We used GSMA software (27) to evaluate empirically the significance of the SR. Briefly, for each study, the observed rank values were randomly reassigned to 118 bins, allowing for tied ranks in each study to be incorporated in the null distribution. Bin ranks were summed across studies; this procedure was repeated 10,000 times. The empirical P-value of SR was calculated by counting the proportion of bins in which a summed rank value was equal to or larger than the observed one. In addition, a POR is calculated as the proportion of the simulated nth highest ordered sum rank (OR), which is equal to or greater than the observed nth highest summed rank through the same permutation procedure. Simulation studies have shown that bins with significant P-values (P < 0.05) of both SR and OR are likely to identify true linkage signals (26). By applying a Bonferroni correction for multiple testing (assuming 118 independent bins), values of PSR, 0.05/118=0.00042 and 1/118=0.0085 correspond to the genomewide significant and suggestive evidence for linkage, respectively. Simulation studies have shown that these thresholds are appropriate
