As noted, rare variants are likely to influence a trait along with common variants.4, 14 In addition, just as interaction effects involving either genetic or environmental factors must be considered in standard GWA studies9, they are also likely to be important in association studies involving rare variants. With these facts in mind, there are a number of different settings in which rare variants within a defined genomic region could influence a phenotype. Figure 2 provides a few contrasting examples, including situations in which: a common variant is associated with a phenotype; rare variants influence a phenotype independently of one another; rare variants, along with variants with more moderate or common frequencies, act synergistically to influence a phenotype; or only a subset of the rare variants influences the phenotype due to their locations in a functional element within the region of interest.
