A clear definition of genetic correlation can be further complicated by the presence of allele frequency differences across samples. Whereas GCTA assumes fixed allele frequencies across the samples included in the analysis [36], there also exist methods which allow for differences in allele frequencies. Ideally, estimates of cross-study genetic-impact correlation accounting for allele frequency differences [24] should be used in the MetaGAP calculator as input for CGR. However, provided the genetic drift is small, whether to account for allele frequency differences across samples or not, will—in all likelihood—hardly affect the CGR estimates. Therefore, under little genetic drift, estimates of CGR obtained by methods ignoring cross-study differences in allele frequencies (e.g., bivariate GREML [37]), suffice as input for the MetaGAP calculator.
