To comprehensively characterize the contribution of rare variants to phenotypic expression, one could either sequence genomic regions of interest using high-throughput DNA sequencing technologies21 or genotype common and rare variants identified in previous sequencing studies using custom genotyping chips. There are a number of ways to approach association studies involving rare variants, which are independent of sequencing or genotyping technology. For example, one could: focus on candidate disease genes 22; focus on genomic regions implicated in linkage or genome-wide association studies, under the assumption that phenotypically-relevant rare variants also exist in those regions; consider multiple functional genomic regions, such as exons 23; or study entire genomes.12, 24 The sampling framework for such studies is also extremely important as one could focus on: cases and controls, possibly in DNA pools22 or with oversampling of controls to achieve greater power in studies of rare diseases; individuals phenotyped for a particular quantitative trait; individuals with ‘extreme’ phenotype values in order to increase efficiency25, 26; or families in order to exploit parent-offspring transmission patterns.12, 24
