Resolving genetic models for the transmission of schizophrenia

Although family studies have consistently reported elevated rates of schizophrenia among the relatives of schizophrenics, the exact nature of the transmission of the disorder remains uncertain. Genetic models hypothesized to explain the transmission of schizophrenia include the generalized single locus and multifactorial threshold models. Here we briefly describe these models and test their goodness-of-fit to a single data set on the pooled morbid risks of schizophrenia among the relatives of schizophrenic probands in nine different classes of relatives with five different degrees of genetic relatedness. The generalized single locus model is rejected, while a pure polygenic threshold model does fit the observed risks. Allowance for environmental sources of familial resemblance under the multifactorial threshold model significantly improved the fit of the model to the data. An application of the multifactorial model to family data on tuberculosis is also reported. For tuberculosis, a strong familial environmental but not genetic effect was found, consistent with the known infectious etiology of this condition, showing that the finding of a strong genetic effect upon schizophrenia is not a necessary bias of these methods of analysis. The implications of these results for the search for major gene effects in schizophrenia are discussed.