Genome-wide association studies (GWAS) of common single nucleotide polymorphisms (SNPs) have identified loci accounting for only a modest proportion of the heritability of most complex diseases. Although some of this ‘missing heritability’ may be ascribed to a large number of SNPs with weak effect [1], [2], it is becoming increasingly likely that there is a substantial contribution from rare variants with large effect that are not readily identifiable by SNP-based methods [3]–[5]. Thus, resequencing of known risk loci has been pursued to reveal rare point mutations that may have an appreciable impact on disease risk or severity[6]–[8].
