Skip to main content Accessibility help

Is There Really A Split in Schizophrenia?: The Genetic Evidence

  • P. McGuffin (a1), A. Farmer (a2) and I. I. Gottesman (a3)


Although the clinical presentation and course of schizophrenia is highly variable, it is unclear whether this reflects heterogeneity at an aetiological level. The genetic evidence is reviewed concerning ‘traditional’ clinical subtypes as well as more novel categories derived from multivariate statistical methods and Crow's type I-type II classification. Recent data based on a twin series and reanalysis of older published family material suggest that attempts to divide up schizophrenia have resulted in splits between two or more categories of disorder which occupy different positions on the same continuum of liability. Thus, apparent heterogeneity is more likely to be due to quantitative difference in familial-genetic loading rather than qualitative differences. Similarly, the hypothesis that schizophrenia can be broadly divided into two groups, one genetic and the other non-genetic has little to support it. It seems improbable that any further useful and genetically relevant subdivision of schizophrenia can be effected on purely clinical grounds. Further progress awaits developments in the discovery of endophenotypes and the application of molecular genetic marker strategies.



Hide All
American Journal Of Human Genetics (1983) The human gene map. American Journal of Human Genetics, 35, 134156.
Andreasan, N. C. (1985) Positive vs negative schizophrenia: A critical evaluation, Schizophrenia Bulletin, 11, 380389.
Andrew, B., Watt, D. C., Gillespie, C. & Chapel, H. (1987) A family study of genetic linkage in schizophrenia. Psychological Medicine, (in press).
Baron, M. (1982) Genetic models of schizophrenia, Acta Psychiatrica Scandinavia, 65, 263275.
Bartko, J. J., Carpenter, W. T. & Strauss, J. S. (1981) Statistical basis for explaining schizophrenia. American Journal of Psychiatry, 138, 941945.
Bleuler, E. (1911) Dementia praecox or the group of schizophrenias, translated by Zinkin, J. (1950). New York: International Universities Press.
Bleuler, M. (1978) The Schizophrenic Disorders, (translated by Clemens, S.). New Haven and London: Yale University.
Botstein, D., White, R. L., Skolnick, M. & Davis, R. W. (1980) Construction of a genetic linkage map in men using restriction fragment length polymorphisms. American Journal of Human Genetics, 32, 312331.
British Medical Journal (1969) Unity and diversity in schizophrenia (Editorial). British Medical Journal, 4, 673674.
Buchsbaum, M. S., Ingvar, D. H., Kessler, R., Waters, R. N., Cappeleti, J. Van K., Ammen, D. P., King, A. C., Johnson, J. L., Manning, A. G., Plynn, R. W., Mann, L. S., Bunney, W. E. & Sokoloff, L. (1982) Cerebral glucography with position tomography. Archives of General Psychiatry, 39, 251259.
Cazzullo, C. L., Smeraldi, E. & Pennati, G. (1974) The leukocyte antigen system HLA as a possible genetic marker of schizophrenia. British Journal of Psychiatry, 25, 2527.
Cern, (1974) Minuit: a package of programmes to minimise a function of a variable. Geneva: CERN Data Handling Division.
Chadda, R., Kulhara, P., Singh, I. & Sehgal, S. (1986) HLA antigens in schizophrenia: a family study. British Journal of Psychiatry, 149, 612615.
Crow, T. J. (1980) Molecular Pathology of schizophrenia: more than one disease process. British Medical Journal, 280, 6668.
Crow, T. J. (1985) The two-syndrome concept: Origins and current status. Schizophrenia Bulletin, 11, 471486.
Davison, K. & Bagley, C. R. (1969) Schizophrenic-like psychoses associated with organic disorders of the central nervous system: a review of the literature. In: Current Problems in Neuropsychiatry: Schizophrenia, Epilepsy and the Temporal Lobe, (ed. R. N. Herrington). Ashford, Kent: Headley Bros.
Dela Chapelle, A. (1985) Mapping hereditary disorders. Nature, 317, 472473.
Dworkin, R. H. & Lenzenweger, M. F. (1984) Symptoms and the genetics of schizophrenia: implications for diagnosis. American Journal of Psychiatry, 141, 15411546.
Eaves, L. J., Kendler, K. S. & Schulz, S. C. (1986) The familial sporadic classification: its power for the resolution of genetic and environmental etiologic factors. Journal of Psychiatric Research, 20, 115130.
Eberhard, G. & Franzen, G., Low, B. (1975) Schizophrenia Susceptibility and HLA Antigens. Neuropsychobiology, 1, 211217.
Edwards, J. H. (1965) Associations between blood groups and disease. Annals of Human Genetics, 29, 7783.
Elandt-Johnson, R. C. (1971) Probability Models and Statistical Methods in Genetics. New York: John Wiley & Sons.
Emery, A. E. H. (1984) An Introduction to Recombined DNA. Chichester: Wiley.
Falconer, D. S. (1965) The inheritance of liability to certain diseases, estimated from the incidence among relatives. Annals of Human Genetics, 29, 5176.
Farmer, A. E., McGuffin, P. & Spitznagel, E. (1983) Heterogeneity in schizophrenia: a cluster analytic approach. Psychiatry Research, 8, 112.
Farmer, A. E., McGuffin, P., & Gottesman, I. I. (1984) Searching for the split in schizophrenia: a twin study perspective. Psychiatry Research, 13, 109118.
Farmer, A. E., Jackson, R. & Storey, P. (1985) Classifying schizophrenia (letter). Lancet, i, 33.
Farmer, A. E., Jackson, R., McGuffin, P. & Storey, P. (1987) Cerebral ventricular enlargement in schizophrenia consistencies and contradictions. British Journal of Psychiatry, 150, 324330.
Festenstein, H. & Demant, P. (1978) HLA and H2. Current Topics in Immunology, Vol. 9. London: Edward Arnold.
Fischer, M. (1971) Psychoses in the offspring of schizophrenia monozygotic twins and their normal co-twins. British Journal of Psychiatry, 115, 981990.
Fischer, M. (1973) Genetic and environmental factors in schizophrenia. Acta Psychiatric Scnadinavia (Suppl) 238.
Giblett, E. R. (1969) Genetic Markers in Human Blood. Oxford: Black well.
Goldin, L. R., De Lisli, L. E. & Gershon, E. S. (1987) The relationship of HLA to schizophrenia in 10 nuclear families. Psychiatry Research, (in press).
Gottesman, I. I. (1968) Severity/concordance and diagnostic refinement in the Maudsley-Bethlem schizophrenia twin study. The Transmission of Schizophrenia, (eds D. Rosenthal & S. S. Kety). Oxford: Pergamon Press.
Gottesman, I. I. & Shields, J. (1967) A polygenic theory of schizophrenia. Proceedings of the National Academy of Sciences, 58, 199205.
Gottesman, I. I. & Shields, J. (1972) Schizophrenia. A Twin Study Vantage Point. Academic Press, London.
Gottesman, I. I. & Shields, J. (1982) Schizophrenia, The Epigenetic Puzzle. Cambridge: Cambridge University Press.
Gottesman, I. L. & Bertelsen, A. (in prep.) The offspring of twins concordant and discordant for schizophrenia.
Helzer, J. E., Stolzman, R. K., Farmer, A. E., Brockington, I., Plesons, D., Singerman, B. & Works, J. (1985) Comparing the DIS with a DIS/DSM Ill-based physician re-evaluation. In Epidemiologic Field Methods in Psychiatry, (ed. W. W. Eaton & L. G. Kessler). Orlando: Academic Press.
Herold, S. & Frackowiak, J. (1986) New methods in brain imaging (editorial). Psychological medicine, 16, 241246.
Johnstone, E. C., Crow, T. J., Frith, C. D. & Kreel, L. (1976) Cerebral ventricular size and cognitive impairment in chronic schizophrenia. Lancet, 2, 924926.
Johnstone, E. C., Crow, T. J., Frith, C. D., Stevens, M., Kreez, L. & Husband, J. (1978) The dementia of dementia praecox. Acta Psychiatric Scandinavia, 57, 305324.
Kallmann, F. J. (1938) The Genetics of Schizophrenia. New York: J. J. Augusta.
Kendell, R. E. (1975) The Role of Diagnosis in Psychiatry. Oxford: Blackwell Scientific Publications.
Kendler, K. S. & Davis, K. L. (1981) The genetics and biochemistry of paranoid schizophrenia and other paranoid psychoses. Schizophrenia Bulletin, 7, 689709.
Kraepelin, E. (1896) Psychiatric, ein Lehrbuch fur studierende und Arzte, 5th ed. Leipzig: Barch.
Kringlen, E. (1967) Heredity and Environment in the Functional Psychoses. Heinman: London.
Leonhard, K. (1959) Autfelung der Endogen Psychosen. Berlin: Akademic Verlag.
Luxenburger, H. (1928) Vorlaufiger Bericht ubcr psychiatrische Serien untersuchurgen an 2 willilngen. Zeitschrift fur gesamte Neurologie und Psychiatrie, 116, 297326.
McGue, M., Gottesman, I. I. & Rao, D. C. (1985) Resolving genetic models for the transmission of schizophrenia. Genetic Epidemiology, 2, 99110.
McGuffin, P. (1979) Is schizophrenia an HLA associated disease? Psychological Medicine, 9, 721728.
McGuffin, P. (1984) Genetic influences on personality, neurosis and psychosis. In Scientific Principles of Psychopathology, (ed. P. McGuffin, M. F. Shanks & R. Hodgson). London: Grune & Stratton.
McGuffin, P. (1984a) Principles and method in psychiatric genetics. In Scientific Principles of Psychopathology, (ed. P. McGuffin, R. Hodgson & R. Shanks). London: Grune & Stratton.
McGuffin, P. (1984b) Biological markers and psychosis. Psychological Medicine, 14, 255259.
McGuffin, P. & Sturt, E. (1986) Genetic Markers in Schizophrenia. Human Heredity, 36, 6568.
McGuffin, P., Farmer, A. E. & Yonace, A. (1981) HLA antigens and subtypes of schizophrenia. Psychiatry Research, 5, 115122.
McGuffin, P., Festenstein, W. & Murray, R. M. (1983) A Family study of HLA antigens and other genetic markers in schizophrenia. Psychological Medicine, 13, 3143.
McGuffin, P., Farmer, A. E., Gottesman, I. I., Murray, R. M. & Reveley, A. M. (1984) Twin concordance for Operationally Defined Schizophrenia: Confirmation of Familiarity and Heretability. Archives of General Psychiatry, 41, 541545.
McKuisick, V. A. (1969) On lumpers and splitters, or the nosology of genetic disease. Perspectives on Biology and Medicine, 12, 298301.
McGuffin, P. (1983) Mendelian Inheritance in Man, Baltimore and London: John Hopkins University Press.
McNeill, R. F. & Kaij, L. (1978) Obstetric factors in the development of schizophrenia: complications in the birth of pre-schizophrenics and in reproduction of schizophrenic parents. In The Nature of Schizophrenia, (eds L. C. Wynne, R. L. Cromwell & S. Matthyse). Chichester: Wiley.
Meltzer, H. Y. (1979) Biology of schizophrenic subtypes: a review and proposal for method of study. Schizophrenia Bulletin, 5, 460.
Meltzer, H. Y., Arora, R. C., Jackman, H., Pscheidt, G. & Smith, M. D. (1980) Platelet monoamine oxidase and plasma amino oxidase in psychiatric patients. Schizophrenia Bulletin, 6, 213219.
Murray, R. M., Lewis, S. & Reveley, A. M. (1985) Towards an aetiological classification of schizophrenia. Lancet, i, 10231026.
Nasrallah, H. A., Charles, G. T., McCalley-Whitters, M. & Kuperman, S. (1982) Cerebral ventricular enlargement in subtypes of chronic schizophrenia. Archives of General Psychiatry, 39, 774777.
O'Rourke, D. H., Gottesman, I. I., Suarez, B. K., Rice, J. & Reich, T. (1982) Refuation of the general single locus model in the aetiology of schizophrenia. American Journal of Human Genetics, 34, 630649.
Owen, D. G. C., Johnstone, E. C., Crow, T. J., Frith, C. D., Jague, J. R. & Kreel, L. (1985) Lateral ventricular size in schizophrenia: relationship to the disease process and its clinical manifestations. Psychological Medicine, 15, 2741.
Paykel, E. S. (1981) Have multivariate statistics contributed to classification? British Journal of Psychiatry, 139, 357362.
Penrose, L. S. (1952) Measurement of pleiotropic effects in phenyl ketonuria. Annals of Eugenics, 18, 120124.
Pogue-Geile, M. F. & Harrow, M. (1985) Negative symptoms in schizophrenia: their longitudinal course and prognostic importance. Schizophrenia Bulletin, 11, 427439.
Pollin, W. & Stabenau, J. R. (1968) Biological psychological and historical differences in a series of monozygotic twins discordant for schizophrenia. The Transmission of Schizophrenia, (eds D. Rosenthal & S. S. Kety). Oxford: Pergamon.
Potkin, S. G., Cannon, H. E., Murray, D. L. & Wyatt, R. J. (1978) Are paranoid schizophrenics biologically different from other schizophrenics? New England Journal of Medicine, 298, 6166.
Propping, P. (1983) Genetic disorders presenting as ‘schizophrenia’. Karl Bonhoeffer's early view of the psychoses in the light of medical genetics. Human Genetics, 65, 119.
Reich, T., James, J. W. & Morris, C. A. (1972) The use of multiple thresholds in determining the mode of transmission of semi-continuous traits. Annals of Human Genetics, 36, 163184.
Reich, T., Cloniger, C. R., Wette, R. & James, J. (1979) The use of multiple thresholds and segregation analysis in analysing the phenotypic heterogeneity of multifactorial traits. Annals of Human Genetics, 42, 371.
Reveley, A. M., Reveley, M. A., Clifford, C. A. & Murray, R. M. (1982) Cerebral ventricular size in twins discordant for schizophrenia. Lancet, i, 540541.
Reveley, A. M., Reveley, M. A., & Murray, R. M. (1984) Cerebral ventricular enlargement in nongenetic schizophrenia: A controlled twin study. British Journal of Psychiatry, 144, 8993.
Reveley, A. M., Reveley, M. A., Clifford, C. A., Murray, R. M. (1985) CT scans in schizophrenia. British Journal of Psychiatry, 146, 367371.
Reveley, M. A., Chitkara, B. (1985) Subtypes in schizophrenia. (Letter) Lancet, i, 1503.
Rice, J. P., McGuffin, P. & Shaskan, E. G. (1982) A commingling analysis of platelet monoamine oxidase activity. Psychiatry Research, 7, 325335.
Rice, J., McGuffin, P., Goldin, L. R., Shaskan, E. G. & Gershon, E. S. (1984) Platelet monoamine oxidase activity: Evidence for a single major locus. American Journal of Human Genetics, 36, 3643.
Rudduck, C. (1985) Genetic markers and schizophrenia. PhD Thesis, University of Lund.
Scharfetter, C. & Nusperli, M. (1980) The group of schizophrenias, schizoaffective psychoses, and affective disorders. Schizophrenia Bulletin, 6, 586591.
Shuckitt, M. (1986) Trait (and state) markers of predisposition to psychopathology. In Psychiatry, Vol. 3, 53, 1–19, (ed. R. Michels, J. O. Cavenar, H. R. H. Brodie, Arnold M. Cooper, S. B. Guze, L. L. Judd, G. L. Klerman & A. J. Solnir). Philadelphia: Lippincott.
Slater, E. (1947) Genetical causes of schizophrenic symptoms. Monatsschrift fur Psychiatrie und Neurologie, 113, 5058. (Reprinted in Man, Mind and Heredity , (ed. J. Shields & I. L. Gottesman).
Slater, E. & Cowie, V. (1971) The Genetics of Mental Disorders. Oxford: Oxford University Press.
Smith, G. W. & Iacono, W. G. (1986) Lateral ventricular size in schizophrenia and the choice of a control group (letter), Lancet, i, 1450.
Snezhevnevsky, A. V. (1968) The symptomatology, clinical forms and nosology of schizophrenia. In Modern Perspectives in World Psychiatry, (ed. J. G. Howells). Edinburgh: Oliver and Boyd.
Strauss, J. S., Bartko, J. J. & Carpenter, W. T. (1973) The use of clustering techniques for the classification of psychiatric patients. British Journal of Psychiatry, 122, 531538.
Sturt, E. & McGuffin, P. (1985) Can linkage and marker association resolve the genetic aetiology of psychiatric disorders? Review and argument. Psychological Medicine, 15, 455462.
Sturt, E., Kamakura, N. & Der, G. (1984) How depressing life is: Lifelong morbidity risk for depressive disorder in the general population. Journal of Affective Disorders, 7, 109122.
Thomson, G. (1981) A review of the theoretical aspects of HLA and disease association. Theoretical Population Biology, 20, 168208.
Tsuang, M. T. & Winokur, G. (1974) Criteria for sub-typing schizophrenia. Archives of General Psychiatry, 31, 4347.
Tsuang, M. T. & Crowe, R. (1980) Morbidity risks of schizophrenia and affective disorders among first degree relatives of patients with schizophrenia, mania, depression and surgical conditions. British Journal of Psychiatry, 137, 497504.
Tsuang, M., Fowler, R. L., Cadoret, R. J. & Monnelly, E. (1974) Schizophrenia among first degree relatives of paranoid and nonparanoid schizophrenics. Comprehensive Psychiatry, 15, 295302.
Turner, S., Toone, B. & Brett-Jones, J. (1986) Computerised tomography and changes in early schizophrenia-preliminary findings. Psychological Medicine, 16, 219225.
Turner, W. J. (1979) Genetic markers for schizotaxia. Biological Psychiatry, 14, 177205.
Weinberger, D. R., Berman, K. F. & Zec, R. F. (1986) Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia I. Regional cerebral blood flow evidence. Archives of General Psychiatry, 43, 114125.
White, R., Leppert, M., Bishop, T., Barker, D., Berkowitz, J., Brown, C., Callahan, P., Holm, T. & Jerominski, L. (1985) Construction of linkage maps with DNA markers for human chromosomes. Nature, 313, 101105.
Williams, A. O., Reveley, M. A., Kolakowska, T., Arden, M. & Mandelbrote, B. M. (1985) Schizophrenia with good and poor outcome: II Cerebral ventricular size and its clinical significance. British Journal of Psychiatry, 146, 239246.
Woolf, B. (1955) On estimating the relation between blood groups and disease. Annals of Human Genetics, 19, 251253.

Is There Really A Split in Schizophrenia?: The Genetic Evidence

  • P. McGuffin (a1), A. Farmer (a2) and I. I. Gottesman (a3)


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed

Is There Really A Split in Schizophrenia?: The Genetic Evidence

  • P. McGuffin (a1), A. Farmer (a2) and I. I. Gottesman (a3)
Submit a response


No eLetters have been published for this article.


Reply to: Submit a response

Your details

Conflicting interests

Do you have any conflicting interests? *