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

A Moayyeri, YH Hsu, D Karasik, Karol Estrada Gil, SM Xiao, C Nielson, P Srikanth, S Giroux, SG Wilson, HF Zheng, AV Smith, SR Pye, PJ Leo, A Teumer, JY Hwang, C Ohlsson, F McGuigan, RL Minster, C Hayward, JM OlmosLP Lyytikainen, JR Lewis, KMA Swart, L Masi, C Oldmeadow, EG Holliday, SL Cheng, NM Schoor, NC Harvey, M van der Kruk, M Greco, W Igl, O Trummer, E Grigoriou, R Luben, CT Liu, YH Zhou, Ling Oei - Oei, C Medina-Gomez, J Zmuda, G Tranah, SJ Brown, FM Williams, N Soranzo, J Jakobsdottir, K Siggeirsdottir, KL Holliday, A Hannemann, MJ Go, M Garcia, O Polasek, M Laaksonen, K Zhu, Anke Enneman, M McEvoy, R Peel, PC Sham, M Jaworski, A Johansson, AA Hicks, P Pludowski, R Scott, RAM Dhonukshe-Rutten, Nathalie van der Velde, M Kahonen, JS Viikari, H Sievanen, OT Raitakari, J Gonzalez-Macias, JL Hernandez, D Mellstroom, O Ljunggren, YS Cho, U Volker, M Nauck, G Homuth, H Volzke, R Haring, MA Brown, E McCloskey, GC Nicholson, R Eastell, JA Eisman, G Jones, IR Reid, EM Dennison, J Wark, S Boonen, D Vanderschueren, FCW Wu, T Aspelund, JB Richards, D Bauer, Bert Hofman, KT Khaw, G Dedoussis, B Obermayer-Pietsch, U Gyllensten, PP Pramstaller, RS Lorenc, C Cooper, AWC Kung, P Lips, M Alen, J Attia, ML Brandi, LCPGM (Lisette) de Groot, T Lehtimaki, JA Riancho, H Campbell, YM Liu, TB Harris, K Akesson, M Karlsson, JY Lee, H Wallaschofski, EL Duncan, TW O'Neill, V Gudnason, TD Spector, F Rousseau, E Orwoll, SR Cummings, NJ Wareham, Fernando Rivadeneira, André Uitterlinden, RL Prince, DP Kiel, J Reeve, SK Kaptoge

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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 x 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 x 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 x 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.
Original languageUndefined/Unknown
Pages (from-to)3054-3068
Number of pages15
JournalHuman Molecular Genetics
Volume23
Issue number11
DOIs
Publication statusPublished - 2014

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