Despite the success of genome wide association (GWA) studies in identifying common single nucleotide variants (SNVs) that contribute to complex diseases1, the vast majority of genetic variants contributing to disease susceptibility are yet to be discovered. In fact, it has been argued that these variants are not likely to be captured in current GWA study paradigms that focus on common SNVs.2 It is now widely believed that many genetic and epigenetic factors are likely to contribute to common complex diseases, including multiple rare SNVs (defined by convention as those that have frequencies < 1%), copy number variations (CNVs), and other forms of structural variation. 3–12 Irrespective of how one might define ‘rare variant’ (which, although we have adopted the convention <1% frequency, might range from <0.1% to <0.01% depending on the context13) it is essential to recognize that such variants likely contribute to phenotypic expression in conjunction with, or over-and-above, common variants. This consideration has important implications when designing a study or choosing a statistical method for analyzing associations involving rare variants.
