- Title
- Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
- Creator
- Moayyeri, Alireza; Hsu, Yi-Hsiang; Smith, Albert V.; Cooper, Cyrus; Kung, Annie Wai Chee; Lips, Paul; Alen, Markku; Attia, John; Luisa Brandi, Maria; de Groot, Lisette C. P. G. M.; Lehtimäeki, Terho; Riancho, José A.; Campbell, Harry; Pye, Stephen R.; 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.; Leo, Paul J.; Rousseau, François; Orwoll, Eric; Cummings, Steven R.; Wareham, Nick J.; Rivadeneira, Fernando; Uitterlinden, Andre G.; Prince, Richard L.; Kiel, Douglas P.; Reeve, Jonathan; Kaptoge, Stephen K.; Teumer, Alexander; Hwang, Joo-Yeon; Ohlsson, Claes; McGuigan, Fiona; Minster, Ryan L.; Hayward, Caroline; Olmos, José M.; Karasik, David; Lyytikäeinen, 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; Estrada, Karol; del Greco M, Fabiola; Igl, Wilmar; Trummer, Olivia; Grigoriou, Efi; Luben, Robert; Liu, Ching-Ti; Zhou, Yanhua; Oei, Ling; Medina-Gomez, Carolina; Zmuda, Joseph; Xiao, Su-Mei; Tranah, Greg; Brown, Suzanne J.; Williams, Frances M.; Soranzo, Nicole; Jakobsdottir, Jphanna; Siggeirsdottir, Kristin; Holliday, Kate L.; Hannemann, Anke; Go, Min Jin; Garcia, Melissa; Nielson, Carrie; Polasek, Ozren; Laaksonen, Marika; Zhu, Kun; Enneman, Anke W.; McEvoy, Mark; Peel, Roseanne; Sham, Pak Chung; Jaworski, Maciej; Johansson, Åsa; Hicks, Andrew A.; Srikanth, Priya; Pludowski, Pawel; Scott, Rodney; Dhonukshe-Rutten, Rosalie A. M.; van der Velde, Nathalie; Käehöenen, Mika; Viikari, Jorma S.; Sieväenen, Harri; Raitakari, Olli T.; González-Macías, Jesús; Hernández, Jose L.; Giroux, Sylvie; Mellströem, Dan; Ljunggren, Östen; Cho, Yoon Shin; Vöelker, Uwe; Nauck, Matthias; Homuth, Georg; Vöelzke, Henry; Haring, Robin; Brown, Matthew A.; McCloskey, Eugene; Wilson, Scott G.; 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.; Zheng, Hou-Feng; 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.
- Relation
- Human Molecular Genetics Vol. 23, Issue 11, p. 3054-3068
- Publisher Link
- http://dx.doi.org/10.1093/hmg/ddt675
- Publisher
- Oxford University Press
- Resource Type
- journal article
- Date
- 2014
- Description
- 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.
- Subject
- GEFOS/GENOMOS consortium; genetic determinants; heel bone properties; bone mineral density (BMD)
- Identifier
- http://hdl.handle.net/1959.13/1302575
- Identifier
- uon:20501
- Identifier
- ISSN:0964-6906
- Language
- eng
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