . SNAP-25, enSNAREd in neurotransmission and regulation of behaviour. Biochem Soc Trans 1996; 24: 670–676.

    Article  CAS  PubMed  Google Scholar 

  43. Jakob H, Beckmann H . Gross and histological criteria for developmental disorders in brains of schizophrenics. J R Soc Med 1989; 82: 466–469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Thompson PM, Sower AC, Perrone-Bizzozero NI . Altered levels of the synaptosomal associated protein SNAP-25 in schizophrenia. Biol Psychiatry 1998; 43: 239–243.

    Article  CAS  PubMed  Google Scholar 

  45. Maglott DR, Feldblyum TV, Durkin AS, Nierman WC . Radiation hybrid mapping of SNAP, PCSK2, and THBD (human chromosome 20p). Mamm Genome 1996; 7: 400–401.

    Article  CAS  PubMed  Google Scholar 

  46. Gejman PV . Chromosomes 19 and 20 report. Am J Med Genet 1999; 88: 271.

    Article  CAS  PubMed  Google Scholar 

  47. Thomas EA, Danielson PE, Nelson PA, Pribyl TM, Hilbush BS, Hasel KW et al. Clozapine increases apolipoprotein D expression in rodent brain: towards a mechanism for neuroleptic pharmacotherapy. J Neurochem 2001; 76: 789–796.

    Article  CAS  PubMed  Google Scholar 

  48. Fu H, Subramanian RR, Masters SC . 14-3-3 proteins: structure function and regulation. Annu Rev Pharmacol Toxicol 2000; 40: 617–647.

    Article  CAS  PubMed  Google Scholar 

  49. van Hemert MJ, Steensma HY, van Heusden GP . 14-3-3 proteins: key regulators of cell division, signalling and apoptosis. Bioessays 2001; 23: 936–946.

    Article  CAS  PubMed  Google Scholar 

  50. Muratake T, Hayashi S, Ichikawa T, Kumanishi T, Ichimura Y, Kuwano R et al. Structural organization and chromosomal assignment of the human 14-3-3 eta chain gene (YWHAH). Genomics 1996; 36: 63–69.

    Article  CAS  PubMed  Google Scholar 

  51. Pulver AE, Karayiorgou M, Wolyniec PS, Lasseter VK, Kasch L, Nestadt G et al. Sequential strategy to identify a susceptibility gene for schizophrenia: report of potential linkage on chromosome 22q12-q13.1: Part 1. Am J Med Genet 1994; 54: 36–43.

    Article  CAS  PubMed  Google Scholar 

  52. Coon H, Jensen S, Holik J, Hoff M, Hoff M, Myles-Worsley M et al. Genomic scan for genes predisposing to schizophrenia. Am J Med Genet 1994; 54: 59–71.

    Article  CAS  PubMed  Google Scholar 

  53. Gill M, Vallada H, Collier D, Sham P, Holmans P, Murray R et al. A combined analysis of D22S278 marker alleles in affected sib-pairs: support for a susceptibility locus for schizophrenia at chromosome 22q12. Schizophrenia Collaborative Linkage Group (Chromosome 22). Am J Med Genet 1996; 67: 40–45.

    Article  CAS  PubMed  Google Scholar 

  54. Hovatta I, Lichtermann D, Juvonen H, Suvisaari J, Terwilliger JD, Arajarvi R et al. Linkage analysis of putative schizophrenia gene candidate regions on chromosomes 3p, 5q, 6p, 8p, 20p and 22q in a population-based sampled Finnish family set. Mol Psychiatry 1998; 3: 452–457.

    Article  CAS  PubMed  Google Scholar 

  55. Kalsi G, Brynjolfsson J, Butler R, Sherrington R, Curtis D, Sigmundsson T et al. Linkage analysis of chromosome 22q12–13 in a United Kingdom/Icelandic sample of 23 multiplex schizophrenia families. Am J Med Genet 1995; 60: 298–301.

    Article  CAS  PubMed  Google Scholar 

  56. Parsian A, Suarez BK, Isenberg K, Hampe CL, Fisher L, Chakraverty S et al. No evidence for a schizophrenia susceptibility gene in the vicinity of IL2RB on chromosome 22. Am J Med Genet 1997; 74: 361–364.

    Article  CAS  PubMed  Google Scholar 

  57. Riley B, Mogudi-Carter M, Jenkins T, Williamson R . No evidence for linkage of chromosome 22 markers to schizophrenia in southern African Bantu-speaking families. Am J Med Genet 1996; 67: 515–522.

    Article  CAS  PubMed  Google Scholar 

  58. Amati F, Conti E, Novelli A, Bengala M, Diglio MC, Marino B et al. Atypical deletions suggest five 22q11.2 critical regions related to the DiGeorge/velo-cardio-facial syndrome. Eur J Hum Genet 1999; 7: 903–909.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge the support of the Canadian Institutes for Health Research, the National Institute for Mental Health, NARSAD, the Ontario Mental Health Foundation, the Canadian Psychiatric Research Foundation, and the Ontario Ministry of Health in funding this research. Dr Van Tol is supported by the Canadian Research Chair Program.

Thanks are due to Drs Barbara K Lipska and Daniel R Weinberger at NIMH for their helpful advice during this project. We also thank Tascha Cate, Jane Dalton, Greg Wong, Lisa Lee, Helena Madeiros, Celia Carvalho, Tersesa Shandrel, Camille Della Torre, Maria Soares, and Amy Bauer for their help in recruiting and interviewing clinical subjects.

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Authors and Affiliations

  1. Centre for Addiction and Mental Health, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    A H C Wong, F Macciardi, T Klempan, W Kawczynski, S Lakatoo, M Wong, C Buckle, J Trakalo, E Boffa, J Oak, J L Kennedy & H H M Van Tol

  2. Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    A H C Wong, F Macciardi, C L Barr, E Boffa, J L Kennedy & H H M Van Tol

  3. Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    H H M Van Tol

  4. Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    A H C Wong, T Klempan, J L Kennedy & H H M Van Tol

  5. Department of Psychiatry, University of Coimbra, Portugal

    M-H Azevedo, A Dourado, I Coelho, A Macedo, A Vicente & J Valente

  6. State University of New York, Buffalo, NY, USA

    C P Ferreira, M T Pato & C N Pato

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Wong, A., Macciardi, F., Klempan, T. et al. Identification of candidate genes for psychosis in rat models, and possible association between schizophrenia and the 14-3-3η gene. Mol Psychiatry 8, 156–166 (2003). https://doi.org/10.1038/sj.mp.4001237

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