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Is There Really A Split in Schizophrenia?

The Genetic Evidence

Published online by Cambridge University Press:  02 January 2018

P. McGuffin
Affiliation:
Institute of Psychiatry, London, and Department of Psychological Medicine, Kings College Hospital, London
A. Farmer
Affiliation:
Institute of Psychiatry, London
I. I. Gottesman
Affiliation:
Department of Psychology and Professor of Paediatrics, University of Virginia, Charlottesville, Virginia, USA

Abstract

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.

Type
Lecture
Copyright
Copyright © 1987 The Royal College of Psychiatrists 

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References

American Journal Of Human Genetics (1983) The human gene map. American Journal of Human Genetics, 35, 134156.Google Scholar
Andreasan, N. C. (1985) Positive vs negative schizophrenia: A critical evaluation, Schizophrenia Bulletin, 11, 380389.CrossRefGoogle Scholar
Andrew, B., Watt, D. C., Gillespie, C. & Chapel, H. (1987) A family study of genetic linkage in schizophrenia. Psychological Medicine, (in press).CrossRefGoogle Scholar
Baron, M. (1982) Genetic models of schizophrenia, Acta Psychiatrica Scandinavia, 65, 263275.CrossRefGoogle ScholarPubMed
Bartko, J. J., Carpenter, W. T. & Strauss, J. S. (1981) Statistical basis for explaining schizophrenia. American Journal of Psychiatry, 138, 941945.Google Scholar
Bleuler, E. (1911) Dementia praecox or the group of schizophrenias, translated by Zinkin, J. (1950). New York: International Universities Press.Google Scholar
Bleuler, M. (1978) The Schizophrenic Disorders, (translated by Clemens, S.). New Haven and London: Yale University.Google Scholar
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.Google Scholar
British Medical Journal (1969) Unity and diversity in schizophrenia (Editorial). British Medical Journal, 4, 673674.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
Cern, (1974) Minuit: a package of programmes to minimise a function of a variable. Geneva: CERN Data Handling Division.Google Scholar
Chadda, R., Kulhara, P., Singh, I. & Sehgal, S. (1986) HLA antigens in schizophrenia: a family study. British Journal of Psychiatry, 149, 612615.CrossRefGoogle ScholarPubMed
Crow, T. J. (1980) Molecular Pathology of schizophrenia: more than one disease process. British Medical Journal, 280, 6668.CrossRefGoogle ScholarPubMed
Crow, T. J. (1985) The two-syndrome concept: Origins and current status. Schizophrenia Bulletin, 11, 471486.CrossRefGoogle ScholarPubMed
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.Google Scholar
Dela Chapelle, A. (1985) Mapping hereditary disorders. Nature, 317, 472473.CrossRefGoogle Scholar
Dworkin, R. H. & Lenzenweger, M. F. (1984) Symptoms and the genetics of schizophrenia: implications for diagnosis. American Journal of Psychiatry, 141, 15411546.Google ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Eberhard, G. & Franzen, G., Low, B. (1975) Schizophrenia Susceptibility and HLA Antigens. Neuropsychobiology, 1, 211217.CrossRefGoogle Scholar
Edwards, J. H. (1965) Associations between blood groups and disease. Annals of Human Genetics, 29, 7783.CrossRefGoogle Scholar
Elandt-Johnson, R. C. (1971) Probability Models and Statistical Methods in Genetics. New York: John Wiley & Sons.Google Scholar
Emery, A. E. H. (1984) An Introduction to Recombined DNA. Chichester: Wiley.Google Scholar
Falconer, D. S. (1965) The inheritance of liability to certain diseases, estimated from the incidence among relatives. Annals of Human Genetics, 29, 5176.CrossRefGoogle Scholar
Farmer, A. E., McGuffin, P. & Spitznagel, E. (1983) Heterogeneity in schizophrenia: a cluster analytic approach. Psychiatry Research, 8, 112.CrossRefGoogle ScholarPubMed
Farmer, A. E., McGuffin, P., & Gottesman, I. I. (1984) Searching for the split in schizophrenia: a twin study perspective. Psychiatry Research, 13, 109118.CrossRefGoogle ScholarPubMed
Farmer, A. E., Jackson, R. & Storey, P. (1985) Classifying schizophrenia (letter). Lancet, i, 33.Google Scholar
Farmer, A. E., Jackson, R., McGuffin, P. & Storey, P. (1987) Cerebral ventricular enlargement in schizophrenia consistencies and contradictions. British Journal of Psychiatry, 150, 324330.CrossRefGoogle ScholarPubMed
Festenstein, H. & Demant, P. (1978) HLA and H2. Current Topics in Immunology, Vol. 9. London: Edward Arnold.Google Scholar
Fischer, M. (1971) Psychoses in the offspring of schizophrenia monozygotic twins and their normal co-twins. British Journal of Psychiatry, 115, 981990.CrossRefGoogle Scholar
Fischer, M. (1973) Genetic and environmental factors in schizophrenia. Acta Psychiatric Scnadinavia (Suppl) 238.Google Scholar
Giblett, E. R. (1969) Genetic Markers in Human Blood. Oxford: Black well.Google Scholar
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).CrossRefGoogle Scholar
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.Google Scholar
Gottesman, I. I. & Shields, J. (1967) A polygenic theory of schizophrenia. Proceedings of the National Academy of Sciences, 58, 199205.CrossRefGoogle ScholarPubMed
Gottesman, I. I. & Shields, J. (1972) Schizophrenia. A Twin Study Vantage Point. Academic Press, London.Google Scholar
Gottesman, I. I. & Shields, J. (1982) Schizophrenia, The Epigenetic Puzzle. Cambridge: Cambridge University Press.Google Scholar
Gottesman, I. L. & Bertelsen, A. (in prep.) The offspring of twins concordant and discordant for schizophrenia.Google Scholar
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.Google Scholar
Herold, S. & Frackowiak, J. (1986) New methods in brain imaging (editorial). Psychological medicine, 16, 241246.CrossRefGoogle Scholar
Johnstone, E. C., Crow, T. J., Frith, C. D. & Kreel, L. (1976) Cerebral ventricular size and cognitive impairment in chronic schizophrenia. Lancet, 2, 924926.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Kallmann, F. J. (1938) The Genetics of Schizophrenia. New York: J. J. Augusta.Google Scholar
Kendell, R. E. (1975) The Role of Diagnosis in Psychiatry. Oxford: Blackwell Scientific Publications.Google Scholar
Kendler, K. S. & Davis, K. L. (1981) The genetics and biochemistry of paranoid schizophrenia and other paranoid psychoses. Schizophrenia Bulletin, 7, 689709.CrossRefGoogle ScholarPubMed
Kraepelin, E. (1896) Psychiatric, ein Lehrbuch fur studierende und Arzte, 5th ed. Leipzig: Barch.Google Scholar
Kringlen, E. (1967) Heredity and Environment in the Functional Psychoses. Heinman: London.Google Scholar
Leonhard, K. (1959) Autfelung der Endogen Psychosen. Berlin: Akademic Verlag.Google Scholar
Luxenburger, H. (1928) Vorlaufiger Bericht ubcr psychiatrische Serien untersuchurgen an 2 willilngen. Zeitschrift fur gesamte Neurologie und Psychiatrie, 116, 297326.CrossRefGoogle Scholar
McGue, M., Gottesman, I. I. & Rao, D. C. (1985) Resolving genetic models for the transmission of schizophrenia. Genetic Epidemiology, 2, 99110.CrossRefGoogle ScholarPubMed
McGuffin, P. (1979) Is schizophrenia an HLA associated disease? Psychological Medicine, 9, 721728.CrossRefGoogle ScholarPubMed
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.Google Scholar
McGuffin, P. (1984a) Principles and method in psychiatric genetics. In Scientific Principles of Psychopathology, (ed. P. McGuffin, R. Hodgson & R. Shanks). London: Grune & Stratton.Google Scholar
McGuffin, P. (1984b) Biological markers and psychosis. Psychological Medicine, 14, 255259.CrossRefGoogle ScholarPubMed
McGuffin, P. & Sturt, E. (1986) Genetic Markers in Schizophrenia. Human Heredity, 36, 6568.CrossRefGoogle ScholarPubMed
McGuffin, P., Farmer, A. E. & Yonace, A. (1981) HLA antigens and subtypes of schizophrenia. Psychiatry Research, 5, 115122.CrossRefGoogle ScholarPubMed
McGuffin, P., Festenstein, W. & Murray, R. M. (1983) A Family study of HLA antigens and other genetic markers in schizophrenia. Psychological Medicine, 13, 3143.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
McKuisick, V. A. (1969) On lumpers and splitters, or the nosology of genetic disease. Perspectives on Biology and Medicine, 12, 298301.CrossRefGoogle Scholar
McGuffin, P. (1983) Mendelian Inheritance in Man, Baltimore and London: John Hopkins University Press.Google Scholar
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.Google Scholar
Meltzer, H. Y. (1979) Biology of schizophrenic subtypes: a review and proposal for method of study. Schizophrenia Bulletin, 5, 460.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
Murray, R. M., Lewis, S. & Reveley, A. M. (1985) Towards an aetiological classification of schizophrenia. Lancet, i, 10231026.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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.Google ScholarPubMed
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.CrossRefGoogle Scholar
Paykel, E. S. (1981) Have multivariate statistics contributed to classification? British Journal of Psychiatry, 139, 357362.CrossRefGoogle ScholarPubMed
Penrose, L. S. (1952) Measurement of pleiotropic effects in phenyl ketonuria. Annals of Eugenics, 18, 120124.CrossRefGoogle Scholar
Pogue-Geile, M. F. & Harrow, M. (1985) Negative symptoms in schizophrenia: their longitudinal course and prognostic importance. Schizophrenia Bulletin, 11, 427439.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Reveley, A. M., Reveley, M. A., Clifford, C. A. & Murray, R. M. (1982) Cerebral ventricular size in twins discordant for schizophrenia. Lancet, i, 540541.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
Reveley, A. M., Reveley, M. A., Clifford, C. A., Murray, R. M. (1985) CT scans in schizophrenia. British Journal of Psychiatry, 146, 367371.CrossRefGoogle ScholarPubMed
Reveley, M. A., Chitkara, B. (1985) Subtypes in schizophrenia. (Letter) Lancet, i, 1503.Google Scholar
Rice, J. P., McGuffin, P. & Shaskan, E. G. (1982) A commingling analysis of platelet monoamine oxidase activity. Psychiatry Research, 7, 325335.CrossRefGoogle ScholarPubMed
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.Google ScholarPubMed
Rudduck, C. (1985) Genetic markers and schizophrenia. PhD Thesis, University of Lund.Google Scholar
Scharfetter, C. & Nusperli, M. (1980) The group of schizophrenias, schizoaffective psychoses, and affective disorders. Schizophrenia Bulletin, 6, 586591.CrossRefGoogle Scholar
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.Google Scholar
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).CrossRefGoogle ScholarPubMed
Slater, E. & Cowie, V. (1971) The Genetics of Mental Disorders. Oxford: Oxford University Press.Google Scholar
Smith, G. W. & Iacono, W. G. (1986) Lateral ventricular size in schizophrenia and the choice of a control group (letter), Lancet, i, 1450.CrossRefGoogle Scholar
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.Google Scholar
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.CrossRefGoogle ScholarPubMed
Sturt, E. & McGuffin, P. (1985) Can linkage and marker association resolve the genetic aetiology of psychiatric disorders? Review and argument. Psychological Medicine, 15, 455462.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle Scholar
Thomson, G. (1981) A review of the theoretical aspects of HLA and disease association. Theoretical Population Biology, 20, 168208.CrossRefGoogle Scholar
Tsuang, M. T. & Winokur, G. (1974) Criteria for sub-typing schizophrenia. Archives of General Psychiatry, 31, 4347.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Turner, S., Toone, B. & Brett-Jones, J. (1986) Computerised tomography and changes in early schizophrenia-preliminary findings. Psychological Medicine, 16, 219225.CrossRefGoogle ScholarPubMed
Turner, W. J. (1979) Genetic markers for schizotaxia. Biological Psychiatry, 14, 177205.Google ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
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.CrossRefGoogle ScholarPubMed
Woolf, B. (1955) On estimating the relation between blood groups and disease. Annals of Human Genetics, 19, 251253.CrossRefGoogle Scholar
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