The second hypothesis to explore is the idea that larger-effect loci might be detected if MD were to be analyzed differently. For example, consider the possibility that MD is not one but two disorders that cannot be differentiated on a clinical basis alone. Suppose that 50 variants contribute to disease through one pathway (leading to one subtype of MD) and 50 to a second pathway (leading to the second subtype). Unbeknownst to investigators, a study contained equal numbers of the two subtypes. Since variation in the first pathway is irrelevant to disease susceptibility in the second subtype, the genetic effect of loci acting on one pathway is reduced by half, and power is similarly reduced. This point is not merely important in helping design genetic studies, it is critically important for their interpretation. Without knowledge of the existence of two unrelated mechanisms, it would be difficult, perhaps impossible, to interpret the results of the study. We would be left guessing whether the 100 variants represented one, two, or more mechanistic pathways.
