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

Abstract

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.

DOI: 10.1038/ng.2249

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@inproceedings{Estrada2012GenomewideMI, title={Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture}, author={Karol Estrada and Unnur Styrkarsdottir and Evangelos Evangelou and Yi-Hsiang Hsu and Emma L. Duncan and Evangelia E. Ntzani and Ling Oei and Omar M. E. Albagha and Najaf Amin and John P. Kemp and Daniel L. Koller and Guo Li and Ching-Ti Liu and Ryan L. Minster and Alireza Moayyeri and Liesbeth Vandenput and Dana Willner and Su-mei Xiao and Laura M Yerges-Armstrong and Hou-Feng Zheng and Nerea Alonso and Joel Eriksson and Candace M. Kammerer and Stephen K Kaptoge and Paul J Leo and Gudmar Thorleifsson and Scott G. Wilson and James F Wilson and Ville Aalto and Markku J Al{\'e}n and Aaron Aragaki and Thor Aspelund and Jacqueline R. Center and Zoe H. Dailiana and David Duggan and Melissa E . Garcia and Natalia Garcia-Giralt and Sylvie K Giroux and G{\"{o}ran Hallmans and Lynne J. Hocking and Lise Bjerre Husted and Karen A. Jameson and Rita I Khusainova and G S Kim and Charles Kooperberg and Theodora Koromila and Marcin Kruk and Marika M.L. Laaksonen and Andrea Z. Lacroix and Seung Hun Lee and Ping Chung Leung and Joshua R Lewis and Laura Masi and Simona Mencej-Bedra{\vc} and Tuan V. Nguyen and Xavier Nogu{\'e}s and Millan S Patel and J. Prezelj and Lynda M . Rose and Serena A. Scollen and Kristin Siggeirsdottir and Albert V. Smith and Olle Svensson and Stella Trompet and Olivia Trummer and Natasja M. van Schoor and Jean Woo and Kun Zhu and Susana Balcells and Maria Luisa Brandi and Brendan M. Buckley and Sulin Cheng and Claus Christiansen and Cyrus Cooper and George V. Z. Dedoussis and Ian Ford and Morten Frost and David Goltzman and Jes{\'u}s Gonz{\'a}lez-Mac{\'i}as and Mika K{\"a}h{\"{o}nen and Magnus Karlsson and Elza K. Khusnutdinova and Jung-Min Koh and Panagoula Kollia and Bente Lomholt Langdahl and William D Leslie and Paul Th A M Lips and {\"{O}sten Ljunggren and Roman S. Lorenc and Janja Marc and Dan Mellstr{\"{o}m and Barbara Maria Obermayer-Pietsch and Jos{\'e} M Olmos and Ulrika Pettersson-Kymmer and David M. Reid and Jos{\'e} A Riancho and Paul M. Ridker and François Rousseau and Pieternella E Slagboom and Nelson L. S. Tang and Roser Urreizti and Wim van Hul and Jorma Viikari and Mar{\'i}a Teresa Zarrabeitia and Yurii S. Aulchenko and Martha C. Casta{\~n}o-Betancourt and Elin Grundberg and Lizbeth Herrera and Thorvaldur Ingvarsson and Hrefna S J{\'o}hannsd{\'o}ttir and Tony T. M. Kwan and Rui Li and Robert N Luben and Carolina Medina-Gomez and Stefan Th Palsson and Sjur Reppe and Jerome I. Rotter and Gunnar Th Sigurdsson and Joyce B. J. van Meurs and Dominique J. Verlaan and Frances M K Williams and Andrew R Wood and Yanhua Zhou and Kaare M. Gautvik and Tomi Pastinen and Soumya Raychaudhuri and Jane A. Cauley and Daniel Chasman and Graeme Clark and Steve Cummings and Patrick A Danoy and Elaine M. Dennison and Richard Eastell and John Allan Eisman and Vilmundur Gudnason and Albert Hofman and Rebecca D. Jackson and Graeme Jones and J Wouter Jukema and Kay-Tee Khaw and Terho Lehtim{\"a}ki and Yongmei Liu and M Lorentzon and Eugene V. McCloskey and Braxton D. Mitchell and Kannabiran Nandakumar and Geoffrey Charles Nicholson and Ben A. Oostra and Munro Peacock and Huibert A . P . Pols and Richard L Prince and Olli Raitakari and Ian R Reid and John Adam Robbins and Philip N. Sambrook and Pak Chung Sham and Alan R. Shuldiner and Fran Tylavsky and Cornelia Marja van Duijn and Nicholas J Wareham and L. Adrienne Cupples and Michael J. Econs and David M. Evans and Tamara B. Harris and Annie Wai Chee Kung and Bruce M . Psaty and Jonathan Reeve and Tim D. Spector and Elizabeth A. Streeten and M. Carola Zillikens and Unnur Thorsteinsdottir and Claes Ohlsson and David Karasik and J Brent Richards and Matt Brown and K{\'a}ri Stef{\'a}nsson and Andr{\'e} G. Uitterlinden and Stuart H . Ralston and John P. A. Ioannidis and Douglas P . Kiel and Fernando Rivadeneira}, booktitle={Nature genetics}, year={2012} }