Another interim approach between GWA studies and sequencing is to assay rare (and common) variants in coding regions of the genome using inexpensive chip technology. A chip assaying most variation identified from exome sequencing >12,000 individuals is available from Illumina and soon from Affymetrix (http://genome.sph.umich.edu/wiki/Exome_Chip_Design). This will allow for testing of rare variants (except for private mutations and the ~15% of variants that cannot be designed for chip-based assays) that are the most likely to be functional by changing the amino acid make-up of a protein. There are still hurdles with experiments of this type. In the early stage of an experiment, one challenge is to call rare variants using clustering algorithms designed for common variants, and some progress towards rare-variant-specific approaches has been made (23). A challenge in the later stages of an experiment is to use statistical tests that aggregate the evidence for association across all functional variants in a biologically-equivalent unit (gene or pathway (4)). We expect to find a mix of functional and non-functional variants in most genes, but identifying which variants are likely to be
