There are many settings in which a collection of rare variants might exhibit an association with a trait. Of the many different methods that could be used for testing associations, not all of them are likely to work well in each of these settings. Here, we consider the rationales behind different data analysis methods, pointing out their limitations and advantages. We also outline areas for further research. As noted, appropriately sophisticated methods for identifying variants, assigning genotypes, and sampling individuals are crucial for rare variant analyses, but we do not discuss them here. There are, however, a few additional issues that researchers need to consider in any association study involving rare variants, as briefly described in Box 1. Finally, although we focus on the analysis of rare SNVs, aspects of the analytical methods discussed can be used with other forms of variation including rare CNVs, although certain caveats apply, which we mention briefly.
