The effects of variable age-of-onset and diagnostic criteria on the estimates of linkage: an example using manic-depressive illness and color blindness.

Three pedigrees were selected from the literature for their compatibility with the hypothesis of linkage between the X-chromosome marker color blindness and bipolar affective disorder. We compared the results of linkage analyses of these pedigrees when both penetrance function and diagnostic classification were varied. The analyses show that the incorporation of age-of-onset information into a penetrance function significantly increased the evidence for linkage. In addition, assumptions about diagnostic classification affected the lod scores. These results demonstrate the need for careful consideration of diagnostic criteria and variable age-of-onset when pursuing linkage analysis of complex traits.