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Copy number variation showers in schizophrenia: an emerging hypothesis

Molecular Psychiatry volume 14, pages 356–358 (2009)Cite this article

Abstract

Genetic discoveries on Schizophrenia remain challenging. Traditional approaches have provided clues, but no genes. Novel theories that must account for extensive heterogeneity, including high discordance of monozygotic (MZD) twins, are needed. To this end, the extensive repeats of the human genome may provide the predisposition for DNA replication errors operational at every cell cycle during meiosis and mitosis. These errors will shower the genome with replication errors including copy number variations. Depending on the timing and the genes involved, this will contribute to the mutational load and disease. The evidence for such a mechanism in schizophrenia is emerging.

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References

  1. Rudin E . Zur Vererbung und Neuentstehung der Dementia Praecox. Springer-Verlag: Berlin and New York, 1916.

    Google Scholar 

  2. Huxley J, Mayr E, Osmond H, Hoffer A . Schizophrenia as a genetic morphism. Nature 1964; 204: 220–221.

    Article  CAS  PubMed  Google Scholar 

  3. Karayiorgou M, Gogos JA . A turning point in schizophrenia genetics. Neuron 1997; 19: 967–979.

    Article  CAS  PubMed  Google Scholar 

  4. Sullivan PF . The genetics of schizophrenia. PLoS Med 2005; 2: e212.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Craddock N, O'Donovan MC, Owen MJ . Genome-wide association studies in psychiatry: lessons from early studies of non-psychiatric and psychiatric phenotypes. Mol Psychiatry 2008; 13: 649–653.

    Article  CAS  PubMed  Google Scholar 

  6. Burmeister M, McInnis MG, Zollner S . Psychiatric genetics: progress amid controversy. Nat Rev Genet 2008; 9: 527–540.

    Article  CAS  PubMed  Google Scholar 

  7. Tandon R, Keshavan MS, Nasrallah HA . Schizophrenia, ‘Just the Facts’ what we know in 2008. 2. Epidemiology and etiology. Schizophr Res 2008; 102: 1–18.

    Article  PubMed  Google Scholar 

  8. Gottesman II . Schizophrenia Genesis: the Origin of Madness. W.H. Freeman and Co.: New York, 1991.

    Google Scholar 

  9. Pritchard JK, Cox NJ . The allelic architecture of human disease genes: common disease-common variant… or not? Hum Mol Genet 2002; 11: 2417–2423.

    Article  CAS  PubMed  Google Scholar 

  10. Becker KG . The common variants/multiple disease hypothesis of common complex genetic disorders. Med Hypotheses 2004; 62: 309–317.

    Article  CAS  PubMed  Google Scholar 

  11. Berrettini W . Bipolar disorder and schizophrenia: not so distant relatives? World Psychiatry 2003; 2: 68–72.

    PubMed  PubMed Central  Google Scholar 

  12. Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB et al. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 2003; 362: 798–805.

    Article  CAS  PubMed  Google Scholar 

  13. Abbott A . Psychiatric genetics: the brains of the family. Nature 2008; 454: 154–157.

    Article  CAS  PubMed  Google Scholar 

  14. Braff DL, Greenwood TA, Swerdlow NR, Light GA, Schork NJ, The Investigators of the Consortium on the Genetics of Schizophrenia. Advances in endophenotyping schizophrenia. World Psychiatry 2008; 7: 11–18.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Torrey EF, Torrey BB, Peterson MR . Seasonality of schizophrenic births in the United States. Arch Gen Psychiatry 1977; 34: 1065–1070.

    Article  CAS  PubMed  Google Scholar 

  16. Morgan C, Fisher H . Environment and schizophrenia: environmental factors in schizophrenia: childhood trauma—a critical review. Schizophr Bull 2007; 33: 3–10.

    Article  PubMed  Google Scholar 

  17. Singh SM, McDonald P, Murphy B, O'Reilly R . Incidental neurodevelopmental episodes in the etiology of schizophrenia: an expanded model involving epigenetics and development. Clin Genet 2004; 65: 435–440.

    Article  CAS  PubMed  Google Scholar 

  18. Petronis A, Gottesman II, Kan P, Kennedy JL, Basile VS, Paterson AD et al. Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance? Schizophr Bull 2003; 29: 169–178.

    Article  PubMed  Google Scholar 

  19. Perrin MC, Brown AS, Malaspina D . Aberrant epigenetic regulation could explain the relationship of paternal age to schizophrenia. Schizophr Bull 2007; 33: 1270–1273.

    Article  PubMed  PubMed Central  Google Scholar 

  20. O'Reilly RL, Singh SM . Retroviruses and schizophrenia revisited. Am J Med Genet 1996; 67: 19–24.

    Article  CAS  PubMed  Google Scholar 

  21. Deb-Rinker P, Klempan TA, O'Reilly RL, Torrey EF, Singh SM . Molecular characterization of a MSRV-like sequence identified by RDA from monozygotic twin pairs discordant for schizophrenia. Genomics 1999; 61: 133–144.

    Article  CAS  PubMed  Google Scholar 

  22. van Vliet J, Oates NA, Whitelaw E . Epigenetic mechanisms in the context of complex diseases. Cell Mol Life Sci 2007; 64: 1531–1538.

    Article  CAS  PubMed  Google Scholar 

  23. Guidry J, Kent TA . New genetic hypothesis of schizophrenia. Med Hypotheses 1999; 52: 69–75.

    Article  CAS  PubMed  Google Scholar 

  24. Bruder C, Piotrowski A, Gijsbers A, Andersson R, Erickson S, Diaz de Ståhl T et al. Phenotypically concordant and discordant monozygotic twins display different DNA copy number variation profiles. Am J Hum Genet 2008; 82: 1–9.

    Article  Google Scholar 

  25. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 2005; 102: 10604–10609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 2008; 320: 539–543.

    Article  CAS  PubMed  Google Scholar 

  27. Rapoport JL, Addington A, Frangou S . The neurodevelopmental model of schizophrenia: what can very early onset cases tell us? Curr Psychiatry Rep 2005; 7: 81–82.

    Article  PubMed  Google Scholar 

  28. Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M . Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet 2008; 40: 880–885.

    Article  CAS  PubMed  Google Scholar 

  29. Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: 232–236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. The International Schizophrenia Consortium, manuscript preparation Stone JL, O'Donovan MC, Gurling H, Kirov GK, Blackwood DH, Corvin A et al. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008; 455: 237–241.

    Article  Google Scholar 

  31. Sutrala SR, Norton N, Williams NM, Buckland PR . Gene copy number variation in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 606–611.

    Article  CAS  PubMed  Google Scholar 

  32. Perry GH, Yang F, Marques-Bonet T, Murphy C, Fitzgerald T, Lee AS et al. Copy number variation and evolution in humans and chimpanzees. Genome Res 2008; 18: 1698–1710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Westra JW, Peterson SE, Yung YC, Mutoh T, Barral S, Chun J . Aneuploid mosaicism in the developing and adult cerebellar cortex. J Comp Neurol 2008; 507: 1944–1951.

    Article  PubMed  Google Scholar 

  34. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T et al. Strong association of de novo copy number mutations with autism. Science 2007; 316: 445–449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. University of Western Ontario, London, ON, Canada

    S M Singh, C A Castellani & R L O'Reilly

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  1. S M Singh
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  2. C A Castellani
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  3. R L O'Reilly
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Correspondence to S M Singh.

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Singh, S., Castellani, C. & O'Reilly, R. Copy number variation showers in schizophrenia: an emerging hypothesis. Mol Psychiatry 14, 356–358 (2009). https://doi.org/10.1038/mp.2008.149

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