Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

• Published in: Nature genetics Vol. 44; no. 5; pp. 491 - 501
• Main Authors: Estrada, Karol, Styrkarsdottir, Unnur, Evangelou, Evangelos, Hsu, Yi-Hsiang, Ntzani, Evangelia E, Albagha, Omar M E, Koller, Daniel L, Minster, Ryan L, Moayyeri, Alireza, Vandenput, Liesbeth, Willner, Dana, Xiao, Su-Mei, Zheng, Hou-Feng, Alonso, Nerea, Kammerer, Candace M, Kaptoge, Stephen K, Leo, Paul J, Wilson, James F, Alen, Markku, Aspelund, Thor, Center, Jacqueline R, Dailiana, Zoe, Duggan, David J, Garcia, Melissa, Husted, Lise Bjerre, Jameson, Karen A, Kim, Ghi Su, Kooperberg, Charles, Kruk, Marcin, Laaksonen, Marika, Leung, Ping C, Lewis, Joshua R, Nogues, Xavier, Prezelj, Janez, Scollen, Serena, Svensson, Olle, Trompet, Stella, Woo, Jean, Zhu, Kun, Cheng, Sulin, Dedoussis, George, Frost, Morten, Goltzman, David, Kähönen, Mika, Karlsson, Magnus, Langdahl, Bente Lomholt, Lips, Paul, Lorenc, Roman S, Mellström, Dan, Olmos, José M, Pettersson-Kymmer, Ulrika, Riancho, José A, Ridker, Paul M, Rousseau, François, lagboom, P Eline S, Urreizti, Roser, Zarrabeitia, María T, Castano-Betancourt, Martha, Kwan, Tony, Li, Rui, Luben, Robert, Medina-Gómez, Carolina, Th Palsson, Stefan, Rotter, Jerome I, Sigurdsson, Gunnar, van Meurs, Joyce B J, Williams, Frances M K, Zhou, Yanhua, Pastinen, Tomi, Cauley, Jane A, Chasman, Daniel I, Clark, Graeme R, Cummings, Steven R, Eastell, Richard, Eisman, John A, Hofman, Albert, Jukema, J Wouter, Khaw, Kay-Tee, Lehtimäki, Terho, Liu, Yongmei, Oostra, Ben A, Pols, Huibert A P, Reid, Ian R, Robbins, John, Sambrook, Philip N, Sham, Pak Chung, Shuldiner, Alan R, van Duijn, Cornelia M, Wareham, Nick J, Econs, Michael J, Harris, Tamara B, Kung, Annie Wai Chee, Streeten, Elizabeth A, Thorsteinsdottir, Unnur, Karasik, David, Richards, J Brent, Brown, Matthew A, Ralston, Stuart H, Ioannidis, John P A, Kiel, Douglas P
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2012; Nature Publishing Group
• Subjects: 631/208/205/2138; 631/208/2489/144; 631/208/480; Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Bone; Bone densitometry; Bone Density; Bone Density - genetics; Bone mineral density; Bones; Cancer Research; Cell differentiation; Clinical Medicine; Computational Biology; Densitometria òssia; Density; Endocrinology and Diabetes; Endokrinologi och diabetes; European Continental Ancestry Group; Extracellular Matrix Proteins; Extracellular Matrix Proteins - genetics; Female; Femur; Femur Neck; Femur Neck - physiopathology; Fractures; Fractures, Bone - genetics; Fundamental and applied biological sciences. Psychology; Fèmur; Gene Expression Profiling; Gene Function; Gene loci; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetics; Genetics of eukaryotes. Biological and molecular evolution; genetik; Genome-Wide Association Study; Genomics; Genotype; Gens; Glycoproteins; Glycoproteins - genetics; Human Genetics; Humans; Identification and classification; Intercellular Signaling Peptides and Proteins; Intercellular Signaling Peptides and Proteins - genetics; Klinisk medicin; Low Density Lipoprotein Receptor-Related Protein-5; Low Density Lipoprotein Receptor-Related Protein-5 - genetics; Lumbar Vertebrae; Lumbar Vertebrae - physiopathology; Male; Medical and Health Sciences; Medical research; Medicin och hälsovetenskap; Mitochondrial Membrane Transport Proteins; Mitochondrial Membrane Transport Proteins - genetics; Orthopaedics; Orthopedics; Ortopedi; Osteoporosis; Osteoporosis - genetics; Phosphoproteins; Phosphoproteins - genetics; physiopathology; Polymorphism; Polymorphism, Single Nucleotide - genetics; Quantitative Trait Loci; Risk Factors; Single Nucleotide; Spectrin; Spectrin - genetics; Spine; Stem cells; Vèrtebres lumbars; White People; United States; Osteoarticular system; Diseases of the osteoarticular system; Risk; Fracture; Identification; Bone; Locus; Trauma; Density; Metaanalysis
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.2249

Fernando Rivadeneira and colleagues in the Genetic Factors for Osteoporosis Consortium report a large-scale meta-analysis identifying new loci associated with bone mineral density (BMD) and risk of fracture. Thirty-two new loci are found to be associated with BMD, and 6 loci confer higher risk for low-trauma bone fracture. 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.