The University of Southampton
University of Southampton Institutional Repository

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

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
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 × 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 × 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 × 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.
3054-3068
Moayyeri, Alireza
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Hsu, Yi-Hsiang
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Mellström, Dan
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Eastell, Richard
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de Groot, Lisette C.P.G.M.
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Lehtimäki, Terho
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van der Velde, Nathalie
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Mellström, Dan
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Ljunggren, Osten
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Cho, Yoon Shin
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Wark, John
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Boonen, Steven
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Vanderschueren, Dirk
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Wu, Frederick C.W.
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Aspelund, Thor
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Richards, J.Brent
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Bauer, Doug
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Hofman, Albert
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Khaw, Kay-Tee
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Dedoussis, George
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Obermayer-Pietsch, Barbara
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Gyllensten, Ulf
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Pramstaller, Peter P.
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Lorenc, Roman S.
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Cooper, Cyrus
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Kung, Annie Wai Chee
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Lips, Paul
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Alen, Markku
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Attia, John
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Brandi, Maria Luisa
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de Groot, Lisette C.P.G.M.
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Lehtimäki, Terho
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Riancho, José A.
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Campbell, Harry
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Liu, Yongmei
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Harris, Tamara B.
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Akesson, Kristina
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Karlsson, Magnus
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Lee, Jong-Young
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Wallaschofski, Henri
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Duncan, Emma L.
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O'Neill, Terence W.
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Gudnason, Vilmundur
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Orwoll, Eric
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Prince, Richard L.
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Kiel, Douglas P.
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Reeve, Jonathan
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Kaptoge, Stephen K.
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Moayyeri, Alireza, Hsu, Yi-Hsiang, Karasik, David, Estrada, Karol, Xiao, Su-Mei, Nielson, Carrie, Srikanth, Priya, Giroux, Sylvie, Wilson, Scott G., Zheng, Hou-Feng, Smith, Albert V., Pye, Stephen R., Leo, Paul J., Teumer, Alexander, Hwang, Joo-Yeon, Ohlsson, Claes, McGuigan, Fiona, Minster, Ryan L., Hayward, Caroline, Olmos, José M., Lyytikäinen, Leo-Pekka, Lewis, Joshua R., Swart, Karin M.A., Masi, Laura, Oldmeadow, Chris, Holliday, Elizabeth G., Cheng, Sulin, van Schoor, Natasja M., Harvey, N.C., Kruk, Marcin, del Greco M, Fabiola, Igl, Wilmar, Trummer, Olivia, Grigoriou, Efi, Luben, Robert, Liu, Ching-Ti, Zhou, Yanhua, Oei, Ling, Medina-Gomez, Carolina, Zmuda, Joseph, Tranah, Greg, Brown, Suzanne J., Williams, Frances M, Soranzo, Nicole, Jakobsdottir, Johanna, Siggeirsdottir, Kristin, Holliday, Kate L., Hannemann, Anke, Go, Min Jin, Garcia, Melissa, Polasek, Ozren, Laaksonen, Marika, Zhu, Kun, Enneman, Anke W., McEvoy, Mark, Peel, Roseanne, Sham, Pak Chung, Jaworski, Maciej, Johansson, Åsa, Hicks, Andrew A., Pludowski, Pawel, Scott, Rodney, Dhonukshe-Rutten, Rosalie A.M., van der Velde, Nathalie, Kähönen, Mika, Viikari, Jorma S., Sievänen, Harri, Raitakari, Olli T., González-Macías, Jesús, Hernández, Jose L., Mellström, Dan, Ljunggren, Osten, Cho, Yoon Shin, Völker, Uwe, Nauck, Matthias, Homuth, Georg, Völzke, Henry, Haring, Robin, Brown, Matthew A., McCloskey, Eugene, Nicholson, Geoffrey C., Eastell, Richard, Eisman, John A., Jones, Graeme, Reid, Ian R., Dennison, E.M., Wark, John, Boonen, Steven, Vanderschueren, Dirk, Wu, Frederick C.W., Aspelund, Thor, Richards, J.Brent, Bauer, Doug, Hofman, Albert, Khaw, Kay-Tee, Dedoussis, George, Obermayer-Pietsch, Barbara, Gyllensten, Ulf, Pramstaller, Peter P., Lorenc, Roman S., Cooper, Cyrus, Kung, Annie Wai Chee, Lips, Paul, Alen, Markku, Attia, John, Brandi, Maria Luisa, de Groot, Lisette C.P.G.M., Lehtimäki, Terho, Riancho, José A., Campbell, Harry, Liu, Yongmei, Harris, Tamara B., Akesson, Kristina, Karlsson, Magnus, Lee, Jong-Young, Wallaschofski, Henri, Duncan, Emma L., O'Neill, Terence W., Gudnason, Vilmundur, Spector, Timothy D., Rousseau, François, Orwoll, Eric, Cummings, Steven R., Wareham, Nick J., Rivadeneira, Fernando, Uitterlinden, Andre G., Prince, Richard L., Kiel, Douglas P., Reeve, Jonathan and Kaptoge, Stephen 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. (doi:10.1093/hmg/ddt675). (PMID:24430505)

Record type: Article

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 × 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 × 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 × 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.

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Published date: 1 June 2014
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 366475
URI: http://eprints.soton.ac.uk/id/eprint/366475
PURE UUID: 0117cb22-ac3d-4fee-bcd3-5dfe94851354
ORCID for N.C. Harvey: ORCID iD orcid.org/0000-0002-8194-2512
ORCID for E.M. Dennison: ORCID iD orcid.org/0000-0002-3048-4961
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709

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Date deposited: 01 Jul 2014 11:21
Last modified: 18 Feb 2021 17:02

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Contributors

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

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