to succeed. Under our model, the causal sites are both rare and relatively high-penetrant contributors to disease, and will therefore be unlikely to be detected in a small number of control samples. Finally, the focus of attention on genes that are near GWAS signals may be incomplete or misleading in that the actual causal sites may occur in many different genes surrounding the implicated common variant. It is also worth emphasizing that as few as one or two rare variants, at much lower frequency than the associated common SNP, can create a significant synthetic association. In such a case, sequencing a small number of cases that carry the “at risk” common variant might miss entirely the causal rare variants even if the correct genome region is resequenced. These considerations argue for caution in efforts to resequence around genome-wide associations and argue instead that genome-wide sequencing in carefully phenotyped cohorts might be a better use of resources.
