Unipolar relatives in bipolar pedigrees: Are they bipolar?

The ambiguous status of unipolar relatives in the pedigrees of bipolar probands has long plagued investigators, and may have contributed significantly to the difficulties replicating linkage findings for bipolar disorder. We present here a conceptual model, based on a selective review of family and course data, and use it to quantify this problem, concluding that 65-74% of the unipolar relatives of bipolars must be bipolar from the genetic point of view. We then offer a set of predictions for the characteristics of UP individuals who are “genetically bipolar”, and suggest that these characteristics should lead to differences between UP relatives of BPs and other UP groups. Such differences could then be combined to form a caseness index that would rank unipolar relatives by the chances that they are “genetically bipolar”, and could serve as Ott’s measure of certainty that weights the contribution of individual unipolar relatives in a linkage analysis. We conclude with a review of the implications of this model for the unipolar-bipolar distinction and the potential benefits and limitations of this approach to classification in linkage analyses of bipolar and other psychiatric disorders.