The typical resolution of the observation that disease is categorical (people are either cases or controls) yet genetic contributions are complex, is that disease is generally a threshold-dependent response superimposed over a continuous liability120. This interpretation actually provides a straightforward framework for integrating rare and common variant effects (Figure 4). Liability is quite likely to be established by the additive and infinitesimal contributions of hundreds of polymorphisms, each regulating a series of biochemical traits that impinge on the phenotype: metabolite abundance, gene expression, and hormone levels, for example. Disease arises either in individuals at the extremes of the liability scale who move beyond the threshold, or in individuals close to the threshold who are pushed into adversity through environmental and behavioral agents, or because they carry one or more rare variants. On this model, the rare variant can either increase or decrease function, and whether or not it associates with disease will be conditional on the background liability. The notion that even rare variants have variable penetrance thus blurs the distinction between infinitesimal and major-effect models of disease susceptibility.
