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

Estrada, K and Styrkarsdottir, U and Evangelou, E and Hsu, YH and Duncan, EL and Ntzani, EE and Oei, L and Albagha, OME and Amin, N and Kemp, JP and Koller, DL and Li, G and Liu, CT and Minster, RL and Moayyeri, A and Vandenput, L and Willner, D and Xiao, SM and Yerges-Armstrong, LM and Zheng, HF and Alonso, N and Eriksson, J and Kammerer, CM and Kaptoge, SK and Leo, PJ and Thorleifsson, G and Wilson, SG and Wilson, JF and Aalto, V and Alen, M and Aragaki, AK and Aspelund, T and Center, JR and Dailiana, Z and Duggan, DJ and Garcia, M and Garcia-Giralt, N and Giroux, S and Hallmans, G and Hocking, LJ and Husted, LB and Jameson, KA and Khusainova, R and Kim, GS and Kooperberg, C and Koromila, T and Kruk, M and Laaksonen, M and Lacroix, AZ and Lee, SH and Leung, PC and Lewis, JR and Masi, L and Mencej-Bedrac, S and Nguyen, TV and Nogues, X and Patel, MS and Prezelj, J and Rose, LM and Scollen, S and Siggeirsdottir, K and Smith, AV and Svensson, O and Trompet, S and Trummer, O and Van Schoor, NM and Woo, J and Zhu, K and Balcells, S and Brandi, ML and Buckley, BM and Cheng, S and Christiansen, C and Cooper, C and Dedoussis, G and Ford, I and Frost, M and Goltzman, D and González-Macías, J and Kähönen, M and Karlsson, M and Khusnutdinova, E and Koh, JM and Kollia, P and Langdahl, BL and Leslie, WD and Lips, P and Ljunggren, Ø and Lorenc, RS and Marc, J and Mellström, D and Obermayer-Pietsch, B and Olmos, JM and Pettersson-Kymmer, U and Reid, DM and Riancho, JA and Ridker, PM and Rousseau, F and Lagboom, PES and Tang, NLS (2012) Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nature Genetics, 44 (5). 491 - 501. ISSN 1061-4036

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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. © 2012 Nature America, Inc. All rights reserved.


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Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Estrada, K
Styrkarsdottir, U
Evangelou, E
Hsu, YH
Duncan, EL
Ntzani, EE
Oei, L
Albagha, OME
Amin, N
Kemp, JP
Koller, DL
Li, G
Liu, CT
Minster, RLrminster@pitt.eduRMINSTER
Moayyeri, A
Vandenput, L
Willner, D
Xiao, SM
Yerges-Armstrong, LM
Zheng, HF
Alonso, N
Eriksson, J
Kammerer, CMcmk3@pitt.eduCMK3
Kaptoge, SK
Leo, PJ
Thorleifsson, G
Wilson, SG
Wilson, JF
Aalto, V
Alen, M
Aragaki, AK
Aspelund, T
Center, JR
Dailiana, Z
Duggan, DJ
Garcia, M
Garcia-Giralt, N
Giroux, S
Hallmans, G
Hocking, LJ
Husted, LB
Jameson, KA
Khusainova, R
Kim, GS
Kooperberg, C
Koromila, T
Kruk, M
Laaksonen, M
Lacroix, AZ
Lee, SH
Leung, PC
Lewis, JR
Masi, L
Mencej-Bedrac, S
Nguyen, TV
Nogues, X
Patel, MS
Prezelj, J
Rose, LM
Scollen, S
Siggeirsdottir, K
Smith, AV
Svensson, O
Trompet, S
Trummer, O
Van Schoor, NM
Woo, J
Zhu, K
Balcells, S
Brandi, ML
Buckley, BM
Cheng, S
Christiansen, C
Cooper, C
Dedoussis, G
Ford, I
Frost, M
Goltzman, D
González-Macías, J
Kähönen, M
Karlsson, M
Khusnutdinova, E
Koh, JM
Kollia, P
Langdahl, BL
Leslie, WD
Lips, P
Ljunggren, Ø
Lorenc, RS
Marc, J
Mellström, D
Obermayer-Pietsch, B
Olmos, JM
Pettersson-Kymmer, U
Reid, DM
Riancho, JA
Ridker, PM
Rousseau, F
Lagboom, PES
Tang, NLS
Date: 1 May 2012
Date Type: Publication
Journal or Publication Title: Nature Genetics
Volume: 44
Number: 5
Page Range: 491 - 501
DOI or Unique Handle: 10.1038/ng.2249
Schools and Programs: Graduate School of Public Health > Epidemiology
Refereed: Yes
ISSN: 1061-4036
Date Deposited: 03 Apr 2015 01:10
Last Modified: 08 Jun 2019 14:55
URI: http://d-scholarship.pitt.edu/id/eprint/24112

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