Genetic heterogeneity in affective disorders. Implications for psychobiological research

The extent of genetic heterogeneity in major affective illness was estimated via three paradigms of single-major-locus inheritance. In the first paradigm bipolar and unipolar disorders were represented at different liability thresholds on a genetic-environmental continuum. The second paradigm incorporated sex-related thresholds into the model, thereby testing the hypothesis that affective illness is a transmitted trait whose phenotypic expression is a function of the individual's sex. The third paradigm included both clinical polarity and sex effect as threshold phenomena. All three paradigms predicted considerable genetic heterogeneity in affective disorders. Bipolar homozygotes were far more common than unipolar homozygotes, although the majority of ill individuals in the first two paradigms were heterozygotes. According to the third paradigm bipolar males had the highest proportion of homozygotes amongst the affected population. Significant increases in homozygosity occurred using the dual mating sampling method. Depending on the model paradigm and parameters these increases were 140-25,000% over the random sample method. The implications for biologic and genetic research in affective disorders were discussed.