Journal of Molecular Neuroscience

, Volume 7, Issue 2, pp 147–157 | Cite as

The molecular genetics of schizophrenia

  • Kieran C. Murphy
  • Alastair G. Cardno
  • Peter McGuffin


There is overwhelming evidence for a significant genetic contribution to the etiology of schizophrenia. Molecular genetic techniques are now sufficiently advanced to be applied to complex genetic disorders with uncertain phenotypes, such as schizophrenia. In this article we first briefly discuss certain pertinent background issues: the evidence that schizophrenia has a heritable basis, the possible modes of inheritance involved, and how best to define schizophrenia in the light of this evidence; we then review the current status of research in the field. Large collaborative studies are currently underway that pave the way for the detection of genes of both major and minor effects. We may now be seeing the first consistently replicated results from chromosome 6 and 22 and from candidate genes, such as the dopamine D3 receptor gene.

Index Entries

Schizophrenia twin studies linkage studies association studies D3 receptor 


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  1. American Psychiatric Association (1994)Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric AssociationWashington, DC.Google Scholar
  2. Antonarakis S. E., Blouin J.-L., Pulver A. E., Wolynlec P., Lasseter V. K., Nestadt G., et al. (1995) Schizophrenia susceptibility and chromosome 6p24-22.Nature Genet. 11, 235,236.CrossRefGoogle Scholar
  3. Arranz M., Collier D., Sodhi M., Ball D., Roberts G., Price J., et al. (1995) Association between clozapine response and allelic variation in 5-HT2a receptor genes.Lancet 346, 281,282.CrossRefGoogle Scholar
  4. Asherson P., Parfitt E., Sargeant M., Tidmarsh S., Buckland P., Taylor C., et al. (1992) No evidence for a pseudoautosomal locus for schizophrenia. Linkage analysis of multiply affected families.Br. J. Psychiatr. 161, 63–68.Google Scholar
  5. Baily-Wilson J. E. and Bamba V. (1993) Sib-pair linkage analysis of Alzheimer’s disease.Genet. Epidemiol. 10, 371–376.CrossRefGoogle Scholar
  6. Bassett A. S., McGillivray B. C., Jones B. D., and Pantzar J. T. (1988) Partial trisomy chromosome 5 cosegregating with schizophrenia.Lancet i, 799–801.CrossRefGoogle Scholar
  7. Buckland P. R., O’Donovan M. C., and McGuffin P. (1993) Clozapine and sulpiride upregulate dopamine D3 receptor mRNA levels.Neuropharmacology 32(9), 901–907.PubMedCrossRefGoogle Scholar
  8. Chamberlain S., Shaw J., Rowland A., Wallis J., South S., Nakamura Y., et al. (1988) Mapping of mutation causing Friedrich’s ataxia to human chromosome 9.Nature 334, 248–250.PubMedCrossRefGoogle Scholar
  9. Cloninger C. R. (1994) Turning point in the design of linkage studies of schizophrenia.Am. J. Med. Genet. 54(2), 83–92.PubMedCrossRefGoogle Scholar
  10. Collinge J., DeLisi L. E., Boceio E., Johnstone E. C., Lane A., Larkin C., et al. (1991) Evidence for a pseudoautosomal locus for schizophrenia using the methods of affected sibling pairs.Br. J. Psychiatr. 158, 624–629.CrossRefGoogle Scholar
  11. Crocq M.-A., Mant R., Asherson P., Williams J., Hode Y., Mayerouda A., et al. (1992) Association between schizophrenia and homozygosity at the dopamine D3 receptor gene.J. Med. Genet. 29, 858–860.PubMedGoogle Scholar
  12. Crow T. J. (1988) Sex chromosomes and psychosis.Br. J. Psychiatr. 153, 675–683.Google Scholar
  13. Davies J. L., Kawaguchi Y., Bennett S. T., Copeman J. B., Cordell H. J., Pritchard C. E., et al. (1994) A genome-wide search for human type 1 diabetes susceptibility genes.Nature 371, 130–136.PubMedCrossRefGoogle Scholar
  14. Falconer D. S. (1965) The inheritance of liability to certain diseases, estimated from the incidence among relatives.Ann. Hum. Genet. 29, 51–76.CrossRefGoogle Scholar
  15. Farmer A. E., McGuffin P., and Gottesman I. I. (1984) Searching for the split in schizophrenia: a twin study perspective.Psychiatr. Res. 13, 109–118.CrossRefGoogle Scholar
  16. Farmer A. E., McGuffin P., and Gottesman I. I. (1987) Twin concordance for DSM-III schizophrenia: scrutinising the validity of the definition.Arch. Gen. Psychiatr. 44, 634–641.PubMedGoogle Scholar
  17. Gaddum J. H. (1954) Drugs antagonistic to 5-hydroxy-tryptamine, inCiba Foundation Symposium on Hypertension (Wolstenholme, G. W., ed.), Little Brown and Co., Boston, MA pp. 75–77.Google Scholar
  18. Gill M., McGuffin P., Parfitt E., Mant R., Asherson P., Collier D., et al. (1993) A linkage study of schizophrenia with DNA markers from the long arm of chromosome 11.Psych. Med. 23, 27–44.Google Scholar
  19. Goldin L. R., DeLisi L. E., and Gershon E. S. (1987) The relationship of HLA to schizophrenia in 10 nuclear families.Psychiatr. Res. 20, 69–78.CrossRefGoogle Scholar
  20. Gottesman I. I. (1991)Schizophrenia Genesis. W. H. Freeman, New York.Google Scholar
  21. Gottesman I. I. and Bertelsen A. (1989) Confirming unexpressed genotypes for schizophrenia: risks in the offspring of Fischer’s Danish identical and fraternal discordant twins.Arch. Gen. Psychiatr. 46, 867–872.PubMedGoogle Scholar
  22. Gottesman I. I. and Shields J. (1967) A polygenic theory of schizophrenia.Proc. Natl. Acad. Sci. USA 58, 199–205.PubMedCrossRefGoogle Scholar
  23. Gottesman I. I. and Shields J. (1972)Schizophrenia and Genetics: A Twin Study Vantage Point. Academic, New York.Google Scholar
  24. Gottesman I. I. and Shields J. (1982)Schizophrenia: The Epigenetic Puzzle. Cambridge University Press, Cambridge, UK.Google Scholar
  25. Gurling H., Kalsi G., Chen A. H. S., Green M., Butler R., Read T., et al. (1995) Schizophrenia susceptibility and chromosome 6p24-22.Nature Genet. 11, 234,235.CrossRefGoogle Scholar
  26. Gusella J. F., Wexler N. S., Conneally P. M., Naylor S. L., Anderson M. A., Tanzi R. E., et al. (1983) A polymorphic marker limited to Huntington’s disease.Nature 306, 234–238.PubMedCrossRefGoogle Scholar
  27. Heston L. L. (1966) Psychiatric disorders in foster home reared children of schizophrenic mothers.Br. J. Psychiatr. 112, 819–825.CrossRefGoogle Scholar
  28. James J. W. (1971) Frequency in relatives for an all-or-none-trait.Ann. Hum. Genet. 35, 47–49.PubMedCrossRefGoogle Scholar
  29. Karayiorgou M., Morris M., Morrow B., Shprintzen R. J., Goldberg R., Borrow J., et al. (1995) Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11.Proc. Natl. Acad. Sci. USA 92, 7612–7616.PubMedCrossRefGoogle Scholar
  30. Kendler K. S., Gruenberg A. M., and Kinney D. K. (1994) Independent diagnoses of adoptees and relatives as defined by DSM-III in the provincial and national samples of the Danish adoption study of schizophrenia.Arch. Gen. Psychiatr. 51, 456–468.PubMedGoogle Scholar
  31. Kendler K. S., McGuire M., Gruenberg A. M., O’Hare A., Spellman M., Walsh D., et al. (1993a) The Roscommon family study. I. Methods, diagnosis of probands, and risk of schizophrenia in relatives.Arch. Gen. Psychiatr. 50, 527–540.PubMedGoogle Scholar
  32. Kendler K. S., McGuire M., Gruenberg A. M., O’Hare A., Spellman M., Walsh D., et al. (1993b) The Roscommon family study. III. Schizophreniarelated personality disorders in relatives.Arch. Gen. Psychiatr. 50, 781–788.PubMedGoogle Scholar
  33. Kendler K. S., Neale M. C., and Walsh D. (1995) Evaluating the spectrum concept of schizophrenia in the Roscommon family study.Am. J. Psychiatr. 152, 749–754.PubMedGoogle Scholar
  34. Kety S. S., Wender P., Jacobsen B., Ingraham L. J., Jansson L., Faber B., et al. (1994) Mental illness in the biological and adoptive relatives of schizophrenic adoptees: replication of the Copenhagen study in the rest of Denmark.Arch. Gen. Psychiatr. 51, 442–455.PubMedGoogle Scholar
  35. Kringlen E. and Cramer G. (1989) Offspring of monozygotic twins discordant for schizophrenia.Arch. Gen. Psychiatr. 46, 873–877.PubMedGoogle Scholar
  36. Lander E. and Kruglyak L. (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.Nature Genet. 11(3), 241–247.PubMedCrossRefGoogle Scholar
  37. Lannfelt L., Sokoloff P., Martres M., Pilon C., Giros B., Jonsson E., et al. (1992) Amino-acid substitution in the dopamine D3 receptor as a useful polymorphism for investigating psychiatric disorders.Psychiatr. Genet. 2, 249–256.CrossRefGoogle Scholar
  38. Leboyer M. and McGuffin P. (1991) Collaborative strategies in the molecular genetics of the major psychoses.Br. J. Psychiatr. 158, 605–610.Google Scholar
  39. Li C. C. (1976)First Course in Population Genetics. Boxwood, Pacific Grove, CA, pp. 255–310.Google Scholar
  40. McGue M., Gottesman I. I., and Rao D. C. (1985) Resolving genetic models for the transmission of schizophrenia.Genet. Epidemiol. 2, 99–110.PubMedCrossRefGoogle Scholar
  41. McGuffin P., Asherson P., Owen M., and Farmer A. (1994) The strength of the genetic effect—is there room for an environmental influence in the aetiology of schizophrenia?Br. J. Psychiatr. 164, 593–599.Google Scholar
  42. McGuffin P., Fesenstein H., and Murray R. M. (1983) A family study of HLA antigens and other genetic markers in schizophrenia.Psych. Med. 13, 31–43.CrossRefGoogle Scholar
  43. McGuffin P., Sargeant M., Hetti G., Tidmarsh S., Whatley S., and Marchbanks R. M. (1990) Exclusion of a schizophrenic susceptibility gene from the chromosome 5q11–q13 region. New data and a reanalysis of previous reports.Am. J. Hum. Genet. 47, 524–535.PubMedGoogle Scholar
  44. McGuffin P. and Sturt E. (1986) Genetic markers in schizophrenia.Hum. Hered. 16, 461–465.Google Scholar
  45. Moises H. W., Gelertner J., Giuffra L., Zarcone V., Wetterberg L., Civelli O., et al. (1991) No linkage between D2 dopamine receptor gene region and schizophrenia.Arch. Gen. Psych. 48, 643–647.Google Scholar
  46. Moises H. W., Yang L., Kristbjarnarson H., Wiese C., Byerley W., Macciardi F., et al. (1995) An international two-stage genome-wide search for schizophrenia susceptibility genes.Nature Genet. 11, 321–324.PubMedCrossRefGoogle Scholar
  47. Morton N. E. and MacLean C. J. (1974) Analysis of family resemblance. III. Complex segregation of quantitative traits.Am. J. Hum. Genet. 26, 489–503.PubMedGoogle Scholar
  48. Morton N. E. (1955) Sequential tests for the detection of linkage.Am. J. Hum. Genet. 7, 277–318.PubMedGoogle Scholar
  49. Mowry B. J., Nancarrow D. J., Lennon D. P., Sandkuijl C. A., Crowe R. R., Silverman J. M., et al. (1995) Schizophrenia susceptibility and chromosome 6p24-22.Nature Genet. 11, 233,234.CrossRefGoogle Scholar
  50. O’Donovan M. C., Buckland P. R., and McGuffin P. (1991) Simultaneous quantification of several mRNA species by solution hybridisation with oligonucleotides.Nucleic Acids Res. 19, 3466.PubMedCrossRefGoogle Scholar
  51. O’Donovan M. C., Guy C., Craddock N., Murphy K. C., Cardno A. G., Jones L. A., et al. (1995) Expanded CAG repeats in schizophrenia and bipolar disorder.Nature Genet. 10, 380,381.CrossRefGoogle Scholar
  52. Onstad S., Skre I., Torgersen S., and Kringlen E. (1991) Twin concordance for DSM-III-R schizophrenia.Acta Psychiatr. Scand. 83, 395–401.PubMedCrossRefGoogle Scholar
  53. O’Rourke D. H., Gottesman I. I., Suarez B. K., Rice J., and Reich T. (1982) Refutation of the single locus model for the etiology of schizophrenia.Am. J. Hum. Genet. 34, 630–649.PubMedGoogle Scholar
  54. Pulver A. E., Karayiorgou M., Wolyniec P. S., Lasseter U. K., Kasch L., Westadt G., et al. (1994) A sequential strategy to identify a susceptibility gene for schizophrenia. 1. Report of potential linkage on chromosome 22q12–q13. 1.Am. J. Med. Genet. 54, 36–43.PubMedCrossRefGoogle Scholar
  55. Reich T., James J. W., and Morris C. A. (1972) The use of multiple thresholds in determining the mode of transmission of semi-continuous traits.Ann. Hum. Genet. 36, 163–184.PubMedCrossRefGoogle Scholar
  56. Risch N. (1990) Linkage strategies for genetically complex traits. III. The effect of marker polymorphism analysis on affected relative pairs.Am. J. Hum. Genet. 46, 242–253.PubMedGoogle Scholar
  57. Risch N. and Baron M. (1984) Segregation analysis of schizophrenia and related disorders.Am. J. Hum. Genet. 36, 1039–1059.PubMedGoogle Scholar
  58. Schizophrenia Collaborative Linkage Group (1996) A combined analysis of D22S278 marker alleles in affected sib-pairs, support for a susceptibility locus for schizophrenia at 22q12.Am. J. Med. Genet. (Neuropsychiatr. Genet.) 67, 40–45.CrossRefGoogle Scholar
  59. Schwab S. G., Albus M., Hallmayer J., Honig S., Borrman M., Lichtermann D., et al. (1995) Evaluation of a susceptibility locus for schizophrenia on chromosome 6p by multipoint affected sibpair linkage analysis.Nature Genet. 11, 325–327.PubMedCrossRefGoogle Scholar
  60. Shaikh S., Gill M., Owen M., Asherson P., McGuffin P., Nanko S., et al. (1994) Failure to find linkage between a functional polymorphism in the dopamine D4 receptor gene and schizophrenia.Am. J. Med. Genet. (Neuropsych. Genet.) 54, 8–11.CrossRefGoogle Scholar
  61. Sherrington R., Brynjolfsson J., Petursson H., Potter M., Duddleston K., Barrodough B., et al. (1988) Localization of a susceptibility locus for schizophrenia on chromosome 5.Nature 336, 164–167.PubMedCrossRefGoogle Scholar
  62. Shprintzen R. J., Goldberg R. B., and Golding-Kushner K. J. (1992) Late-onset psychosis in the Velo-Cardio-Facial syndrome.Am. J. Med. Genet. 42, 141,142.CrossRefGoogle Scholar
  63. Slater E. and Cowie V. (1971)The Genetics of Mental Disorders. Oxford University Press, London, UK.Google Scholar
  64. Spitzer R. L., Endicott J., and Robins E. (1978)Research Diagnostic Criteria for a Selected Group of Functional Disorders, 3rd ed. New York State Psychiatric Institute, New York.Google Scholar
  65. Snell R. G., McMillan J. C., Cheadle J. P., Fenton I., Lazarou L. P., Davies P., et al. (1993) Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington’s disease.Nature Genet. 4, 394–397.CrossRefGoogle Scholar
  66. St. Clair D., Blackwood D., Muir W., Carothers A., Walker M., Spowart G., et al. (1990) Association within a family of balanced autosomal translocation with major mental illness.Lancet 336, 13–16.PubMedCrossRefGoogle Scholar
  67. Straub R. E., MacLean C. J., O’Neill A. F., Burke J., Murphy B., Duke F., et al. (1995) A potential vulnerability locus for schizophrenia on chromosome 6p24-22, evidence for genetic heterogeneity.Nature Genet. 11, 287–293.PubMedCrossRefGoogle Scholar
  68. Turner W. J. (1979) Genetic markers for schizophrenia.Biol. Pshychiatr. 14, 177–205.Google Scholar
  69. Vogler G. P., Gottesman I. I., McGue M. K., and Rao D. C. (1991) Mixed model segregation analysis of schizophrenia in the Lindelius Swedish pedigrees.Behav. Genet. 20, 461–472.CrossRefGoogle Scholar
  70. Wang Z. W., Black D., Andreasen N., and Crowe R. R. (1993) Pseudoautosomal locus for schizophrenia is excluded in 12 pedigrees.Arch. Gen. Psych. 50, 199–204.Google Scholar
  71. Wang S., Sun C., Walczak C. A., Ziegle J. S., Kipps B. R., Goldin L. R., et al. (1995) Evidence for a susceptibility locus for schizophrenia on chromosome 6pter-p22.Nature Genet. 10, 41–46.PubMedCrossRefGoogle Scholar
  72. Wildenaur D. B., Schwab S., Wurl D., Ert L. M., Ackenheil M., Schmidt S., et al. (1991) Linkage analysis in schizophrenia, exclusion of 5q11-q13, 5q34-qter, 11q22,23, Xpter and chromosome 19 in 15 systematically ascertained European families.Am. J. Hum. Genet. 49(Suppl.), 363.Google Scholar
  73. Williams J., Mant R., Holmans P., McGuffin P., Owen M. J., Spurlock G., et al. (1996a) A family based association study of the dopamine D3 receptor gene and highly familial schizophrenia.Am. J. Med. Genet. (Neuropsychiatr. Genet.), submitted.Google Scholar
  74. Williams J., Spurlock G., McGuffin P., Mallet J., Nothen M., Gill M., et al. (1996b) Association between schizophrenia and the 5-HT2a receptor gene in a large European sample.Lancet,34, 1294–1296.Google Scholar
  75. Wing J. K., Babor T., Brugha T., Burke J., Cooper J. E., Giel R., et al. (1990) SCAN: schedules for clinical assessment in neuropsychiatry.Arch. Gen. Psychiatr. 47, 589–593.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 1996

Authors and Affiliations

  • Kieran C. Murphy
    • 1
  • Alastair G. Cardno
    • 1
  • Peter McGuffin
    • 1
  1. 1.Department of Psychological MedicineUniversity of Wales College of MedicineCardiffUK

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