The ability to discover a new association depends on the effect size and allele frequency for the associated variant and on the sample size encompassed by the meta-analysis. Because the effect sizes and frequencies for as yet undiscovered associations are by definition unknown, it is not easy to predict precisely what a given sample size will yield in new associations. Different groups have made different assumptions about the distributions of effect sizes (22, 100). Some of these attempts to fit mathematical distributions to the effect sizes based on results from early association studies produced inaccurate predictions of the effect sizes seen in subsequent, larger meta-analyses (54). However, consideration of empirical results across a number of different polygenic diseases and traits can provide some sense of the general pattern of outcomes as meta-analyses increase in size, even if the actual distribution of effect sizes does not fit a simple mathematical formula.
