As expected, the estimated effect sizes in the GWA meta-analysis were generally larger than the effect sizes observed in replication samples, because of the well-known ‘winner’s curse’ phenomenon34. Perhaps less well appreciated is that the magnitude of the winner’s curse effect depends on the underlying distribution of effect sizes: the greater the number of variants with small effects, the more likely it is that one or more of these variants will approach genome-wide significance even in a study that is not well powered to detect these very modest effects35. Such variants will then prove difficult to convincingly replicate, unless very large replication cohorts are used. Thus, it is possible that even some of the initial associations that we failed to replicate will eventually be validated.
