Common Disease Is More Complex Than Implied by the Core Gene Omnigenic Model

The evidence that most adult-onset common diseases have a polygenic genetic architecture fully consistent with robust biological systems supported by multiple back-up mechanisms is now overwhelming. In this context, we consider the recent omnigenic'' or core genes'' model. A key assumption of the model is that there is a relatively small number of core genes relevant to any disease. While intuitively appealing, this model may underestimate the biological complexity of common disease, and therefore, the goal to discover core genes should not guide experimental design. We consider other implications of polygenicity, concluding that a focus on patient stratification is needed to achieve the goals of precision medicine.