Genetics of Osteoporosis

Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass, defects in the microarchitecture of bone tissue, and an increased risk of fragility fractures.Twin and family studies have shown high heritability of bone mineral density (BMD) and other determinants of fracture risk such as ultrasound properties of bone, skeletal geometry, and bone turnover.Osteoporotic fractures also have a heritable component, but this reduces with age as environmental factors such as risk of falling come into play.Susceptibility to osteoporosis is governed by many different genetic variants and their interaction with environmental factors such as diet and exercise.Notable successes in identification of genes that regulate BMD have come from the study of rare Mendelian bone diseases characterized by major abnormalities of bone mass where variants of large effect size are operative.Genome-wide association studies have also identified common genetic variants of small effect size that contribute to regulation of BMD and fracture risk in the general population.In many cases, the loci and genes identified by these studies had not previously been suspected to play a role in bone metabolism.Although there has been extensive progress in identifying the genes and loci that contribute to the regulation of BMD and fracture over the past 15 yr, most of the genetic variants that regulate these phenotypes remain to be discovered.(Endocrine Reviews 31: 629 -662, 2010) I. Introduction II.Regulation of Bone Mass and Bone Turnover III.Pathogenesis of Fractures IV.Heritability of Osteoporosis-Related Traits A. Bone mineral density B. Bone loss C. Fracture D. Other phenotypes V. Genetic Architecture of Osteoporosis VI.Single Gene Disorders of Relevance to Osteoporosis A. Osteogenesis imperfecta B. Mendelian osteoporosis syndromes C. High bone mass syndromes D. Osteopetrosis E. Camurati-Engelmann disease VII.Methods for Identifying Osteoporosis Susceptibility Genes A. Linkage analysis B. Candidate gene association studies C. Genome-wide association studies (GWAS) D. Genome-wide sequencing E. Meta-analysis F. Functional studies VIII.Human Linkage Studies IX.Linkage Studies in Model Organisms X. Candidate Genes and GWAS for Osteoporosis A. Loci and genes with significant evidence for association with BMD B. Loci and genes with significant evidence for association with quantitative ultrasound C. Other candidate genes for susceptibility to osteoporosis XI.Gene-Gene Interactions XII.Genetic Determinants of Treatment Response A. Calcium and vitamin D B. Hormone