Increasing attention is being paid to the possibility that rare variants might account for at least some of the missing heritability144. Next-generation sequencing methods are making it feasible to sequence portions of the genome identified through a GWA study in a subset of study subjects. Until it becomes possible to obtain and manage genome-wide sequence information on the massive sample sizes that would be required to discover associations with rare variants directly, some form of informative sampling approaches will be required. For example, one might sequence a subsample of cases and controls, stratified by associated SNPs in a given region, family history, and environmental factors, to discover novel variants in the region and for a joint analysis of subsample and main study data94,145. The imminent availability of the 1000 Genomes Project146 data will doubtless have a profound effect on the design of such studies.
