Over the past few years, interest in the identification of rare variants that influence human phenotype has led to the development of many statistical methods for testing for association between sets of rare variants and binary or quantitative traits. Here, I review some of the most important ideas that underlie these methods and the most relevant issues when choosing a method for analysis. In addition to the tests for association, I review crucial issues in performing a rare variant study, from experimental design to interpretation and validation. I also discuss the many challenges of these studies, some of their limitations, and future research directions.
Keywords: burden test; effect size; exome sequencing; genetic association studies; rare variants; study design; variance components; variant annotation; whole-genome sequencing.