In conclusion, GWAS represent one forward step towards a more complete understanding of the genetic architecture of complex disorders. Unbiased by prior pathophysiological assumptions, more than 350 GWAS have substantially changed the landscape of genetic associations for more than 80 traits and provided new insights into disease mechanisms.4,5,29 The independence of GWAS from the need of biological candidates has led to their characterization as “hypothesis-free” or “agnostic” experiments. However, these terms can be misleading; in essence, GWAS are based on prior hypotheses, implicitly determined by the statistical analysis or the design of the genotyping array. GWAS to date have largely focused on the role of common SNPs and probably most of the heritability of complex disorders captured by these variants has been accounted for.6 The remaining variance may be due to rare SNPs, structural variants, epigenetic effects, other unsuspected genomic mechanisms, gene-gene or gene-environment interactions that have not been adequately modeled.9,27
