Our study also provides indication that there is sex- and site-specificity underlying BMD variation. One of the GWAS signals (Xp22.31) was only significant in the sex-stratified analysis in men and displayed significant sex heterogeneity (Phet=1.62×10−8). This is expected considering the sexual dimorphism of bone.28,29 In fact, in a recent GWAS, the rs5934507 SNP mapping to Xp22.31, which is associated with BMD in the current study, has been previously associated with male serum testosterone levels.30 Thus, it is likely that rs5934507 affects serum testosterone, which in turn regulates BMD. In line with the different types of bone composition at the different skeletal sites (predominantly trabecular at the lumbar spine while predominantly cortical at the femoral neck) we observed some indication of site specificity in 10 of the 56 BMD loci, suggesting differential genetic influences on BMD determination across skeletal sites. As has been previously shown31, we did not find in our results major differences in effect sizes between individuals of European and East Asian ancestry (Supplementary Fig. 7). However, this may be due to reduced power given the smaller number of
