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The genetics of schizophrenia: a current, genetic-epidemiologic perspective.

In the "Special Report on Schizophrenia" published in the Schizophrenia Bulletin in 1987, the genetic basis of schizophrenia was reviewed. Here, we provide our perspective on the current status of this area of investigation, focusing largely but not exclusively on recent findings. Methodologically rigorous family studies have now clearly shown that schizophrenia substantially aggregates in families. Familial factors that predispose to schizophrenia also increase the risk for certain schizophrenia-related personality disorders and probably for some forms of non-schizophrenic nonaffective psychosis. Results from one new twin study and updates from two ongoing adoption studies continue to support the hypothesis that genetic factors play a major role in the etiology of schizophrenia. Little is known about how genetic liability to schizophrenia is transmitted, although statistical models suggest that transmission is probably not due solely to a single major gene. Schizophrenia is clearly a complex disorder in that gene carriers need not manifest the illness (incomplete penetrance), affected individuals need not have the gene (environmental forms of phenocopies), diagnostic uncertainties cannot be avoided, and different families may carry different susceptibility genes (genetic heterogeneity). Therefore, segregation or linkage analyses are far more difficult to perform with schizophrenia than with Mendelian genetic disorders. Given this complexity, it is not too surprising that no replicated positive evidence for linkage to schizophrenia has been reported to date. However, just as linkage analysis of schizophrenia should not be excessively embraced as the only form of viable genetic research in schizophrenia, it also shouldn't be prematurely spurned. If one or several genes of major effect exist for schizophrenia, large samples using new statistical and laboratory methodologies have a good chance of detecting them. The authors thus recommend a balanced research approach to the genetics of schizophrenia that includes traditional methods of family, twin, and adoption studies as well as a major effort in large-sample linkage studies.