In studies of rare mendelian diseases, the extended haplotype sharing surrounding recent mutations, usually with a frequency of much less than 1%, has been exploited to great advantage through homo-zygosity mapping30,31 and haplotype sharing32 methods. In studies of common disease, extended haplotype sharing among patients potentially offers a route for identifying rare variants (MAF in the range of 1–5%) of high penetrance33,34, which tend to be poorly captured through single-marker association with genome-wide arrays. To illustrate the idea, we identified SNPs where only two copies of the minor allele are present (referred to as ‘2-SNPs’), which have minor allele frequencies of 1–2%. We find that these are enriched approximately sevenfold (Table 5) among regions of IBD identified by the hidden Markov model approach. Notably, identification of IBD regions can be performed with the same genome-wide SNP data being collected in large-scale association studies, making haplotype-sharing approaches an attractive and complementary analysis to standard SNP association tests, with the potential to identify rare variants associated with complex disease.
