GWAS have largely focused on common variants, but because most genetic heritability remains unexplained, future work will increasingly focus on variants of low minor-allele frequency (0.5%<MAF<5%) or rare variants (MAF<0.5%)40. First, new low-frequency variants will be identified by the 1000 Genomes Project (see Web Resources) and included in next-generation genotyping arrays. Here, the issues are generally similar to those involving common variants, except that deviation from model specification is more likely, for example if normality assumptions are violated or the genotypic variance of a SNP varies across subpopulations41. Second, exome resequencing projects will aim to identify genes in which individuals with extreme phenotypes have an aggregate excess or deficiency of rare nonsynonymous variants42. Differences in allele frequency spectrum across ancestral populations make stratification a potential concern, but genetic ancestry can be inferred from genotyping array data from the same samples, if available, and included as a covariate. Finally, the advent of whole-exome or whole-genome resequencing raises the question of whether rare variants can be used to infer genetic ancestry with greater precision, perhaps using different methods than the methods currently applied to common variants.
