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, José M. OlmosLeo Pekka Lyytikäinen, 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, Fabiola M. 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 Pee, Pak Chung Sham, Maciej Jaworski, Asa Johansson, Andrew A. Hicks, Pawel Pludowski, Rodney Scott, Rosalie A.M. Dhonukshe-Rutten, Nathalie V. van Der Velde, Mika Kaöhönen, Jorma S. Viikari, Harri Sievaönen, Olli T. Raitakari, Jesús González-Macías, Jose L. Hernández, Dan Mellström, Östen Ljunggren, Yoon Shin Cho, Uwe Völker, Matthias Nauck, Georg Homuth, Henry Völzke, 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 Lehtimäki, José A. Riancho, Harry Campbell, Yongmei Liu, Tamara B. Harris, Kristina Akesson, Magnus Karlsson, Young Jong-Lee, Henri Wallaschofski, Emma L. Duncan, Terence W. O'Neill, Vilmundur Gudnason, Timothy D. Spector, François 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

Research output: Contribution to journalArticle

59 Scopus citations

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 5 14 260), velocity of sound (VOS; n 5 15 514) and BMD (n 5 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n 5 11 452) and new genotyping in 15 cohorts (de novo n 5 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 3 108) 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 3 1014). 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 3 106 also had the expected direction of association with any fracture (P < 0.05), including threeSNPswithP < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, thisGWAstudy reveals the effect of several genescommon to central DXA-derivedBMDand heel ultrasound/DXAmeasures and points to anewgenetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Original languageEnglish (US)
Article numberddt675
Pages (from-to)3054-3068
Number of pages15
JournalHuman molecular genetics
Volume23
Issue number11
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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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. [ddt675]. https://doi.org/10.1093/hmg/ddt675