X-CHROMOSOME THRESHOLD MODELS OF BIPOLAR MANIC-DEPRESSIVE ILLNESS

The hypothesis of single X-locus two alleles transmission of manic-depressive illness (BP and UP forms) has been tested with a comprehensive genetic model. The model takes into account the prevalence and type of illness in all categories of first degree relatives of the patients according to sex. It makes provision for the posibility of phenocopies, multiple manifestations of the genotypes for affective illness and explicity specifies threshold effects which might affect penetrance and determine polarity of illness, it test also for a dominance variance. Three threshold models were applied to three sets of family data from the literature: Winokur (1969), 1 Mendlewicz (1974), 44 Gershon (1975), 3 These three models are: (a) a single threshold model with UP relatives considered in the same class as normal relatives so that only the transmission of BP is tested in the model (Model I); (b) a single threshold for illness in the relatives considering UP equivalent to BP with regard to genetic transmission (Mode II); and (c) separate thresholds for UP and BP illness in the relatives (Model III). Each model was studied separately with or without sex effect on the position of the thresholds. For Winokur all three hypotheses gave an acceptable solution (p≳0.05), but qualitatively Models I and III are the best fitted to the data, the gene frequencies are 0.03 (Model I) and 0.022 (Model III). For Mendlewicz, the only testable hypothesis did not give any acceptable fit, whereas for Gershon's, Models II and III can be rejected and Model I gives a tentatively acceptable fit with a gene frequency of 0.19. These results show that X-chromosome single-locus transmission does not consistently describe the transmission of affective illness in the families of BP probands. The different results for each author compared to the other might be due to heterogeneity of mode of transmission: certain families being strictly X-linked (Winokur) and other mixing autosomal and X-linked mode of transmission (Gershon, Mendlewicz). The implications of these results for currently available X-linkage analysis in BP manic-depressive illness is discussed. © 1980.