Clinical genetics as clues to the "real" genetics of schizophrenia (a decade of modest gains while playing for time).

Although a decade has passed since the genetics of schizophrenia was examined for the Schizophrenia Bulletin, the epigenetic puzzle of schizophrenia has not yielded its secrets to any scientific break-through. In this article we review a sample of the highlights relevant to enlightened genetic thinking, i.e., a broad diathesis-stressor framework with multifactorial causation assumed and with provision for the epigenetic interaction of psychosocial as well as neurobiological factors. The clinical genetic epidemiologist needs to know the lifetime morbid risks generated by different definitions of schizophrenia, as well as the consequences for the familial risks generated by the various family, twin, and adoption strategies. Schizophrenia appears to occur through an interaction of a genetic susceptibility with some kind of environmental stress; the stress need not be an environment containing a person with a diagnosis in the schizophrenia spectrum; the genetic factors in schizophrenia have specificity as they do not increase the risk for major affective disorders or delusional disorder. Clearly, schizophrenia is clinically or phenotypically heterogeneous, but whether this variety is paralleled by etiological heterogeneity or to what extent is problematic. Once the existence of an important genetic predisposition to developing schizophrenia has been established, it becomes important to provide a theory (or theories) to account for its mode (modes) of transmission. Psychiatric geneticists have not yet solved the problem, in part because of the difficulty of specifying the appropriate phenotype to analyze and also because of the unknown degree of heterogeneity. Genetic markers are a special category of biological markers. In addition to conventional markers, the advent of "the new genetics" of recombinant DNA has meant that many more genetic markers (probes) are now available and that the day is not far off when the human genome will be extensively mapped. Considerable optimism exists about the future usefulness of genetic markers in detecting major gene effects and resolving problems of heterogeneity in schizophrenia.