In Reply.—
The hypothesis of X-linked manic-depressive illness is a general hypothesis not restricted to pedigrees without apparent male-tomale transmission. Risch et al,1 in their analysis of our published family study of a large series of subjects with bipolar affective disorder unselected for sex or type of illness in relatives, concluded that our data were compatible with a significant proportion of cases of X-linked transmission (25% of males with bipolar [BP] illness and 40% of females with BP illness). The exclusion of families with apparent male-to-male transmission is a way of enriching a pedigree series for the X-linked proportion (if there is population genetic heterogeneity), and we excluded pedigrees with ill father-son pairs for this reason.In a common disease, it is probable that at least one case of illness will appear among relatives of well people if enough relatives are studied. For example, when studying first-degree relatives of 50 psychiatrically