The genetic architecture of osteoporosis and fracture risk

Osteoporosis and fracture risk are common complex diseases, caused by an interaction of numerous disease susceptibility genes and environmental factors. With the advances in genomic technologies, large-scale genome-wide association studies (GWAS) have been performed which have broadened our understanding of the genetic architecture and biological mechanisms of complex disease. Currently, more than ~90 loci have been found associated with DXA derived bone mineral density (BMD), over ~500 loci with heel estimated BMD and several others with other less widely available bone parameters such as bone geometry, shape, and microarchitecture. Notably, several of the pathways identified by the GWAS efforts correspond to pathways that are currently targeted for the treatment of osteoporosis. Overall, tremendous progress in the field of the genetics of osteoporosis has been achieved with the discovery of WNT16, EN1, DAAM2, and GPC6 among others. Assessment of the function and biological mechanisms of the remaining genes may further untangle the complex genetic landscape of osteoporosis and fracture risk. With this review we aimed to provide a general overview of the existing GWAS studies on osteoporosis traits and fracture risk.