Difficulties in identifying genes for bipolar disorder (BD) have generally been attributed to such factors as genetic heterogeneity and small gene effects. However, it is also possible that the diagnostic systems (DSM-IV and others) used in genetic studies of BD may not optimally define the illness for genetic mapping. Various mood-related traits and disorders with a range of severity are often observed in the families of BD probands (1–3), yet current categorical diagnostic systems are limited in their ability to adequately define this phenotypic variation. Some have suggested that BD and other mood disorders may be better conceptualized in a more quantitative manner as part of a continuous distribution of affective phenotypes ranging from very mild, subclinical affective traits to severe affective psychoses (3–6). This BD spectrum model would be consistent with that of a polygenic trait for which interactions between many genes of small effect produce a continuous variation in phenotype. The use of a quantitative phenotype to model this variation and the associated biological mechanisms may be a powerful tool for identifying the genetic underpinnings of a polygenic trait like BD, yet few such quantitative phenotypes have been proposed for this purpose.
