Genetic control of bone mass.

Bone mineral density (BMD) is a quantitative traits used as a surrogate phenotype for the diagnosis of osteoporosis, a common metabolic disorder characterized by increased fracture risk as a result of a decreased bone mass and deterioration of the microarchitecture of the bone. Normal variation in BMD is determined by both environmental and genetic factors. According to heritability studies, 50-85% of the variance in BMD is controlled by genetic factors which are mostly polygenic. In contrast to the complex etiology of osteoporosis, there are disorders with deviating BMD values caused by one mutation with a large impact. These mutations can result in monogenic bone disorders with either an extreme high (sclerosteosis, Van Buchem disease, osteopetrosis, high bone mass phenotype) or low BMD (osteogenesis imperfecta, juvenile osteoporosis, primary osteoporosis). Identification of the disease causing genes, increased the knowledge on the regulation of BMD and highlighted important signaling pathways and novel therapeutic targets such as sclerostin, RANKL and cathepsin K. Genetic variation in genes involved in these pathways are often also involved in the regulation of normal variation in BMD and osteoporosis susceptibility. In the last decades, identification of genetic factors regulating BMD has proven to be a challenge. Several approaches have been tested such as linkage studies and candidate and genome wide association studies. Although, throughout the years, technological developments made it possible to study increasing numbers of genetic variants in populations with increasing sample sizes at the same time, only a small fraction of the genetic impact can yet be explained. In order to elucidate the missing heritability, the focus shifted to studying the role of rare variants, copy number variations and epigenetic influences. This review summarizes the genetic cause of different monogenic bone disorders with deviating BMD and the knowledge on genetic factors explaining normal variation in BMD and osteoporosis risk.