BMD and fracture genetic effects correlate to some extent, but some important fracture risk variants may have minimal impact on BMD and vice versa. This is the case for the 18p11.21 signal (Fig. 2B) mapping to a gene coding for a protein of unknown function, which despite a modest effect on BMD (0.02% variance explained) displayed the most significant association with fracture risk (OR=1.08, 95%CI[1.06–1.10], P=8.8×10−13). This is in contrast to variants with known stronger effects on BMD which were not significantly associated with fracture risk. For example, variants in the RANK-RANKL-OPG pathway, known to play a critical role in osteoclastogenesis, had clear associations with BMD but not fracture risk (Fig. 2A). Even though loci discovery was based on the BMD phenotype, these findings reflect the heterogeneous and complex nature of the mechanistic pathways leading to fracture. Therefore, given our study design, we cannot rule out the possibility that yet unidentified genetic loci are influencing risk of fracture independently of BMD. Future well-powered GWAS meta-analyses on fracture risk will address this question while corroborating the associations with fracture that we report for some of the BMD loci (particularly those not associated with fracture at P<5×10−8).
