will not be detectable by population association studies based on the use of linked polymorphic markers. Consequently, if the CDCV hypothesis does not hold, or at least holds only in some of the cases, then the “missing heritability” will not be tracked by GWAS. Rare variants are more likely to be detected by extensive resequencing of carefully selected candidate genes in relatively large numbers of carefully chosen cases, together with a thorough analysis of the functional effects of any suspected variants.14 Multiple rare pathogenic variants have been detected by this approach.15,16 However, candidate gene sequencing will probably not suffice to identify important rare variants and sequencing on a whole-genome basis will be required.9 It is anticipated that advances in genotyping technologies and novel genetic variation maps that capture rare variants (1,000 Genomes Project17) will make whole-genome searches for rare variants feasible.
