Knowledge of the likely mode of inheritance of a disorder is useful for design of linkage studies, choice of mode of statistical analysis and estimation of power to detect disease genes. In their paper, "Bipolar Disorder: Evidence for a Major Locus," Spence et al. [1995] report complex segregation analyses of Bipolar Disorder in which the best fitting model was a single, dominant mendelian major locus. Although the authors provide cautionary statements, they conclude that their results "should be at least somewhat reassuring to those using linkage studies in the search for a major bipolar locus." In contrast, we have recently applied a novel method of analysis to recurrence risk data on Bipolar Disorder and found that one or more major loci are most unlikely to underlie transmission of Bipolar Disorder whereas oligogenic epistatic models are plausible . Our findings will certainly not reassure those using conventional lod score approaches in large, densely affected families in a search for a presumed major bipolar locus because, under plausible oligogenic models, linkage strategies using non-parametric methods of analysis in large samples of affected sib-pairs are more appropriate .
In view of the marked difference between our findings and those of Spence et al., we would like to point out two weaknesses of complex segregation analysis.