Current Psychiatry Reports

, Volume 10, Issue 4, pp 339–343

Schizophrenia: From genes to phenes to disease

  • Charlotte L. Allan
  • Alastair G. Cardno
  • Peter McGuffin
Article

Abstract

This article provides an overview of the past year’s literature on schizophrenia genetics. Quantitative genetics continues to be an important foundation in which family and twin studies have been used to evaluate potential endophenotypes. Research in molecular genetics has focused on detecting multiple genes of small effect, and developments relating to key positional and functional candidate genes are reviewed. Large-scale, multicenter studies are proving to be important in this quest. Research using neuroimaging and animal modeling studies continues to link genotype with phenotype. It is increasingly apparent that some candidate genes considered important in schizophrenia are likely to be relevant to the etiology of other psychotic disorders, including bipolar disorder. This notion may challenge traditional disease classifications, not only in research but potentially in clinical practice.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Craddock N, O’Donovan MC, Owen MJ: The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet 2005, 42:193–204.PubMedCrossRefGoogle Scholar
  2. 2.
    Lichtenstein P, Björk C, Hultman CM: Recurrence risks for schizophrenia in a Swedish national cohort. Psychol Med 2006, 36:1417–1425.PubMedCrossRefGoogle Scholar
  3. 3.
    Craddock N, O’Donovan MC, Owen MJ: Phenotypic and genetic complexity of psychosis. Invited commentary on … schizophrenia: a common disease caused by multiple rare alleles. Br J Psychiatry 2007, 190:200–203.PubMedCrossRefGoogle Scholar
  4. 4.
    Braff D, Schork NJ, Gottesman II: Endophenotyping schizophrenia. Am J Psychiatry 2007, 164:705–707.PubMedCrossRefGoogle Scholar
  5. 5.
    Greenwood TA, Braff DL, Light GA, et al.: Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia. Arch Gen Psychiatry 2007, 64:1242–1250.PubMedCrossRefGoogle Scholar
  6. 6.
    Bearden CE, van Erp TG, Thompson PM: Cortical mapping of genotype-phenotype relationships in schizophrenia. Hum Brain Mapp 2007, 28:519–532.PubMedCrossRefGoogle Scholar
  7. 7.
    Cannon TD, Keller MC: Endophenotypes in the genetic analyses of mental disorders. Annu Rev Clin Psychol 2006, 2:267–290.PubMedCrossRefGoogle Scholar
  8. 8.
    Burdick KE, Goldberg TE, Funke B, et al.: DTNBP1 genotype influences cognitive decline in schizophrenia. Schizophr Res 2007, 89:169–172.PubMedCrossRefGoogle Scholar
  9. 9.
    Hall MH, Rijsdijk F, Picchioni M, et al.: Substantial shared genetic influences on schizophrenia and event-related potentials. Am J Psychiatry 2007, 164:804–812.PubMedCrossRefGoogle Scholar
  10. 10.
    Toulopoulou T, Picchioni M, Rijsdijk F, et al.: Substantial genetic overlap between neurocognition and schizophrenia: genetic modeling in twin samples. Arch Gen Psychiatry 2007, 64:1348–1355.PubMedCrossRefGoogle Scholar
  11. 11.
    Karlsgodt KH, Glahn DC, van Erp TG, et al.: The relationship between performance and fMRI signal during working memory in patients with schizophrenia, unaffected co-twins, and control subjects. Schizophr Res 2007, 89:191–197.PubMedCrossRefGoogle Scholar
  12. 12.
    McClellan JM, Susser E, King MC: Schizophrenia: a common disease caused by multiple rare alleles. Br J Psychiatry 2007, 190:194–199.PubMedCrossRefGoogle Scholar
  13. 13.
    Crow TJ: How and why genetic linkage has not solved the problem of psychosis: review and hypothesis. Am J Psychiatry 2007, 164:13–21.PubMedCrossRefGoogle Scholar
  14. 14.
    Faraone SV, Hwu HG, Liu CM, et al.: Genome scan of Han Chinese schizophrenia families from Taiwan: confirmation of linkage to 10q22.3. Am J Psychiatry 2006, 163:1760–1766.PubMedCrossRefGoogle Scholar
  15. 15.
    Bulayeva KB, Glatt SJ, Bulayev OA, et al.: Genome-wide linkage scan of schizophrenia: a cross-isolate study. Genomics 2007, 89:167–177.PubMedCrossRefGoogle Scholar
  16. 16.
    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.Google Scholar
  17. 17.
    The Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007, 447:661–678.CrossRefGoogle Scholar
  18. 18.
    Owen MJ, Craddock N, Jablensky A: The genetic deconstruction of psychosis. Schizophr Bull 2007, 33:905–911.PubMedCrossRefGoogle Scholar
  19. 19.
    Li D, He L: Association study between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia: a meta-analysis. Schizophr Res 2007, 96:112–118.PubMedCrossRefGoogle Scholar
  20. 20.
    Bray NJ, Holmans PA, van den Bree MB, et al.: Cis-and trans-loci influence expression of the schizophrenia susceptibility gene DTNBP1. Hum Mol Genet 2008, 17:1169–1174.PubMedCrossRefGoogle Scholar
  21. 21.
    DeRosse P, Funke B, Burdick KE, et al.: Dysbindin genotype and negative symptoms in schizophrenia. Am J Psychiatry 2006, 163:532–534.PubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    Harrison PJ, Law AJ: Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry 2006, 60:132–140.PubMedCrossRefGoogle Scholar
  24. 24.
    Munafò MR, Attwood AS, Flint J: Neuregulin 1 genotype and schizophrenia. Schizophr Bull 2008, 34:9–12.PubMedCrossRefGoogle Scholar
  25. 25.
    Turunen JA: The role of DTNBP1, NRG1, and AKT1 in the genetics of schizophrenia in Finland. Schizophr Res 2007, 91:27–36.PubMedCrossRefGoogle Scholar
  26. 26.
    Thomson PA, Christoforou A, Morris SW, et al.: Association of neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population. Mol Psychiatry 2007, 12:94–104.PubMedCrossRefGoogle Scholar
  27. 27.
    Malhi GS, Lagopoulos J: Making sense of neuroimaging in psychiatry. Acta Psychiatr Scand 2008, 117:100–117.PubMedGoogle Scholar
  28. 28.
    Konrad A, Winterer G: Disturbed structural connectivity in schizophrenia primary factor in pathology or epiphenomenon? Schizophr Bull 2008, 34:72–92.PubMedCrossRefGoogle Scholar
  29. 29.
    O’Tuathaigh CM, Babovic D, O’Meara G, et al.: Susceptibility genes for schizophrenia: characterisation of mutant mouse models at the level of phenotypic behaviour. Neurosci Biobehav Rev 2007, 31:60–78.PubMedCrossRefGoogle Scholar
  30. 30.
    Chubb JE, Bradshaw NJ, Soares DC, et al.: The DISC locus in psychiatric illness. Mol Psychiatry 2008, 13:36–64.PubMedCrossRefGoogle Scholar
  31. 31.
    Matsuzaki S, Tohyama M: Molecular mechanism of schizophrenia with reference to disrupted-in-schizophrenia 1 (DISC1). Neurochem Int 2007, 51:165–172.PubMedCrossRefGoogle Scholar
  32. 32.
    Mackie S, Millar JK, Porteous DJ: Role of DISC1 in neural development and schizophrenia. Curr Opin Neurobiol 2007, 17:95–102.PubMedCrossRefGoogle Scholar
  33. 33.
    Sanders AR, Duan J, Levinson DF, et al.: No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. Am J Psychiatry 2008, 165:497–506.PubMedCrossRefGoogle Scholar
  34. 34.
    Roberts RC: Schizophrenia in translation: disrupted in schizophrenia (DISC1): integrating clinical and basic findings. Schizophr Bull 2007, 33:11–15.PubMedCrossRefGoogle Scholar
  35. 35.
    Garety PA, Bebbington P, Fowler D, et al.: Implications for neurobiological research of cognitive models of psychosis: a theoretical paper. Psychol Med 2007, 37:1377–1391.PubMedCrossRefGoogle Scholar
  36. 36.
    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.PubMedCrossRefGoogle Scholar
  37. 37.
    Corvin A, McGhee KA, Murphy K, et al.: Evidence for association and epistasis at the DAOA/G30 and D-amino acid oxidase loci in an Irish schizophrenia sample. Am J Med Genet B Neuropsychiatr Genet 2007, 144:949–953.Google Scholar
  38. 38.
    Wood LS, Pickering EH, Dechairo BM: Significant support for DAO as a schizophrenia susceptibility locus: examination of five genes putatively associated with schizophrenia. Biol Psychiatry 2007, 61:1195–1199.PubMedCrossRefGoogle Scholar
  39. 39.
    Spurlock G, Williams J, McGuffin P, et al.: European multicentre association study of schizophrenia: a study of the DRD2 Ser311Cys and DRD3 Ser9Gly polymorphisms. Am J Med Genet 1998, 81:24–28.PubMedCrossRefGoogle Scholar
  40. 40.
    Talkowski ME, Bamne M, Mansour H, et al.: Dopamine genes and schizophrenia: case closed or evidence pending? Schizophr Bull 2007, 33:1071–1081.PubMedCrossRefGoogle Scholar
  41. 41.
    Yu R, Zhang XN, Huang XX, et al.: Association analysis of COMT polymorphisms and schizophrenia in a Chinese Han population: a case-control study. Am J Med Genet B Neuropsychiatr Genet 2007, 144:570–573.Google Scholar
  42. 42.
    Gothelf D, Feinstein C, Thompson T, et al.: Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome. Am J Psychiatry 2007, 164:663–669.PubMedCrossRefGoogle Scholar
  43. 43.
    Williams HJ, Owen MJ, O’Donovan MC: Is COMT a susceptibility gene for schizophrenia? Schizophr Bull 2007, 33:635–641.PubMedCrossRefGoogle Scholar
  44. 44.
    Ma X, Sun J, Yao J, et al.: A quantitative association study between schizotypal traits and COMT, PRODH and BDNF genes in a healthy Chinese population. Psychiatry Res 2007, 153:7–15.PubMedCrossRefGoogle Scholar
  45. 45.
    Zinkstok J, Schmitz N, van Amelsvoort T, et al.: Genetic variation in COMT and PRODH is associated with brain anatomy in patients with schizophrenia. Genes Brain Behav 2008, 7:61–69.PubMedGoogle Scholar
  46. 46.
    Gilbody S, Lewis S, Lightfoot T: Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol 2007, 165:1–13.PubMedCrossRefGoogle Scholar
  47. 47.
    Gaysina D, Cohen S, Craddock N, et al.: No association with the 5,10-methylenetetrahydrofolate reductase gene and major depressive disorder: results of the depression case control (DeCC) study and a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2007 Dec 28 (Epub ahead of print).Google Scholar
  48. 48.
    Farmer A, Elkin A, McGuffin P: The genetics of bipolar affective disorder. Curr Opin Psychiatry 2007, 20:8–12.PubMedCrossRefGoogle Scholar
  49. 49.
    Lake CR, Hurwitz N: Schizoaffective disorder merges schizophrenia and bipolar disorders as one disease—there is no schizoaffective disorder. Curr Opin Psychiatry 2007, 20:365–379.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2008

Authors and Affiliations

  • Charlotte L. Allan
    • 1
  • Alastair G. Cardno
  • Peter McGuffin
  1. 1.Academic Unit of Psychiatry and Behavioral Sciences, Leeds Institute of Health SciencesUniversity of LeedsLeedsUK

Personalised recommendations