0.40 across markers (Supplementary Table 7) and was estimated in a subset of Stage 2 samples (including n=8,594 cases and 23,218 controls) by modeling the BMD SNP effect on fracture risk with and without the inclusion of BMD as covariate. In general, the effect of these SNPs on BMD was larger than on fracture risk (Fig. 2A) except for the most significantly associated fracture locus 18p11.21 (Fig. 2B). SNPs in genes of the RANK-RANKL-OPG pathway (TNFRSF11A-TNFSF11-TNFRSF11B) despite being the strongest-associated BMD loci were not significantly associated with fracture. All 31 BMD loci with nominal association with fracture risk (P<0.05) showed consistent direction (decreasing BMD allele increased risk of fracture). When we performed subgroup analyses using “cleaner” phenotype definitions such as limiting to clinically-validated fractures and stratifying by anatomical site (i.e. “non-vertebral” fractures and “vertebral” fractures), we did not gain any additional signals (Supplementary Table 8). At a nominally significant level (P<0.05) only three loci were associated with vertebral fracture and all 14 BMD loci were associated with non-vertebral fracture, but these difference in effects between fracture sites were not significant. Therefore, the power of our study did not benefit from improving phenotype definition at expense of (a lower) sample size.
