۱- Introduction

۲- Heritability of bone properties

۳- Fracture risk: an extremely complex trait

۴- Genetic studies of bone mineral density

۵- Genetic studies of fracture risk

۶- Genetic studies of other bone parameters

۷- Variance explained in bone traits by bone-associated variants

۸- Biological pathways underlying common bone conditions

۹- The fulfilled and unfulfilled promises of genomics

۱۰- Post-GWAS analyses and concluding remarks

References

Abstract

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 genomewide 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.

Introduction

Osteoporosis is a progressive silent disease with devastating clinical and economic consequences. Approximately 1/3 of postmenopausal women suffer osteoporosis worldwide and at least half of these will experience a fragility fracture during their lifetime. Fragility fractures are often associated with increased morbidity and mortality, dramatically decreasing quality of life [1–۳]. As population age, the prevalence of osteoporosis and its sequelae will increase substantially, becoming one of the largest global healthcare burdens. Osteoporosis and fracture risk are determined by a complex interplay of genetic and environmental factors. Positive family history of osteoporosis is an important risk factor for fracture, which underscores the pivotal relationship between an individual’s genetic makeup and disease susceptibility. Many monogenic forms of bone fragility have been identified, which are caused by a single mutation in a gene that has a major role in skeletal biology such as observed in X-linked osteoporosis, osteogenesis imperfecta and Paget disease among many others [4]. However, these monogenic mutations explain a very small fraction of the variation in bone mineral density (BMD) and osteoporosis risk in the general population.