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 supportive of a genetic architecture where both common and rare genetic variation may reside in the same locus.24 Other genes have not been reported to be associated with monogenic forms for osteoporosis but have clear involvement in bone development in animal models. For example, SNPs in the 16q12.1 BMD locus map near CYLD. Human mutations in this gene have been described to cause familial cylindromatosis a condition without phenotypic skeletal manifestations. However, it has been shown that Cyld knock-out mice have significant bone loss leading to a severe osteoporosis phenotype25 and also that CYLD regulates osteoclastogenesis.26 Moreover, evidence from the GWAS and eQTL analyses also suggests some loci contain more than one common variant with independent effects on BMD and fracture risk. On the other hand, when no correlation is observed between gene expression and a particular SNP, it is difficult to draw conclusions. A correlation might be missed if the expression of the transcript was not measured in a
