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Genetic determinants of heel bone properties: Genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
journal contribution
posted on 2023-05-18, 06:50 authored by 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, Lyytikainen, LP, Lewis, JR, Swart, KMA, Masi, L, Oldmeadow, C, Holliday, EG, Cheng, S, Van Schoor, NM, Harvey, NC, Kruk, M, Del Greco, FM, 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, Pee, R, Sham, PC, Jaworski, M, Johansson, A, Hicks, AA, Pludowski, P, Scott, R, Dhonukshe-Rutten, RAM, Van Der Velde, NV, Kaohonen, M, Viikari, JS, Sievaonen, H, Raitakari, OT, Gonzalez-Macias, J, Hernandez, JL, Mellstrom, D, Ljunggren, O, Cho, Y-S, Volker, U, Nauck, M, Homuth, G, Volzke, H, Haring, R, Brown, MA, McCloskey, E, Nicholson, GC, Eastell, R, Eisman, JA, Graeme JonesGraeme Jones, 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, Lehtimaki, T, Riancho, JA, Campbell, H, Liu, Y, Harris, TB, Akesson, K, Karlsson, M, Jong-Lee, 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, SKQuantitative 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 5 14 260), velocity of sound (VOS; n 5 15 514) and BMD (n 5 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n 5 11 452) and new genotyping in 15 cohorts (de novo n 5 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 3 108) 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 3 1014). 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 3 106 also had the expected direction of association with any fracture (P < 0.05), including threeSNPswithP < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, thisGWAstudy reveals the effect of several genescommon to central DXA-derivedBMDand heel ultrasound/DXAmeasures and points to anewgenetic locus with potential implications for better understanding of osteoporosis pathophysiology.
History
Publication title
Human Molecular GeneticsVolume
23Issue
11Pagination
3054-3068ISSN
0964-6906Department/School
Menzies Institute for Medical ResearchPublisher
Oxford Univ PressPlace of publication
Great Clarendon St, Oxford, England, Ox2 6DpRights statement
Copyright 2014 The AuthorRepository Status
- Restricted
