Genetics of osteoporosis: accelerating pace in gene identification and validation

• Published in: Human genetics 2010-03, Vol.127 (3), p.249-285
• Main Authors: Li, Wen-Feng, Hou, Shu-Xun, Yu, Bin, Li, Meng-Meng, Férec, Claude, Chen, Jian-Min
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Classical genetics, quantitative genetics, hybrids; Diseases of the osteoarticular system; DNA Mutational Analysis - methods; Estrogen; Estrogens - genetics; Estrogens - metabolism; Fractures; Fundamental and applied biological sciences. Psychology; Gene Function; Genes; Genes - physiology; Genetic aspects; Genetic Linkage; Genetic Predisposition to Disease; Genetic research; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Human; Human Genetics; Humans; Medical sciences; Metabolic Diseases; Metabolic Networks and Pathways - genetics; Molecular Medicine; Osteoporosis; Osteoporosis - genetics; Osteoporosis. Osteomalacia. Paget disease; Review Article; Time Factors; Validation Studies as Topic; Vitamin D - genetics; Vitamin D - metabolism
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-009-0773-z

Osteoporosis is characterized by low bone mineral density and structural deterioration of bone tissue, leading to an increased risk of fractures. It is the most common metabolic bone disorder worldwide, affecting one in three women and one in eight men over the age of 50. In the past 15 years, a large number of genes have been reported as being associated with osteoporosis. However, only in the past 4 years we have witnessed an accelerated pace in identifying and validating osteoporosis susceptibility loci. This increase in pace is mostly due to large-scale association studies, meta-analyses, and genome-wide association studies of both single nucleotide polymorphisms and copy number variations. A comprehensive review of these developments revealed that, to date, at least 15 genes ( VDR , ESR1 , ESR2 , LRP5 , LRP4 , SOST , GRP177 , OPG , RANK , RANKL , COLIA1 , SPP1 , ITGA1 , SP7 , and SOX6 ) can be reasonably assigned as confirmed osteoporosis susceptibility genes, whereas, another >30 genes are promising candidate genes. Notably, confirmed and promising genes are clustered in three biological pathways, the estrogen endocrine pathway, the Wnt/β-catenin signaling pathway, and the RANKL/RANK/OPG pathway. New biological pathways will certainly emerge when more osteoporosis genes are identified and validated. These genetic findings may provide new routes toward improved therapeutic and preventive interventions of this complex disease.