Skip to main content
SpringerLink
Log in

Genetics of clinical features and subtypes of schizophrenia: A review of the recent literature

  • Published:
Current Psychiatry Reports Aims and scope Submit manuscript

Abstract

Since its earliest descriptions, schizophrenia has been thought to be clinically heterogeneous. Symptomatic features and subtypes tend to aggregate in families, suggesting that genetic factors contribute to individual differences in illness presentation. Over the past 5 years, evidence from genetic linkage and association studies has mounted to suggest that some susceptibility genes are etiologic factors for more or less specific illness subtypes. Furthermore, modifier genes may affect clinical features dimensionally only after a given patient is already affected with the illness. In this paper, we review recent findings supporting the existence of such “modifier” genes. To date, DTNBP1 has provided the greatest evidence of illness modification, as associations with negative and cognitive symptoms and worse outcome have been published in independent samples. Future directions include using whole-genome association studies to search for genetic modifiers of schizophrenia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Peralta V, Cuesta MJ: How many and which are the psychopathological dimensions in schizophrenia? Issues influencing their ascertainment. Schizophr Res 2001, 49:269–285.

    Article  PubMed  CAS  Google Scholar 

  2. American Psychiatric Association: Diagnostic and Statistical Manual IV, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association; 2000.

    Google Scholar 

  3. McGlashan TH, Fenton WS: Classical subtypes for schizophrenia: literature review for DSM-IV. Schizophr Bull 1991, 17:609–632.

    PubMed  CAS  Google Scholar 

  4. Andreasen NC, Carpenter WT, Jr: Diagnosis and classification of schizophrenia. Schizophr Bull 1993, 19:199–214.

    PubMed  CAS  Google Scholar 

  5. Berrios GE: Unitary psychosis concept. In A History of Clinical Psychiatry. Edited by Berrios GE, Porter R. London: The Athlone Press; 1995:313–335.

    Google Scholar 

  6. Bleuler E: Dementia Praecox (The Group of Schizophrenias). New York: International Universities Press; 1950.

    Google Scholar 

  7. Choi KS, Jeon HO, Lee YS, et al.: Familial association of schizophrenia symptoms retrospectively measured on a lifetime basis. Psychiatr Genet 2007, 17:103–107.

    Article  PubMed  Google Scholar 

  8. Kendler KS, Karkowski-Shuman L, O’Neill FA, et al.: Resemblance of psychotic symptoms and syndromes in affected sibling pairs from the Irish Study of High-Density Schizophrenia Families: evidence for possible etiologic heterogeneity. Am J Psychiatry 1997, 154:191–198.

    PubMed  CAS  Google Scholar 

  9. Riley B, Kendler KS: Molecular genetic studies of schizophrenia. Eur J Hum Genet 2006, 14:669–680.

    Article  PubMed  Google Scholar 

  10. Fanous AH, Kendler KS: Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework. Mol Psychiatry 2005, 10:6–13.

    Article  PubMed  CAS  Google Scholar 

  11. Boyle MP: Strategies for identifying modifier genes in cystic fibrosis. Proc Am Thorac Soc 2007, 4:52–57.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Craddock N, O’Donovan MC, Owen MJ: Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophr Bull 2006, 32:9–16.

    Article  PubMed  Google Scholar 

  14. Owen MJ, Craddock N, Jablensky A: The genetic deconstruction of psychosis. Schizophr Bull 2007, 33:905–911.

    Article  PubMed  Google Scholar 

  15. Tosato S, Ruggeri M, Bonetto C, et al.: Association study of dysbindin gene with clinical and outcome measures in a representative cohort of Italian schizophrenic patients. Am J Med Genet B Neuropsychiatr Genet 2007, 144:647–659.

    PubMed  Google Scholar 

  16. Burdick KE, Goldberg TE, Funke B, et al.: DTNBP1 genotype influences cognitive decline in schizophrenia. Schizophr Res 2007, 89:169–172.

    Article  PubMed  Google Scholar 

  17. Fanous AH, Van Den Oord EJ, Riley BP, et al.: Relationship between a high-risk haplotype in the DTNBP1 (dysbindin) gene and clinical features of schizophrenia. Am J Psychiatry 2005, 162:1824–1832.

    Article  PubMed  Google Scholar 

  18. Straub RE, Jiang Y, MacLean CJ, et al.: Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 2002, 71:337–348.

    Article  PubMed  CAS  Google Scholar 

  19. DeRosse P, Funke B, Burdick KE, et al.: Dysbindin genotype and negative symptoms in schizophrenia. Am J Psychiatry 2006, 163:532–534.

    Article  PubMed  Google Scholar 

  20. Heydebrand G, Weiser M, Rabinowitz J, et al.: Correlates of cognitive deficits in first episode schizophrenia. Schizophr Res 2004, 68:1–9.

    Article  PubMed  Google Scholar 

  21. Hughes C, Kumari V, Soni W, et al.: Longitudinal study of symptoms and cognitive function in chronic schizophrenia. Schizophr Res 2003, 59:137–146.

    Article  PubMed  Google Scholar 

  22. Chubb JE, Bradshaw NJ, Soares DC, et al.: The DISC locus in psychiatric illness. Mol Psychiatry 2008, 13:36–64.

    Article  PubMed  CAS  Google Scholar 

  23. DeRosse P, Hodgkinson CA, Lencz T, et al.: Disrupted in schizophrenia 1 genotype and positive symptoms in schizophrenia. Biol Psychiatry 2007, 61:1208–1210.

    Article  PubMed  Google Scholar 

  24. Chumakov I, Blumenfeld M, Guerassimenko O, et al.: Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci U S A 2002, 99:13675–13680.

    Article  PubMed  CAS  Google Scholar 

  25. Goff DC, Coyle JT: The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 2001, 158:1367–1377.

    Article  PubMed  CAS  Google Scholar 

  26. Yue W, Kang G, Zhang Y, et al.: Association of DAOA polymorphisms with schizophrenia and clinical symptoms or therapeutic effects. Neurosci Lett 2007, 416:96–100.

    Article  PubMed  Google Scholar 

  27. Schulze TG, Ohlraun S, Czerski PM, et al.: Genotype-phenotype studies in bipolar disorder showing association between the DAOA/G30 locus and persecutory delusions: a first step toward a molecular genetic classification of psychiatric phenotypes. Am J Psychiatry 2005, 162:2101–2108.

    Article  PubMed  Google Scholar 

  28. Georgi A, Jamra RA, Klein K, et al.: Possible association between genetic variants at the GRIN1 gene and schizophrenia with lifetime history of depressive symptoms in a German sample. Psychiatr Genet 2007, 17:308–310.

    Article  PubMed  Google Scholar 

  29. Petryshen TL, Middleton FA, Tahl AR, et al.: Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia. Mol Psychiatry 2005, 10:1074–1088, 1057.

    Article  PubMed  CAS  Google Scholar 

  30. Lo WS, Harano M, Gawlik M, et al.: GABRB2 association with schizophrenia: commonalities and differences between ethnic groups and clinical subtypes. Biol Psychiatry 2007, 61:653–660.

    Article  PubMed  Google Scholar 

  31. Emamian ES, Hall D, Birnbaum MJ, et al.: Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 2004, 36:131–137.

    Article  PubMed  CAS  Google Scholar 

  32. Thiselton DL, Vladimirov VI, Kuo PH, et al.: AKT1 is associated with schizophrenia across multiple symptom dimensions in the Irish Study of High Density Schizophrenia Families. Biol Psychiatry 2007 [Epub ahead of print.]

  33. Duan J, Martinez M, Sanders AR, et al.: Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia. Am J Hum Genet 2004, 75:624–638.

    Article  PubMed  CAS  Google Scholar 

  34. Vladimirov V, Thiselton DL, Kuo PH, et al.: A region of 35 kb containing the trace amine associate receptor 6 (TAAR6) gene is associated with schizophrenia in the Irish study of high-density schizophrenia families. Mol Psychiatry 2007, 12:842–853.

    Article  PubMed  CAS  Google Scholar 

  35. McClay JL, Fanous A, Van Den Oord EJ, et al.: Catechol-O-methyltransferase and the clinical features of psychosis. Am J Med Genet B Neuropsychiatr Genet 2006, 141:935–938.

    PubMed  CAS  Google Scholar 

  36. DeRosse P, Funke B, Burdick KE, et al.: COMT genotype and manic symptoms in schizophrenia. Schizophr Res 2006, 87:28–31.

    Article  PubMed  Google Scholar 

  37. Shifman S, Bronstein M, Sternfeld M, et al.: COMT: a common susceptibility gene in bipolar disorder and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2004, 128:61–64.

    Article  PubMed  Google Scholar 

  38. Tao R, Wei J, Guo Y, et al.: The PLA2G4A gene and negative symptoms in a Chinese population. Schizophr Res 2006, 86:326–328.

    Article  PubMed  Google Scholar 

  39. Verma R, Mukerji M, Grover D, et al.: MLC1 gene is associated with schizophrenia and bipolar disorder in Southern India. Biol Psychiatry 2005, 58:16–22.

    Article  PubMed  Google Scholar 

  40. Selch S, Strobel A, Haderlein J, et al.: MLC1 polymorphisms are specifically associated with periodic catatonia, a subgroup of chronic schizophrenia. Biol Psychiatry 2007, 61:1211–1214.

    Article  PubMed  Google Scholar 

  41. Fanous AH, Neale MC, Straub RE, et al.: Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study. Am J Med Genet 2004, 125B:69–78.

    Article  Google Scholar 

  42. Fanous AH, Neale MC, Webb BT, et al.: A genome-wide scan for modifier loci in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2007, 144:589–595.

    PubMed  Google Scholar 

  43. Andreasen NC: The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations. Br J Psychiatry Suppl 1989, 7:49–58.

    PubMed  Google Scholar 

  44. Andreasen NC: The Scale for the Assessment of Positive Symptoms (SAPS). Iowa City, IA: University of Iowa; 1984.

    Google Scholar 

  45. Wilcox MA, Faraone SV, Su J, et al.: Genome scan of three quantitative traits in schizophrenia pedigrees. Biol Psychiatry 2002, 52:847–854.

    Article  PubMed  CAS  Google Scholar 

  46. Hallmayer JF, Kalaydjieva L, Badcock J, et al.: Genetic evidence for a distinct subtype of schizophrenia characterized by pervasive cognitive deficit. Am J Hum Genet 2005, 77:468–476.

    Article  PubMed  Google Scholar 

  47. Fanous AH, Neale MC, Webb BT, et al.: Novel linkage to chromosome 20p using latent classes of psychotic illness in 270 Irish high-density families. Biol Psychiatry 2008, In press.

  48. Sullivan PF: Spurious genetic associations. Biol Psychiatry 2007, 61:1121–1126.

    Article  PubMed  Google Scholar 

  49. Lencz T, Morgan TV, Athanasiou M, et al.: Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Mol Psychiatry 2007, 12:572–580.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Washington VA Medical Center, 50 Irving Street NW, Washington, DC, 20422, USA

    Ayman H. Fanous

Authors
  1. Ayman H. Fanous
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kenneth S. Kendler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ayman H. Fanous.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fanous, A.H., Kendler, K.S. Genetics of clinical features and subtypes of schizophrenia: A review of the recent literature. Curr Psychiatry Rep 10, 164–170 (2008). https://doi.org/10.1007/s11920-008-0028-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11920-008-0028-z

Keywords

Search

Navigation