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

Moayyeri, A.; Hsu, Y.; Karasik, D.; Estrada, K.; Xiao, S.; Nielson, C.; Srikanth, P.; Giroux, S.; Wilson, S. G.; Zheng, H.; Smith, A. V.; Pye, S. R.; Leo, P. J.; Teumer, A.; Hwang, J.; Ohlsson, C.; Mcguigan, F.; Minster, R. L.; Hayward, C.; Olmos, J. M.; Lyytikäinen, L.; Lewis, J. R.; K. M. A.,; Masi, L.; Oldmeadow, C.; Holliday, E. G.; Cheng, S.; Van, N. M.; Harvey, N. C.; Kruk, M.; Greco, F. D.; Igl, W.; Trummer, O.; Grigoriou, E.; Luben, R.; Liu, C.; Zhou, Y.; Oei, L.; Medina Gomez, C.; Zmuda, J.; Tranah, G.; Brown, S. J.; Williams, F. M.; Soranzo, N.; Jakobsdottir, J.; Siggeirsdottir, K.; Holliday, K. L.; Hannemann, A.; M. J., Go; Garcia, M.; Polasek, O.; Laaksonen, M.; Zhu, K.; Enneman, A. W.; Mcevoy, M.; Peel, R.; Sham, P. C.; Jaworski, M.; Johansson, A.; Hicks, A. A.; Pludowski, P.; Scott, R.; R. A. M.,; Der, N. V.; Kähönen, M.; Viikari, J. S.; Sievänen, H.; Raitakari, O. T.; González Macías, J.; Hernández, J. L.; Mellström, D.; Ljunggren, O.; Cho, Y. S.; Völker, U.; Nauck, M.; Homuth, G.; Völzke, H.; Haring, R.; Brown, M. A.; Mccloskey, E.; Nicholson, G. C.; Eastell, R.; Eisman, J. A.; Jones, G.; Reid, I. R.; Dennison, E. M.; Wark, J.; Boonen, S.; Vanderschueren, D.; F. C. W.,; Aspelund, T.; Richards, J. B.; Bauer, D.; Hofman, A.; Khaw, K.; Dedoussis, G.; Obermayer Pietsch, B.; Gyllensten, U.; Pramstaller, P. P.; Lorenc, R. S.; Cooper, C.; Chee, A. W.; Lips, P.; Alen, M.; Attia, J.; Brandi, Maria Luisa; L. C. P.,; Lehtimäki, T.; Riancho, J. A.; Campbell, H.; Liu, Y.; Harris, T. B.; Akesson, K.; Karlsson, M.; Lee, J.; Wallaschofski, H.; Duncan, E. L.; O'Neill, T. W.; Gudnason, V.; Spector, T. D.; Rousseau, F.; Orwoll, E.; Cummings, S. R.; Wareham, N. J.; Rivadeneira, F.; Uitterlinden, A. G.; Prince, R. L.; Kiel, D. P.; Reeve, J.; Kaptoge, S. K.

doi:10.1093/hmg/ddt675

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.

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium / A. Moayyeri, Y. Hsu, D. Karasik, K. Estrada, S. Xiao, C. Nielson, P. Srikanth, S. Giroux, S. G. Wilson, H. Zheng, A. V. Smith, S. R. Pye, P. J. Leo, A. Teumer, J. Hwang, C. Ohlsson, F. McGuigan, R. L. Minster, C. Hayward, J. M. Olmos, et al.. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - ELETTRONICO. - 23:(2014), pp. 3054-3068. [10.1093/hmg/ddt675]