Our results highlight the highly polygenic nature underlying BMD variation and the critical role of several biological pathways influencing osteoporosis and fracture susceptibility (Supplementary Fig. 10). On top of the Wnt factors known to be associated with BMD (CTNNB1, SOST, LRP4, LRP5, WLS, WNT4, MEF2C) several of the newly discovered loci also implicate additional Wnt signalling factors (including WNT5B, WNT16, DKK1, PTHLH, SFRP4 and AXIN1). Another clearly delineated pathway is that involved in mesenchymal cell differentiation, including the newly identified RUNX2, SOX4 and SOX9 BMD loci along with the previously known SP7. Another bone-relevant pathway includes that of “Endochondral Ossification” which involves essential processes during the fetal development of the mammalian skeleton and which implicated several of our identified BMD loci including: SPP1, MEF2C, RUNX2, SOX6, PTHLH, SP7 and SOX9. In addition, the biological relevance of our associations is accentuated by the identification of genes underlying rare monogenetic forms of osteoporosis and/or high bone mass such as SOST, CLCN7, LRP5 21–23 (Supplementary Table 17) which also contain common variants involved in normal BMD variation at the population level.11,14,16 This is
