Current discussions of GWA studies have suggested that findings of common SNP association may be exploited by examining the region surrounding the initial variant for additional polymorphisms not tagged by the original variant.6–8 Of particular interest are low frequency (between 5 and 1%) and rare ( < 1%) susceptibility polymorphisms that may confer a higher risk than the originally described variant but are unlikely, because of their frequency, to be discovered by standard GWA study. An example of the successful use of this strategy is in nonalcoholic fatty liver disease where the finding of a common PNPLA3 susceptibility allele was followed by the discovery, using re-sequencing, of an excess of null sequence mutations in individuals with the highest hepatic fat levels as well as a protective allele that was rare in European Americans (about 0.3%) but common in African Americans (about 10%).9 To our knowledge, the discovery of rare copy number variants (CNVs) associated with disease in regions initially uncovered through common SNP susceptibility alleles has not been reported.
