Complex human diseases are influenced by common, low-frequency, and rare mutations, and a hypothesis invoking multiple rare variants (as proposed by Dickson) is compatible with the common disease common variant hypothesis [4]. Large-scale sequencing studies of thousands of cases and controls will be required to fully understand the genetic architecture of complex disease. Since the prevalence of synthetic association acutely affects the design of these studies (i.e., in terms of the sample composition and width of genomic region sequenced) it is worth carefully evaluating its contribution to missing heritability. The balance of current evidence suggests that this contribution is likely to be small. Linkage results, preliminary evidence from targeted sequencing studies, pathway analyses and transcontinental replication indicate that common SNP associations arising from GWAS are just that: common SNP associations.
