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

Karol Estrada Gil; U Styrkarsdottir; E Evangelou; YH Hsu; EL Duncan; EE Ntzani; Ling Oei - Oei; OME Albagha; Najaf Amin; JP Kemp; DL Koller; G (Guo) Li; CT Liu; RL Minster; A Moayyeri; L Vandenput; D Willner; SM Xiao; LM Yerges-Armstrong; HF Zheng; N Alonso; J Eriksson; CM Kammerer; SK Kaptoge; PJ Leo; G Thorleifsson; SG Wilson; JF Wilson; V Aalto; M Alen; AK Aragaki; T Aspelund; JR Center; Z Dailiana; DJ Duggan; M Garcia; N Garcia-Giralt; S Giroux; G Hallmans; LJ Hocking; LB Husted; KA Jameson; R Khusainova; GS Kim; C Kooperberg; T Koromila; M van der Kruk; M Laaksonen; AZ Lacroix; SH Lee; PC Leung; JR Lewis; L Masi; S Mencej-Bedrac; TV (Tuan) Nguyen; X Nogues; MS Patel; J Prezelj; LM Rose; S Scollen; K Siggeirsdottir; AV Smith; O Svensson; S Trompet; O Trummer; NM Schoor; J Woo; K Zhu; S Balcells; ML Brandi; BM Buckley; SL Cheng; C Christiansen; C Cooper; G Dedoussis; I Ford; M Frost; D Goltzman; J Gonzalez-Macias; M Kahonen; M Karlsson; E Khusnutdinova; JM Koh; P Kollia; BL Langdahl; WD Leslie; P Lips; O Ljunggren; RS Lorenc; J Marc; D Mellstrom; B Obermayer-Pietsch; JM Olmos; U Pettersson-Kymmer; DM Reid; JA Riancho; PM Ridker; F Rousseau; PE (Eline) Slagboom; NLS Tang; R Urreizti; W van Hul; J Viikari; MT Zarrabeitia; YS Aulchenko; M Castano-Betancourt; E Grundberg; L Herrera; T Ingvarsson; H Johannsdottir; T Kwan; R Li; R Luben; C Medina-Gomez; ST Palsson; S Reppe; JI Rotter; G Sigurdsson; Joyce van Meurs; D Verlaan; FMK Williams; AR Wood; YH Zhou; KM Gautvik; T Pastinen; S Raychaudhuri; JA Cauley; DI Chasman; GR Clark; SR Cummings; P Danoy; EM Dennison; R Eastell; JA Eisman; V Gudnason; Bert Hofman; RD Jackson; G Jones; JW Jukema; KT Khaw; T Lehtimaki; YM Liu; M Lorentzon; E McCloskey; BD Mitchell; K Nandakumar; GC Nicholson; Ben Oostra; M Peacock; Huib Pols; RL Prince; O Raitakari; IR Reid; J Robbins; PN Sambrook; PC Sham; AR Shuldiner; FA Tylavsky; Cornelia Duijn; NJ Wareham; LA Cupples; MJ Econs; DM Evans; TB Harris; AWC Kung; BM Psaty; J Reeve; TD Spector; EA Streeten; M.C. Zillikens; U Thorsteinsdottir; C Ohlsson; D Karasik; JB Richards; MA Brown; K Stefansson; André Uitterlinden; SH Ralston; JPA Ioannidis; DP Kiel; Fernando Rivadeneira

doi:10.1038/ng.2249

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

Karol Estrada Gil, U Styrkarsdottir, E Evangelou, YH Hsu, EL Duncan, EE Ntzani, Ling Oei - Oei, OME Albagha, Najaf Amin, JP Kemp, DL Koller, G (Guo) Li, CT Liu, RL Minster, A Moayyeri, L Vandenput, D Willner, SM Xiao, LM Yerges-Armstrong, HF ZhengN Alonso, J Eriksson, CM Kammerer, SK Kaptoge, PJ Leo, G Thorleifsson, SG Wilson, JF Wilson, V Aalto, M Alen, AK Aragaki, T Aspelund, JR Center, Z Dailiana, DJ Duggan, M Garcia, N Garcia-Giralt, S Giroux, G Hallmans, LJ Hocking, LB Husted, KA Jameson, R Khusainova, GS Kim, C Kooperberg, T Koromila, M van der Kruk, M Laaksonen, AZ Lacroix, SH Lee, PC Leung, JR Lewis, L Masi, S Mencej-Bedrac, TV (Tuan) Nguyen, X Nogues, MS Patel, J Prezelj, LM Rose, S Scollen, K Siggeirsdottir, AV Smith, O Svensson, S Trompet, O Trummer, NM Schoor, J Woo, K Zhu, S Balcells, ML Brandi, BM Buckley, SL Cheng, C Christiansen, C Cooper, G Dedoussis, I Ford, M Frost, D Goltzman, J Gonzalez-Macias, M Kahonen, M Karlsson, E Khusnutdinova, JM Koh, P Kollia, BL Langdahl, WD Leslie, P Lips, O Ljunggren, RS Lorenc, J Marc, D Mellstrom, B Obermayer-Pietsch, JM Olmos, U Pettersson-Kymmer, DM Reid, JA Riancho, PM Ridker, F Rousseau, PE (Eline) Slagboom, NLS Tang, R Urreizti, W van Hul, J Viikari, MT Zarrabeitia, YS Aulchenko, M Castano-Betancourt, E Grundberg, L Herrera, T Ingvarsson, H Johannsdottir, T Kwan, R Li, R Luben, C Medina-Gomez, ST Palsson, S Reppe, JI Rotter, G Sigurdsson, Joyce van Meurs, D Verlaan, FMK Williams, AR Wood, YH Zhou, KM Gautvik, T Pastinen, S Raychaudhuri, JA Cauley, DI Chasman, GR Clark, SR Cummings, P Danoy, EM Dennison, R Eastell, JA Eisman, V Gudnason, Bert Hofman, RD Jackson, G Jones, JW Jukema, KT Khaw, T Lehtimaki, YM Liu, M Lorentzon, E McCloskey, BD Mitchell, K Nandakumar, GC Nicholson, Ben Oostra, M Peacock, Huib Pols, RL Prince, O Raitakari, IR Reid, J Robbins, PN Sambrook, PC Sham, AR Shuldiner, FA Tylavsky, Cornelia Duijn, NJ Wareham, LA Cupples, MJ Econs, DM Evans, TB Harris, AWC Kung, BM Psaty, J Reeve, TD Spector, EA Streeten, M.C. Zillikens, U Thorsteinsdottir, C Ohlsson, D Karasik, JB Richards, MA Brown, K Stefansson, André Uitterlinden, SH Ralston, JPA Ioannidis, DP Kiel, Fernando Rivadeneira

Research output: Contribution to journal › Article › Academic › peer-review

977 Citations (Scopus)

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 x 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 x 10(-4), Bonferroni corrected), of which six reached P < 5 x 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 language	Undefined/Unknown
Pages (from-to)	491-+
Journal	Nature Genetics
Volume	44
Issue number	5
DOIs	https://doi.org/10.1038/ng.2249
Publication status	Published - 2012

Research programs

EMC MGC-02-96-01
EMC MM-01-39-02
EMC MM-01-39-09-A
EMC NIHES-01-64-01
EMC NIHES-01-64-02

Access to Document

10.1038/ng.2249

http://hdl.handle.net/1765/58209

Cite this

Estrada Gil, K., Styrkarsdottir, U., Evangelou, E., Hsu, YH., Duncan, EL., Ntzani, EE., Oei - Oei, L., Albagha, OME., Amin, N., Kemp, JP., Koller, DL., Li, G., Liu, CT., Minster, RL., Moayyeri, A., Vandenput, L., Willner, D., Xiao, SM., Yerges-Armstrong, LM., ... Rivadeneira, F. (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-+. https://doi.org/10.1038/ng.2249

@article{ea3d129667234aa082a5c1ca9f72c7bd,

title = "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 x 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 x 10(-4), Bonferroni corrected), of which six reached P < 5 x 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.",

author = "{Estrada Gil}, Karol and U Styrkarsdottir and E Evangelou and YH Hsu and EL Duncan and EE Ntzani and {Oei - Oei}, Ling and OME Albagha and Najaf Amin and JP Kemp and DL Koller and Li, {G (Guo)} and CT Liu and RL Minster and A Moayyeri and L Vandenput and D Willner and SM Xiao and LM Yerges-Armstrong and HF Zheng and N Alonso and J Eriksson and CM Kammerer and SK Kaptoge and PJ Leo and G Thorleifsson and SG Wilson and JF Wilson and V Aalto and M Alen and AK Aragaki and T Aspelund and JR Center and Z Dailiana and DJ Duggan and M Garcia and N Garcia-Giralt and S Giroux and G Hallmans and LJ Hocking and LB Husted and KA Jameson and R Khusainova and GS Kim and C Kooperberg and T Koromila and {van der Kruk}, M and M Laaksonen and AZ Lacroix and SH Lee and PC Leung and JR Lewis and L Masi and S Mencej-Bedrac and Nguyen, {TV (Tuan)} and X Nogues and MS Patel and J Prezelj and LM Rose and S Scollen and K Siggeirsdottir and AV Smith and O Svensson and S Trompet and O Trummer and NM Schoor and J Woo and K Zhu and S Balcells and ML Brandi and BM Buckley and SL Cheng and C Christiansen and C Cooper and G Dedoussis and I Ford and M Frost and D Goltzman and J Gonzalez-Macias and M Kahonen and M Karlsson and E Khusnutdinova and JM Koh and P Kollia and BL Langdahl and WD Leslie and P Lips and O Ljunggren and RS Lorenc and J Marc and D Mellstrom and B Obermayer-Pietsch and JM Olmos and U Pettersson-Kymmer and DM Reid and JA Riancho and PM Ridker and F Rousseau and Slagboom, {PE (Eline)} and NLS Tang and R Urreizti and {van Hul}, W and J Viikari and MT Zarrabeitia and YS Aulchenko and M Castano-Betancourt and E Grundberg and L Herrera and T Ingvarsson and H Johannsdottir and T Kwan and R Li and R Luben and C Medina-Gomez and ST Palsson and S Reppe and JI Rotter and G Sigurdsson and {van Meurs}, Joyce and D Verlaan and FMK Williams and AR Wood and YH Zhou and KM Gautvik and T Pastinen and S Raychaudhuri and JA Cauley and DI Chasman and GR Clark and SR Cummings and P Danoy and EM Dennison and R Eastell and JA Eisman and V Gudnason and Bert Hofman and RD Jackson and G Jones and JW Jukema and KT Khaw and T Lehtimaki and YM Liu and M Lorentzon and E McCloskey and BD Mitchell and K Nandakumar and GC Nicholson and Ben Oostra and M Peacock and Huib Pols and RL Prince and O Raitakari and IR Reid and J Robbins and PN Sambrook and PC Sham and AR Shuldiner and FA Tylavsky and Cornelia Duijn and NJ Wareham and LA Cupples and MJ Econs and DM Evans and TB Harris and AWC Kung and BM Psaty and J Reeve and TD Spector and EA Streeten and M.C. Zillikens and U Thorsteinsdottir and C Ohlsson and D Karasik and JB Richards and MA Brown and K Stefansson and Andr{\'e} Uitterlinden and SH Ralston and JPA Ioannidis and DP Kiel and Fernando Rivadeneira",

year = "2012",

doi = "10.1038/ng.2249",

language = "Undefined/Unknown",

volume = "44",

pages = "491--+",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "5",

}

Estrada Gil, K, Styrkarsdottir, U, Evangelou, E, Hsu, YH, Duncan, EL, Ntzani, EE, Oei - Oei, L, Albagha, OME, Amin, N, Kemp, JP, Koller, DL, Li, G, Liu, CT, Minster, RL, Moayyeri, A, Vandenput, L, Willner, D, Xiao, SM, Yerges-Armstrong, LM, Zheng, HF, Alonso, N, Eriksson, J, Kammerer, CM, 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, van der 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, Schoor, NM, Woo, J, Zhu, K, Balcells, S, Brandi, ML, Buckley, BM, Cheng, SL, Christiansen, C, Cooper, C, Dedoussis, G, Ford, I, Frost, M, Goltzman, D, Gonzalez-Macias, J, Kahonen, M, Karlsson, M, Khusnutdinova, E, Koh, JM, Kollia, P, Langdahl, BL, Leslie, WD, Lips, P, Ljunggren, O, Lorenc, RS, Marc, J, Mellstrom, D, Obermayer-Pietsch, B, Olmos, JM, Pettersson-Kymmer, U, Reid, DM, Riancho, JA, Ridker, PM, Rousseau, F, Slagboom, PE, Tang, NLS, Urreizti, R, van Hul, W, Viikari, J, Zarrabeitia, MT, Aulchenko, YS, Castano-Betancourt, M, Grundberg, E, Herrera, L, Ingvarsson, T, Johannsdottir, H, Kwan, T, Li, R, Luben, R, Medina-Gomez, C, Palsson, ST, Reppe, S, Rotter, JI, Sigurdsson, G, van Meurs, J, Verlaan, D, Williams, FMK, Wood, AR, Zhou, YH, Gautvik, KM, Pastinen, T, Raychaudhuri, S, Cauley, JA, Chasman, DI, Clark, GR, Cummings, SR, Danoy, P, Dennison, EM, Eastell, R, Eisman, JA, Gudnason, V, Hofman, B, Jackson, RD, Jones, G, Jukema, JW, Khaw, KT, Lehtimaki, T, Liu, YM, Lorentzon, M, McCloskey, E, Mitchell, BD, Nandakumar, K, Nicholson, GC, Oostra, B, Peacock, M, Pols, H, Prince, RL, Raitakari, O, Reid, IR, Robbins, J, Sambrook, PN, Sham, PC, Shuldiner, AR, Tylavsky, FA, Duijn, C, Wareham, NJ, Cupples, LA, Econs, MJ, Evans, DM, Harris, TB, Kung, AWC, Psaty, BM, Reeve, J, Spector, TD, Streeten, EA, Zillikens, MC, Thorsteinsdottir, U, Ohlsson, C, Karasik, D, Richards, JB, Brown, MA, Stefansson, K, Uitterlinden, A, Ralston, SH, Ioannidis, JPA, Kiel, DP & Rivadeneira, F 2012, 'Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture', Nature Genetics, vol. 44, no. 5, pp. 491-+. https://doi.org/10.1038/ng.2249

TY - JOUR

T1 - Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

AU - Estrada Gil, Karol

AU - Styrkarsdottir, U

AU - Evangelou, E

AU - Hsu, YH

AU - Duncan, EL

AU - Ntzani, EE

AU - Oei - Oei, Ling

AU - Albagha, OME

AU - Amin, Najaf

AU - Kemp, JP

AU - Koller, DL

AU - Li, G (Guo)

AU - Liu, CT

AU - Minster, RL

AU - Moayyeri, A

AU - Vandenput, L

AU - Willner, D

AU - Xiao, SM

AU - Yerges-Armstrong, LM

AU - Zheng, HF

AU - Alonso, N

AU - Eriksson, J

AU - Kammerer, CM

AU - Kaptoge, SK

AU - Leo, PJ

AU - Thorleifsson, G

AU - Wilson, SG

AU - Wilson, JF

AU - Aalto, V

AU - Alen, M

AU - Aragaki, AK

AU - Aspelund, T

AU - Center, JR

AU - Dailiana, Z

AU - Duggan, DJ

AU - Garcia, M

AU - Garcia-Giralt, N

AU - Giroux, S

AU - Hallmans, G

AU - Hocking, LJ

AU - Husted, LB

AU - Jameson, KA

AU - Khusainova, R

AU - Kim, GS

AU - Kooperberg, C

AU - Koromila, T

AU - van der Kruk, M

AU - Laaksonen, M

AU - Lacroix, AZ

AU - Lee, SH

AU - Leung, PC

AU - Lewis, JR

AU - Masi, L

AU - Mencej-Bedrac, S

AU - Nguyen, TV (Tuan)

AU - Nogues, X

AU - Patel, MS

AU - Prezelj, J

AU - Rose, LM

AU - Scollen, S

AU - Siggeirsdottir, K

AU - Smith, AV

AU - Svensson, O

AU - Trompet, S

AU - Trummer, O

AU - Schoor, NM

AU - Woo, J

AU - Zhu, K

AU - Balcells, S

AU - Brandi, ML

AU - Buckley, BM

AU - Cheng, SL

AU - Christiansen, C

AU - Cooper, C

AU - Dedoussis, G

AU - Ford, I

AU - Frost, M

AU - Goltzman, D

AU - Gonzalez-Macias, J

AU - Kahonen, M

AU - Karlsson, M

AU - Khusnutdinova, E

AU - Koh, JM

AU - Kollia, P

AU - Langdahl, BL

AU - Leslie, WD

AU - Lips, P

AU - Ljunggren, O

AU - Lorenc, RS

AU - Marc, J

AU - Mellstrom, D

AU - Obermayer-Pietsch, B

AU - Olmos, JM

AU - Pettersson-Kymmer, U

AU - Reid, DM

AU - Riancho, JA

AU - Ridker, PM

AU - Rousseau, F

AU - Slagboom, PE (Eline)

AU - Tang, NLS

AU - Urreizti, R

AU - van Hul, W

AU - Viikari, J

AU - Zarrabeitia, MT

AU - Aulchenko, YS

AU - Castano-Betancourt, M

AU - Grundberg, E

AU - Herrera, L

AU - Ingvarsson, T

AU - Johannsdottir, H

AU - Kwan, T

AU - Li, R

AU - Luben, R

AU - Medina-Gomez, C

AU - Palsson, ST

AU - Reppe, S

AU - Rotter, JI

AU - Sigurdsson, G

AU - van Meurs, Joyce

AU - Verlaan, D

AU - Williams, FMK

AU - Wood, AR

AU - Zhou, YH

AU - Gautvik, KM

AU - Pastinen, T

AU - Raychaudhuri, S

AU - Cauley, JA

AU - Chasman, DI

AU - Clark, GR

AU - Cummings, SR

AU - Danoy, P

AU - Dennison, EM

AU - Eastell, R

AU - Eisman, JA

AU - Gudnason, V

AU - Hofman, Bert

AU - Jackson, RD

AU - Jones, G

AU - Jukema, JW

AU - Khaw, KT

AU - Lehtimaki, T

AU - Liu, YM

AU - Lorentzon, M

AU - McCloskey, E

AU - Mitchell, BD

AU - Nandakumar, K

AU - Nicholson, GC

AU - Oostra, Ben

AU - Peacock, M

AU - Pols, Huib

AU - Prince, RL

AU - Raitakari, O

AU - Reid, IR

AU - Robbins, J

AU - Sambrook, PN

AU - Sham, PC

AU - Shuldiner, AR

AU - Tylavsky, FA

AU - Duijn, Cornelia

AU - Wareham, NJ

AU - Cupples, LA

AU - Econs, MJ

AU - Evans, DM

AU - Harris, TB

AU - Kung, AWC

AU - Psaty, BM

AU - Reeve, J

AU - Spector, TD

AU - Streeten, EA

AU - Zillikens, M.C.

AU - Thorsteinsdottir, U

AU - Ohlsson, C

AU - Karasik, D

AU - Richards, JB

AU - Brown, MA

AU - Stefansson, K

AU - Uitterlinden, André

AU - Ralston, SH

AU - Ioannidis, JPA

AU - Kiel, DP

AU - Rivadeneira, Fernando

PY - 2012

Y1 - 2012

N2 - 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 x 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 x 10(-4), Bonferroni corrected), of which six reached P < 5 x 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.

AB - 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 x 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 x 10(-4), Bonferroni corrected), of which six reached P < 5 x 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.

U2 - 10.1038/ng.2249

DO - 10.1038/ng.2249

M3 - Article

SN - 1061-4036

VL - 44

SP - 491-+

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -