surrounding the implicated variant are not well motivated and are likely to miss many and perhaps most of any rare variants that contribute to synthetic associations (see, for example, [5]). The distance over which synthetic associations occur also offers an alternative explanation to the increasingly common observation of rare variants that occur within the vicinity of a GWAS signal but cannot explain that signal entirely. A simple explanation for such observations is that extending the sequencing to at least 4 Mb and ideally up to 10 Mb around the GWAS signal would pick up other rare variants. In some cases, identifying all the contributing rare variants may explain all of the original signal, whereas in other cases, there could be a combination of rare and common variants contributing. In addition, if synthetic associations are responsible for many of the observed signals, then sequencing in a small number of control samples (even over a much broader genomic region) is also unlikely 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
