many more reproducible associations than we have achieved with any other approach, the fact is that our primary goal in conducting GWAS for a complex trait – achieving a comprehensive understanding of the genetic basis for that trait – remains elusive for most of the traits that have been examined. The failure to achieve this goal is made particularly acute by the recognition that the loci that have been successfully identified not only provide us with little insight into the genetic basis for the trait, but also account for little of the overall heritability [5]. Although there are important caveats to these grim statistics – most published studies have conducted discovery research in populations of European descent, and some important disorders have not even been examined using GWAS yet – the collective experience has led to sharp disagreement as to whether there is sufficient value in targeting near-term investments in genomics to GWAS, or whether such investments are better targeted to sequencing [6]–[8]. The key issue in this controversy is whether the genetic risk factors not yet discovered are largely similar in frequency and effect size to those that have been discovered using GWAS (i.e. common alleles with low risk)
