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Am J Hum Genet. Jul 1982; 34(4): 630–649.
PMCID: PMC1685358

Refutation of the general single-locus model for the etiology of schizophrenia.


All published studies on the familial incidence of schizophrenia appropriate for testing the applicability of the general single-locus two-allele model are examined under the assumption of a unitary etiology for all schizophrenia. We show that the single major locus model is inadequate to predict the incidence in four classes of relatives of schizophrenic probands (parents, siblings, monozygotic, and dizygotic cotwins). In addition, the observed proportion of affected offspring from dual matings differ significantly from the model's prediction. The lack of an overall fit between the published familial distributions and the monogenic model suggests that a single major locus is insufficient for the etiology of schizophrenia. Further efforts in examining multifactorial models, mixed models, and other transmission models may be fruitful.

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  • Lidz T. Commentary on "a critical review of recent adoption, twin, and family studies of schizophrenia: behavioral genetics perspectives". Schizophr Bull. 1976;2(3):402–412. [PubMed]
  • Heston LL. Psychiatric disorders in foster home reared children of schizophrenic mothers. Br J Psychiatry. 1966 Aug;112(489):819–825. [PubMed]
  • Kety SS. Biochemistry and mental states. Calif Med. 1968 May;108(5):362–368. [PMC free article] [PubMed]
  • Kety SS, Rosenthal D, Wender PH, Schulsinger F, Jacobsen B. Mental illness in the biological and adoptive families of adopted individuals who have become schizophrenic: a preliminary report based on psychiatric interviews. Proc Annu Meet Am Psychopathol Assoc. 1975;(63):147–165. [PubMed]
  • Wender PH, Rosenthal D, Kety SS, Schulsinger F, Welner J. Social class and psychopathology in adoptees. A natural experimental method for separating the roles of genetic and experimential factors. Arch Gen Psychiatry. 1973 Mar;28(3):318–325. [PubMed]
  • Wender PH, Rosenthal D, Kety SS, Schulsinger F, Welner J. Crossfostering. A research strategy for clarifying the role of genetic and experiential factors in the etiology of schizophrenia. Arch Gen Psychiatry. 1974 Jan;30(1):121–128. [PubMed]
  • BOOK JA. A genetic and neuropsychiatric investigation of a North-Swedish population. with special regard to schizophrenia and mental deficiency. Acta Genet Stat Med. 1953;4(1):1–100. [PubMed]
  • SLATER E. The monogenic theory of schizophrenia. Acta Genet Stat Med. 1958;8(1):50–56. [PubMed]
  • Golden RR, Meehl PE. Testing a single dominant gene theory without an accepted criterion variable. Ann Hum Genet. 1978 May;41(4):507–514. [PubMed]
  • Heston LL. The genetics of schizophrenic and schizoid disease. Science. 1970 Jan 16;167(3916):249–256. [PubMed]
  • Shields J, Heston LL, Gottesman II. Schizophrenia and the schizoid: the problem for genetic analysis. Proc Annu Meet Am Psychopathol Assoc. 1975;(63):168–197. [PubMed]
  • CRITTENDEN LB. An interpretation of familial aggregation based on multiple genetic and environmental factors. Ann N Y Acad Sci. 1961 Jun 7;91:769–780. [PubMed]
  • Falconer DS. The inheritance of liability to diseases with variable age of onset, with particular reference to diabetes mellitus. Ann Hum Genet. 1967 Aug;31(1):1–20. [PubMed]
  • Reich T, James JW, Morris CA. The use of multiple thresholds in determining the mode of transmission of semi-continuous traits. Ann Hum Genet. 1972 Nov;36(2):163–184. [PubMed]
  • Reich R, Cloninger CR, Guze SB. The multifactorial model of disease transmission: I. Description of the model and its use in psychiatry. Br J Psychiatry. 1975 Jul;127:1–10. [PubMed]
  • Gottesman II, Shields J. A polygenic theory of schizophrenia. Proc Natl Acad Sci U S A. 1967 Jul;58(1):199–205. [PMC free article] [PubMed]
  • Elston RC, Campbell MA. Schizophrenia: evidence for the major gene hypothesis. Behav Genet. 1970 Feb;1(1):3–10. [PubMed]
  • Elston RC, Namboodiri KK, Spence MA, Rainer JD. A genetic study of schizophrenia pedigrees. II. One-locus hypotheses. Neuropsychobiology. 1978;4(4):193–206. [PubMed]
  • Kidd KK, Cavalli-Sforza LL. An analysis of the genetics of schizophrenia. Soc Biol. 1973 Sep;20(3):254–265. [PubMed]
  • Fulker DW. A biometrical genetic approach to intelligence and schizophrenia. Soc Biol. 1973 Sep;20(3):266–275. [PubMed]
  • Morton LA, Kidd KK, Matthysse SW, Richards RL. Recurrence risks in schizophrenia: are they model dependent? Behav Genet. 1979 Sep;9(5):389–406. [PubMed]
  • Matthysse SW, Kidd KK. Estimating the genetic contribution to schizophrenia. Am J Psychiatry. 1976 Feb;133(2):185–191. [PubMed]
  • Bök JA, Wetterberg L, Modrzewska K. Schizophrenia in a North Swedish geographical isolate, 1900--1977. Epidemiology, genetics and biochemistry. Clin Genet. 1978 Dec;14(6):373–394. [PubMed]
  • Debray Q, Caillard V, Stewart J. Schizophrenia: a study of genetic models and some of their implications. Neuropsychobiology. 1978;4(5):257–269. [PubMed]
  • Debray Q, Caillard V, Stewart J. Schizophrenia: a study of genetic models. Hum Hered. 1979;29(1):27–36. [PubMed]
  • Stewart J. Schizophrenia: the systematic construction of genetic models. Am J Hum Genet. 1980 Jan;32(1):47–54. [PMC free article] [PubMed]
  • Stewart J, Debray Q, Caillard V. Schizophrenia: the testing of genetic models by pedigree analysis. Am J Hum Genet. 1980 Jan;32(1):55–63. [PMC free article] [PubMed]
  • Spence MA, Elston RC, Namboodiri KK, Rainer JD. A genetic study of schizophrenia pedigree. I. Demographic studies: sample description, age of onset, ascertainment and classification. Neuropsychobiology. 1976;2(5-6):328–340. [PubMed]
  • Shields J, Gottesman II, Slater E. Kallmann's 1946 schizophrenic twin study in the light of new information. Acta Psychiatr Scand. 1967;43(4):385–396. [PubMed]
  • Pollin W, Allen MG, Hoffer A, Stabenau JR, Hrubec Z. Psychopathology in 15,909 pairs of veteran twins: evidence for a genetic factor in the pathogenesis of schizophrenia and its relative absence in psychoneurosis. Am J Psychiatry. 1969 Nov;126(5):597–610. [PubMed]
  • Gottesman II, Shields J. A critical review of recent adoption, twin, and family studies of schizophrenia: behavioral genetics perspectives. Schizophr Bull. 1976;2(3):360–401. [PubMed]
  • James JW. Frequency in relatives for an all-or-none trait. Ann Hum Genet. 1971 Jul;35(1):47–49. [PubMed]
  • Suarez BK, Reich T, Trost J. Limits of the general two-allele single locus model with incomplete penetrance. Ann Hum Genet. 1976 Nov;40(2):231–243. [PubMed]
  • Suarez BK, Fishman PM, Reich T. Estimating the parameters of the incompletely penetrant single locus model using multiple populations. Hum Hered. 1977;27(5):336–351. [PubMed]
  • Fishman PM, Reich T, Suarez B, James JW. A note on the essential parameters of the two-allele autosomal locus model. Am J Hum Genet. 1978 May;30(3):283–292. [PMC free article] [PubMed]
  • Matthysse S, Kidd KK. The value of dual mating data in estimating genetic parameters. Ann Hum Genet. 1978 May;41(4):477–480. [PubMed]
  • Suarez B, Hodge SE, Reich T. Is juvenile diabetes determined by a single gene closely linked to HLA? Diabetes. 1979 Jun;28(6):527–532. [PubMed]
  • Essen-Möller E, Fischer M. Do the partners of dizygotic schizophrenic twins run a greater risk of schizophrenia than ordinary siblings? Hum Hered. 1979;29(3):161–165. [PubMed]
  • Modrzewska K. The offspring of schizophrenic parents in a North Swedish isolate. Clin Genet. 1980;17(3):191–201. [PubMed]
  • ESSEN-MOLLER E. The calculation of morbid risk in parents of index cases, as applied to a family sample of schizophrenics. Acta Genet Stat Med. 1955;5(4):334–342. [PubMed]
  • Tsuang MT, Fowler RC, Cadoret RJ, Monnelly E. Schizophrenia among first-degree relatives of paranoid and nonparanoid schizophrenics. Compr Psychiatry. 1974 Jul-Aug;15(4):295–302. [PubMed]
  • Morton NE, MacLean CJ. Analysis of family resemblance. 3. Complex segregation of quantitative traits. Am J Hum Genet. 1974 Jul;26(4):489–503. [PMC free article] [PubMed]
  • Rao DC, Morton NE, Gottesman II, Lew R. Path analysis of qualitative data on pairs of relatives: application to schizophrenia. Hum Hered. 1981;31(6):325–333. [PubMed]

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