The genetics of schizophrenia. Current knowledge and future directions

Multiple research paradigms have provided evidence for a substantial genetic component in the etiology of schizophrenic disorders. This article reviews the major research strategies which have been employed in the examination of the genetic hypothesis in schizophrenia. Family studies have provided overwhelming support regarding familial transmission but cannot clearly resolve issues related to genetic-versus-environmental mechanisms. Twin and adoption studies, however, offer consistent evidence for a substantial genetic component and indicate environmental familial factors to be much less important. Quantitative modeling studies represent more specific attempts to identify the genetic mechanism and mode of inheritance responsible for the familial distribution of schizophrenia. To date, however, these quantitative models have not unequivocally supported a specific mode of genetic transmission. For instance, relevant studies provide little support for the mechanism of single major locus inheritance. Furthermore, although a mechanism involving two, three, or four loci cannot be ruled out, there is no compelling support for such models. The multifactorial polygenic model has received the most support and indicates that genetic factors play a greater role than environmental factors in familial transmission. A mixed genetic model including both a multifactorial component and a single major locus cannot be ruled out. Finally, studies of linkage analysis offer a more powerful technique used for testing the hypothesis of a single pathogenic gene, but the results of linkage analysis in schizophrenia are still preliminary and inconsistent. Evidence for a chromosome 5 gene locus has been provided in some studies but not replicated in others. The important implications of genetic-phenotypic heterogeneity and methodological deficiencies are discussed with respect to limitations on the interpretability of these studies and directions for future research.