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;L. Lyytikäinen;J. R. Lewis;K. M. A;L. Masi;C. Oldmeadow;E. G. Holliday;S. Cheng;N. M. van;N. C. Harvey;M. Kruk;F. D. Greco;W. Igl;O. Trummer;E. Grigoriou;R. Luben;C. Liu;Y. Zhou;L. Oei;C. Medina-Gomez;J. Zmuda;G. Tranah;S. J. Brown;F. M. Williams;N. Soranzo;J. Jakobsdottir;K. Siggeirsdottir;K. L. Holliday;A. Hannemann;M. J. Go;M. Garcia;O. Polasek;M. Laaksonen;K. Zhu;A. W. Enneman;M. McEvoy;R. Peel;P. C. Sham;M. Jaworski;A. Johansson;A. A. Hicks;P. Pludowski;R. Scott;R. A. M;N. v. der;M. Kähönen;J. S. Viikari;H. Sievänen;O. T. Raitakari;J. González-Macías;J. L. Hernández;D. Mellström;O. Ljunggren;Y. S. Cho;U. Völker;M. Nauck;G. Homuth;H. Völzke;R. Haring;M. A. Brown;E. McCloskey;G. C. Nicholson;R. Eastell;J. A. Eisman;G. Jones;I. R. Reid;E. M. Dennison;J. Wark;S. Boonen;D. Vanderschueren;F. C. W;T. Aspelund;J. B. Richards;D. Bauer;A. Hofman;K. Khaw;G. Dedoussis;B. Obermayer-Pietsch;U. Gyllensten;P. P. Pramstaller;R. S. Lorenc;C. Cooper;A. W. Chee;P. Lips;M. Alen;J. Attia;M. L. Brandi;L. C. P;T. Lehtimäki;J. A. Riancho;H. Campbell;Y. Liu;T. B. Harris;K. Akesson;M. Karlsson;J. Lee;H. Wallaschofski;E. L. Duncan;T. W. O'Neill;V. Gudnason;T. D. Spector;F. Rousseau;E. Orwoll;S. R. Cummings;N. J. Wareham;F. Rivadeneira;A. G. Uitterlinden;R. L. Prince;D. P. Kiel;J. Reeve;S. K. Kaptoge. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - ELETTRONICO. - 23:(2014), pp. 3054-3068. [10.1093/hmg/ddt675]