Genetic determinants of heel bone properties: Genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
Journal article
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, ... 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), pp. 3054 - 3068. https://doi.org/10.1093/hmg/ddt675
Authors | 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, Nicholas 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, T. Raitakari, Olli, González-Macías, Jesús, Hernández, Jose L., Mellström, Dan, Ljunggren, Östen, 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, Elaine 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. |
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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 × 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. |
Keywords | osteoporosis diagnostic radiologic examination roentgen rays ultrasonography bone mineral density fractures calcaneus chromosomes genes genome heel longevity single nucleotide polymorphism sound genetics chromosome 7q31 genotype determination genome-wide association study attenuation osteoporotic fracture risk |
Year | 2014 |
Journal | Human Molecular Genetics |
Journal citation | 23 (11), pp. 3054 - 3068 |
Publisher | Oxford University Press |
ISSN | 0964-6906 |
Digital Object Identifier (DOI) | https://doi.org/10.1093/hmg/ddt675 |
Scopus EID | 2-s2.0-84893613998 |
Page range | 3054 - 3068 |
Research Group | Institute for Health and Ageing |
Publisher's version | File Access Level Controlled |
Place of publication | United Kingdom |
https://acuresearchbank.acu.edu.au/item/8651x/genetic-determinants-of-heel-bone-properties-genome-wide-association-meta-analysis-and-replication-in-the-gefos-genomos-consortium
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