The genetic implications of age-dependent penetrance in manic-depressive illness

Abstract

An age dependent penetrance function was derived for manic-depressive illness, using age-of-onset data from sixty-one affected probands. The function used was a one-hit model, with earliest age-of-onset at about 14 yr, and a steadily increasing probability of manifesting the illness thereafter. The utility of the penetrance function for pedigree analysis was illustrated, using the families of the sixty-one probands. A sex-linked dominant model of inheritance was about eighty-nine times more likely than an autosomal dominant model, and both were far more likely than autosomal recessive or sex-linked recessive models. The more general single major locus model and the polygenic model cannot be ruled out, but would seem to be unnecessarily over-parameterized for the data at hand. The sex-linked dominant and autosomal dominant models were also compared, by means of the age specific morbidity risks and sibs and children. Both models provided a fairly close fit of expectation and observation, but the sex-linked model was preferable. Although the genetic conclusions cannot automatically be applied to other material, the analytical techniques should be useful elsewhere. Other uses of the penetrance function were indicated.