To combine the effects of completely independent samples (underlined in Table 1), meta-analysis (fixed effect model) was performed to derive the combined p values (underlined in Table 1) using the program METAL (13). This program is designed to facilitate meta-analysis of large datasets in a convenient, rapid and memory efficient manner. It is especially appropriate when data from the individual studies cannot be analyzed together because of differences in ethnicity, phenotype distribution, gender or constraints in sharing of individual level data imposed. It combines p-values across studies, taking sample size and direction of effect (i.e., log(OR)) into account. First, for each marker, a reference allele is selected and a z-statistic characterizing the evidence for association is calculated. The z-statistic summarizes the magnitude and the direction of effect relative to the reference allele and all studies are aligned to the same reference allele. Next, an overall z-statistic and combined p-value are then calculated from a weighted sum of the individual statistics. Weights are proportional to the square-root of the number of individuals contributing to that particular p-value examined in each sample
