Bipolar illness and schizophrenia as oligogenic diseases: implications for the future

As with most complex inheritance diseases, there are at this time no identified susceptibility genes for schizophrenia, bipolar manic-depressive illness, major depression, childhood autism, and other inherited brain disorders whose manifestations are primarily behavioral. Nonetheless, progress has occurred. Genetic epidemiologic research, based on reliable phenotypic definitions, has demonstrated the heritability of many of these disorders. Genetic linkages and associations have been reported and replicated, although there have been inconsistencies between studies, apparently due to the low statistical power of the samples studied to detect small effects genes. Nonreplications of early linkage reports in manic-depressive illness in the 1980s occurred when new cases developed in the same large families in which the linkage was originally reported, and the newly ill persons had the wrong genetic markers in the linkage region. This appears to have resulted from applying inappropriate analytic assumptions of single-gene dominant inheritance of a rare gene, which implied that new cases must arise from the same ancestral gene within the pedigree. When new cases arose in family members not sharing that chromosomal region, the initial linkage report was proved invalid. Under oligogenic inheritance, on the other hand, susceptibility genes are expected to be common, and have a substantial probability of being brought into the pedigree by persons marrying in. Nonspecific psychopathology genes may exist, shared by schizophrenia and bipolar illness, diagnoses which do not co-aggregate in families. The discovery of susceptibility mutations may be expected.