It has been proposed that distant, rare variants may be responsible for association signals with common variants (17) and there are several examples of rare functional variants that were not assayed in the GWA studies because of an absence from the HapMap SNP dataset, such as the PCSK9 R46L variant (85) and three rare coding variants in NOD2 (31) that are not tagged by GWA arrays (6). However, the prevalent theory currently is that most loci that show association with common variants will ultimately identify a functional variant from amongst the most strongly associated SNPs (3) that impacts regulation of nearby genes, as recently described for the SORT1 functional variant at an LDL locus (71) identified by GWA studies (45, 98).
