Ultimately, the proportion of GWAS signals that is due to common versus rare variants is a question that can only be resolved empirically. Our analyses simply illustrate that in following up GWAS signals, the possibility of synthetic associations must be taken into account. If it were true that many signals were synthetic in nature, however, one interesting and potentially encouraging implication of these results is that some of the very modest associations emerging from genome-wide associations may in fact be pointers to rare variants of much larger effect that could be directly informative about disease pathophysiology or be sufficiently high penetrance to be of useful predictive value.
