Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Alireza Moayyeri; Yi-Hsiang Hsu; David Karasik; Karol Estrada; Su-Mei Xiao; Carrie Nielson; Priya Srikanth; Sylvie Giroux; Scott G. Wilson; Hou-Feng Zheng; Albert V. Smith; Stephen R. Pye; Paul J. Leo; Alexander Teumer; Joo-Yeon Hwang; Claes Ohlsson; Fiona McGuigan; Ryan L. Minster; Caroline Hayward; Jose M. Olmos; Leo-Pekka Lyytikaeinen; Joshua R. Lewis; Karin M. A. Swart; Laura Masi; Chris Oldmeadow; Elizabeth G. Holliday; Sulin Cheng; Natasja M. van Schoor; Nicholas C. Harvey; Marcin Kruk; M. Fabiola Del Greco; Wilmar Igl; Olivia Trummer; Efi Grigoriou; Robert Luben; Ching-Ti Liu; Yanhua Zhou; Ling Oei; Carolina Medina-Gomez; Joseph Zmuda; Greg Tranah; Suzanne J. Brown; Frances M. Williams; Nicole Soranzo; Johanna Jakobsdottir; Kristin Siggeirsdottir; Kate L. Holliday; Anke Hannemann; Min Jin Go; Melissa Garcia; Ozren Polasek; Marika Laaksonen; Kun Zhu; Anke W. Enneman; Mark McEvoy; Roseanne Peel; Pak Chung Sham; Maciej Jaworski; Asa Johansson; Andrew A. Hicks; Pawel Pludowski; Rodney Scott; Rosalie A. M. Dhonukshe-Rutten; Nathalie van der Velde; Mika Kaehoenen; Jorma S. Viikari; Harri Sievaenen; Olli T. Raitakari; Jesus Gonzalez-Macias; Jose L. Hernandez; Dan Mellstroem; Oesten Ljunggren; Yoon Shin Cho; Uwe Voelker; Matthias Nauck; Georg Homuth; Henry Voelzke; Robin Haring; Matthew A. Brown; Eugene McCloskey; Geoffrey C. Nicholson; Richard Eastell; John A. Eisman; Graeme Jones; Ian R. Reid; Elaine M. Dennison; John Wark; Steven Boonen; Dirk Vanderschueren; Frederick C. W. Wu; Thor Aspelund; J. Brent Richards; Doug Bauer; Albert Hofman; Kay-Tee Khaw; George Dedoussis; Barbara Obermayer-Pietsch; Ulf Gyllensten; Peter P. Pramstaller; Roman S. Lorenc; Cyrus Cooper; Annie Wai Chee Kung; Paul Lips; Markku Alen; John Attia; Maria Luisa Brandi; Lisette C. P. G. M. de Groot; Terho Lehtimaeki; Jose A. Riancho; Harry Campbell; Yongmei Liu; Tamara B. Harris; Kristina Åkesson; Magnus Karlsson; Jong-Young Lee; Henri Wallaschofski; Emma L. Duncan; Terence W. O'Neill; Vilmundur Gudnason; Timothy D. Spector; Francois Rousseau; Eric Orwoll; Steven R. Cummings; Nick J. Wareham; Fernando Rivadeneira; Andre G. Uitterlinden; Richard L. Prince; Douglas P. Kiel; Jonathan Reeve; Stephen K. Kaptoge

doi:10.1093/hmg/ddt675

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Alireza Moayyeri, Yi-Hsiang Hsu, David Karasik, Karol Estrada, Su-Mei Xiao, Carrie Nielson, Priya Srikanth, Sylvie Giroux, Scott G. Wilson, Hou-Feng Zheng, Albert V. Smith, Stephen R. Pye, Paul J. Leo, Alexander Teumer, Joo-Yeon Hwang, Claes Ohlsson, Fiona McGuigan, Ryan L. Minster, Caroline Hayward, Jose M. OlmosLeo-Pekka Lyytikaeinen, Joshua R. Lewis, Karin M. A. Swart, Laura Masi, Chris Oldmeadow, Elizabeth G. Holliday, Sulin Cheng, Natasja M. van Schoor, Nicholas C. Harvey, Marcin Kruk, M. Fabiola Del Greco, Wilmar Igl, Olivia Trummer, Efi Grigoriou, Robert Luben, Ching-Ti Liu, Yanhua Zhou, Ling Oei, Carolina Medina-Gomez, Joseph Zmuda, Greg Tranah, Suzanne J. Brown, Frances M. Williams, Nicole Soranzo, Johanna Jakobsdottir, Kristin Siggeirsdottir, Kate L. Holliday, Anke Hannemann, Min Jin Go, Melissa Garcia, Ozren Polasek, Marika Laaksonen, Kun Zhu, Anke W. Enneman, Mark McEvoy, Roseanne Peel, Pak Chung Sham, Maciej Jaworski, Asa Johansson, Andrew A. Hicks, Pawel Pludowski, Rodney Scott, Rosalie A. M. Dhonukshe-Rutten, Nathalie van der Velde, Mika Kaehoenen, Jorma S. Viikari, Harri Sievaenen, Olli T. Raitakari, Jesus Gonzalez-Macias, Jose L. Hernandez, Dan Mellstroem, Oesten Ljunggren, Yoon Shin Cho, Uwe Voelker, Matthias Nauck, Georg Homuth, Henry Voelzke, Robin Haring, Matthew A. Brown, Eugene McCloskey, Geoffrey C. Nicholson, Richard Eastell, John A. Eisman, Graeme Jones, Ian R. Reid, Elaine M. Dennison, John Wark, Steven Boonen, Dirk Vanderschueren, Frederick C. W. Wu, Thor Aspelund, J. Brent Richards, Doug Bauer, Albert Hofman, Kay-Tee Khaw, George Dedoussis, Barbara Obermayer-Pietsch, Ulf Gyllensten, Peter P. Pramstaller, Roman S. Lorenc, Cyrus Cooper, Annie Wai Chee Kung, Paul Lips, Markku Alen, John Attia, Maria Luisa Brandi, Lisette C. P. G. M. de Groot, Terho Lehtimaeki, Jose A. Riancho, Harry Campbell, Yongmei Liu, Tamara B. Harris, Kristina Åkesson, Magnus Karlsson, Jong-Young Lee, Henri Wallaschofski, Emma L. Duncan, Terence W. O'Neill, Vilmundur Gudnason, Timothy D. Spector, Francois Rousseau, Eric Orwoll, Steven R. Cummings, Nick J. Wareham, Fernando Rivadeneira, Andre G. Uitterlinden, Richard L. Prince, Douglas P. Kiel, Jonathan Reeve, Stephen K. Kaptoge

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Abstract

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Original language	English
Pages (from-to)	3054-3068
Journal	Human Molecular Genetics
Volume	23
Issue number	11
DOIs	https://doi.org/10.1093/hmg/ddt675
Publication status	Published - 2014

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Medical Genetics

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10.1093/hmg/ddt675

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Moayyeri, A., Hsu, Y.-H., Karasik, D., Estrada, K., Xiao, S.-M., Nielson, C., Srikanth, P., Giroux, S., Wilson, S. G., Zheng, H.-F., Smith, A. V., Pye, S. R., Leo, P. J., Teumer, A., Hwang, J.-Y., Ohlsson, C., McGuigan, F., Minster, R. L., Hayward, C., ... Kaptoge, S. K. (2014). Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium. Human Molecular Genetics, 23(11), 3054-3068. https://doi.org/10.1093/hmg/ddt675

@article{fb63a1c46c5f4f66b206467c0a908ace,

title = "Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium",

abstract = "Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.",

author = "Alireza Moayyeri and Yi-Hsiang Hsu and David Karasik and Karol Estrada and Su-Mei Xiao and Carrie Nielson and Priya Srikanth and Sylvie Giroux and Wilson, {Scott G.} and Hou-Feng Zheng and Smith, {Albert V.} and Pye, {Stephen R.} and Leo, {Paul J.} and Alexander Teumer and Joo-Yeon Hwang and Claes Ohlsson and Fiona McGuigan and Minster, {Ryan L.} and Caroline Hayward and Olmos, {Jose M.} and Leo-Pekka Lyytikaeinen and Lewis, {Joshua R.} and Swart, {Karin M. A.} and Laura Masi and Chris Oldmeadow and Holliday, {Elizabeth G.} and Sulin Cheng and {van Schoor}, {Natasja M.} and Harvey, {Nicholas C.} and Marcin Kruk and {Fabiola Del Greco}, M. and Wilmar Igl and Olivia Trummer and Efi Grigoriou and Robert Luben and Ching-Ti Liu and Yanhua Zhou and Ling Oei and Carolina Medina-Gomez and Joseph Zmuda and Greg Tranah and Brown, {Suzanne J.} and Williams, {Frances M.} and Nicole Soranzo and Johanna Jakobsdottir and Kristin Siggeirsdottir and Holliday, {Kate L.} and Anke Hannemann and Go, {Min Jin} and Melissa Garcia and Ozren Polasek and Marika Laaksonen and Kun Zhu and Enneman, {Anke W.} and Mark McEvoy and Roseanne Peel and Sham, {Pak Chung} and Maciej Jaworski and Asa Johansson and Hicks, {Andrew A.} and Pawel Pludowski and Rodney Scott and Dhonukshe-Rutten, {Rosalie A. M.} and {van der Velde}, Nathalie and Mika Kaehoenen and Viikari, {Jorma S.} and Harri Sievaenen and Raitakari, {Olli T.} and Jesus Gonzalez-Macias and Hernandez, {Jose L.} and Dan Mellstroem and Oesten Ljunggren and Cho, {Yoon Shin} and Uwe Voelker and Matthias Nauck and Georg Homuth and Henry Voelzke and Robin Haring and Brown, {Matthew A.} and Eugene McCloskey and Nicholson, {Geoffrey C.} and Richard Eastell and Eisman, {John A.} and Graeme Jones and Reid, {Ian R.} and Dennison, {Elaine M.} and John Wark and Steven Boonen and Dirk Vanderschueren and Wu, {Frederick C. W.} and Thor Aspelund and Richards, {J. Brent} and Doug Bauer and Albert Hofman and Kay-Tee Khaw and George Dedoussis and Barbara Obermayer-Pietsch and Ulf Gyllensten and Pramstaller, {Peter P.} and Lorenc, {Roman S.} and Cyrus Cooper and Kung, {Annie Wai Chee} and Paul Lips and Markku Alen and John Attia and {Luisa Brandi}, Maria and {de Groot}, {Lisette C. P. G. M.} and Terho Lehtimaeki and Riancho, {Jose A.} and Harry Campbell and Yongmei Liu and Harris, {Tamara B.} and Kristina {\AA}kesson and Magnus Karlsson and Jong-Young Lee and Henri Wallaschofski and Duncan, {Emma L.} and O'Neill, {Terence W.} and Vilmundur Gudnason and Spector, {Timothy D.} and Francois Rousseau and Eric Orwoll and Cummings, {Steven R.} and Wareham, {Nick J.} and Fernando Rivadeneira and Uitterlinden, {Andre G.} and Prince, {Richard L.} and Kiel, {Douglas P.} and Jonathan Reeve and Kaptoge, {Stephen K.}",

year = "2014",

doi = "10.1093/hmg/ddt675",

language = "English",

volume = "23",

pages = "3054--3068",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "11",

}

Moayyeri, A, Hsu, Y-H, Karasik, D, Estrada, K, Xiao, S-M, Nielson, C, Srikanth, P, Giroux, S, Wilson, SG, Zheng, H-F, Smith, AV, Pye, SR, Leo, PJ, Teumer, A, Hwang, J-Y, Ohlsson, C, McGuigan, F, Minster, RL, Hayward, C, Olmos, JM, Lyytikaeinen, L-P, Lewis, JR, Swart, KMA, Masi, L, Oldmeadow, C, Holliday, EG, Cheng, S, van Schoor, NM, Harvey, NC, Kruk, M, Fabiola Del Greco, M, Igl, W, Trummer, O, Grigoriou, E, Luben, R, Liu, C-T, Zhou, Y, Oei, L, Medina-Gomez, C, Zmuda, J, Tranah, G, Brown, SJ, Williams, FM, Soranzo, N, Jakobsdottir, J, Siggeirsdottir, K, Holliday, KL, Hannemann, A, Go, MJ, Garcia, M, Polasek, O, Laaksonen, M, Zhu, K, Enneman, AW, McEvoy, M, Peel, R, Sham, PC, Jaworski, M, Johansson, A, Hicks, AA, Pludowski, P, Scott, R, Dhonukshe-Rutten, RAM, van der Velde, N, Kaehoenen, M, Viikari, JS, Sievaenen, H, Raitakari, OT, Gonzalez-Macias, J, Hernandez, JL, Mellstroem, D, Ljunggren, O, Cho, YS, Voelker, U, Nauck, M, Homuth, G, Voelzke, H, Haring, R, Brown, MA, McCloskey, E, Nicholson, GC, Eastell, R, Eisman, JA, Jones, G, Reid, IR, Dennison, EM, Wark, J, Boonen, S, Vanderschueren, D, Wu, FCW, Aspelund, T, Richards, JB, Bauer, D, Hofman, A, Khaw, K-T, Dedoussis, G, Obermayer-Pietsch, B, Gyllensten, U, Pramstaller, PP, Lorenc, RS, Cooper, C, Kung, AWC, Lips, P, Alen, M, Attia, J, Luisa Brandi, M, de Groot, LCPGM, Lehtimaeki, T, Riancho, JA, Campbell, H, Liu, Y, Harris, TB, Åkesson, K , Karlsson, M, Lee, J-Y, Wallaschofski, H, Duncan, EL, O'Neill, TW, Gudnason, V, Spector, TD, Rousseau, F, Orwoll, E, Cummings, SR, Wareham, NJ, Rivadeneira, F, Uitterlinden, AG, Prince, RL, Kiel, DP, Reeve, J & Kaptoge, SK 2014, 'Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium', Human Molecular Genetics, vol. 23, no. 11, pp. 3054-3068. https://doi.org/10.1093/hmg/ddt675

TY - JOUR

T1 - Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

AU - Moayyeri, Alireza

AU - Hsu, Yi-Hsiang

AU - Karasik, David

AU - Estrada, Karol

AU - Xiao, Su-Mei

AU - Nielson, Carrie

AU - Srikanth, Priya

AU - Giroux, Sylvie

AU - Wilson, Scott G.

AU - Zheng, Hou-Feng

AU - Smith, Albert V.

AU - Pye, Stephen R.

AU - Leo, Paul J.

AU - Teumer, Alexander

AU - Hwang, Joo-Yeon

AU - Ohlsson, Claes

AU - McGuigan, Fiona

AU - Minster, Ryan L.

AU - Hayward, Caroline

AU - Olmos, Jose M.

AU - Lyytikaeinen, Leo-Pekka

AU - Lewis, Joshua R.

AU - Swart, Karin M. A.

AU - Masi, Laura

AU - Oldmeadow, Chris

AU - Holliday, Elizabeth G.

AU - Cheng, Sulin

AU - van Schoor, Natasja M.

AU - Harvey, Nicholas C.

AU - Kruk, Marcin

AU - Fabiola Del Greco, M.

AU - Igl, Wilmar

AU - Trummer, Olivia

AU - Grigoriou, Efi

AU - Luben, Robert

AU - Liu, Ching-Ti

AU - Zhou, Yanhua

AU - Oei, Ling

AU - Medina-Gomez, Carolina

AU - Zmuda, Joseph

AU - Tranah, Greg

AU - Brown, Suzanne J.

AU - Williams, Frances M.

AU - Soranzo, Nicole

AU - Jakobsdottir, Johanna

AU - Siggeirsdottir, Kristin

AU - Holliday, Kate L.

AU - Hannemann, Anke

AU - Go, Min Jin

AU - Garcia, Melissa

AU - Polasek, Ozren

AU - Laaksonen, Marika

AU - Zhu, Kun

AU - Enneman, Anke W.

AU - McEvoy, Mark

AU - Peel, Roseanne

AU - Sham, Pak Chung

AU - Jaworski, Maciej

AU - Johansson, Asa

AU - Hicks, Andrew A.

AU - Pludowski, Pawel

AU - Scott, Rodney

AU - Dhonukshe-Rutten, Rosalie A. M.

AU - van der Velde, Nathalie

AU - Kaehoenen, Mika

AU - Viikari, Jorma S.

AU - Sievaenen, Harri

AU - Raitakari, Olli T.

AU - Gonzalez-Macias, Jesus

AU - Hernandez, Jose L.

AU - Mellstroem, Dan

AU - Ljunggren, Oesten

AU - Cho, Yoon Shin

AU - Voelker, Uwe

AU - Nauck, Matthias

AU - Homuth, Georg

AU - Voelzke, Henry

AU - Haring, Robin

AU - Brown, Matthew A.

AU - McCloskey, Eugene

AU - Nicholson, Geoffrey C.

AU - Eastell, Richard

AU - Eisman, John A.

AU - Jones, Graeme

AU - Reid, Ian R.

AU - Dennison, Elaine M.

AU - Wark, John

AU - Boonen, Steven

AU - Vanderschueren, Dirk

AU - Wu, Frederick C. W.

AU - Aspelund, Thor

AU - Richards, J. Brent

AU - Bauer, Doug

AU - Hofman, Albert

AU - Khaw, Kay-Tee

AU - Dedoussis, George

AU - Obermayer-Pietsch, Barbara

AU - Gyllensten, Ulf

AU - Pramstaller, Peter P.

AU - Lorenc, Roman S.

AU - Cooper, Cyrus

AU - Kung, Annie Wai Chee

AU - Lips, Paul

AU - Alen, Markku

AU - Attia, John

AU - Luisa Brandi, Maria

AU - de Groot, Lisette C. P. G. M.

AU - Lehtimaeki, Terho

AU - Riancho, Jose A.

AU - Campbell, Harry

AU - Liu, Yongmei

AU - Harris, Tamara B.

AU - Åkesson, Kristina

AU - Karlsson, Magnus

AU - Lee, Jong-Young

AU - Wallaschofski, Henri

AU - Duncan, Emma L.

AU - O'Neill, Terence W.

AU - Gudnason, Vilmundur

AU - Spector, Timothy D.

AU - Rousseau, Francois

AU - Orwoll, Eric

AU - Cummings, Steven R.

AU - Wareham, Nick J.

AU - Rivadeneira, Fernando

AU - Uitterlinden, Andre G.

AU - Prince, Richard L.

AU - Kiel, Douglas P.

AU - Reeve, Jonathan

AU - Kaptoge, Stephen K.

PY - 2014

Y1 - 2014

N2 - Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

AB - Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

U2 - 10.1093/hmg/ddt675

DO - 10.1093/hmg/ddt675

M3 - Article

SN - 0964-6906

VL - 23

SP - 3054

EP - 3068

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 11

ER -

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

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