Low reported values of R2 might not directly reflect the degree of missing heritability; but could also reflect the effect of sampling variation on the variance explained by an estimated score (50). Because the individual SNP effects are very small they are estimated with much error. Although we can obtain an unbiased estimate of a SNP effect, a prediction of a phenotype using the estimated SNP effect suffers from the sampling variance with which the effect is estimated. The crudeness of the measures of substance use in the present study might have limited the explained variance. The worse the estimate of the effect size of the variant in the discovery sample, the worse the variance will be explained by the predictor in the validation sample (49,50).
