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Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Original publication




Journal article


Nature genetics

Publication Date





491 - 501


Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.


Femur Neck, Lumbar Vertebrae, Humans, Osteoporosis, Genetic Predisposition to Disease, Glycoproteins, Intercellular Signaling Peptides and Proteins, Spectrin, Mitochondrial Membrane Transport Proteins, Phosphoproteins, Extracellular Matrix Proteins, Risk Factors, Gene Expression Profiling, Computational Biology, Bone Density, Genotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, European Continental Ancestry Group, Female, Male, Fractures, Bone, Genome-Wide Association Study, Low Density Lipoprotein Receptor-Related Protein-5