Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.
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.
Moayyeri, A; Hsu, Y-H; Karasik, D; Estrada, K; Xiao, S-M; Nielson, C; Srikanth, P; Giroux, S; Wilson, SG; Zheng, H-F; Smith, AV; Pye, SR; Leo, PJ; Teumer, A; Hwang, J-Y; Ohlsson, C; McGuigan, F; Minster, RL; Hayward, C; Olmos, JM; Lyytikäinen, L-P; Lewis, JR; Swart, KMA; Masi, L; Oldmeadow, C; Holliday, EG; Cheng, S; van Schoor, NM; Harvey, NC; Kruk, M; del Greco M, F; Igl, W; Trummer, O; Grigoriou, E; Luben, R; Liu, C-T; Zhou, Y; Oei, L; Medina-Gomez, C; Zmuda, J; Tranah, G; Brown, SJ; Williams, FM; Soranzo, N; Jakobsdottir, J; Siggeirsdottir, K; Holliday, KL; Hannemann, A; Go, MJ; Garcia, M; Polasek, O; Laaksonen, M; Zhu, K; Enneman, AW; McEvoy, M; Peel, R; Sham, PC; Jaworski, M; Johansson, Å; Hicks, AA; Pludowski, P; Scott, R; Dhonukshe-Rutten, RAM; van der Velde, N; Kähönen, M; Viikari, JS; Sievänen, H; Raitakari, OT; González-Macías, J; Hernández, JL; Mellström, D; Ljunggren, O; Cho, YS; Völker, U; Nauck, M; Homuth, G; Völzke, H; Haring, R; Brown, MA; McCloskey, E; Nicholson, GC; Eastell, R; Eisman, JA; Jones, G; Reid, IR; Dennison, EM; Wark, J; Boonen, S; Vanderschueren, D; Wu, FCW; Aspelund, T; Richards, JB; Bauer, D; Hofman, A; Khaw, K-T; Dedoussis, G; Obermayer-Pietsch, B; Gyllensten, U; Pramstaller, PP; Lorenc, RS; Cooper, C; Kung, AWC; Lips, P; Alen, M; Attia, J; Brandi, ML; de Groot, LCPGM; Lehtimäki, T; Riancho, JA; Campbell, H; Liu, Y; Harris, TB; Akesson, K; Karlsson, M; Lee, J-Y; Wallaschofski, H; Duncan, EL; O'Neill, TW; Gudnason, V; Spector, TD; Rousseau, F; Orwoll, E; Cummings, SR; Wareham, NJ; Rivadeneira, F; Uitterlinden, AG; Prince, RL; Kiel, DP; Reeve, J; Kaptoge, SK
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