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

Moayyeri, A., Hsu, Y.H., Karasik, D., Estrada, K., Xiao, S.M., Nielson, C., Srikanth, P., Giroux, S., Wilson, S.G., Zheng, H.F., Smith, A.V., Pye, S.R., Leo, P.J., Teumer, A., Hwang, J.Y., Ohlsson, C., McGuigan, F., Minster, R.L., Hayward, C., Olmos, J.M., Lyytikäinen, L.P., Lewis, J.R., Swart, K.M.A., Masi, L., Oldmeadow, C., Holliday, E.G., Cheng, S., Van Schoor, N.M., Harvey, N.C., Kruk, M., Del Greco, F.M., Igl, W., Trummer, O., Grigoriou, E., Luben, R., Liu, C.T., 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., Go, M.J., Garcia, M., Polasek, O., Laaksonen, M., Zhu, K., Enneman, A.W., McEvoy, M., Pee, R., Sham, P.C., Jaworski, M., Johansson, A., Hicks, A.A., Pludowski, P., Scott, R., Dhonukshe-Rutten, R.A.M., van Der Velde, N.V., Kaöhönen, M., Viikari, J.S., Sievaönen, 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., Wu, F.C.W., Aspelund, T., Richards, J.B., Bauer, D., Hofman, A., Khaw, K.T., Dedoussis, G., Obermayer-Pietsch, B., Gyllensten, U., Pramstaller, P.P., Lorenc, R.S., Cooper, C., Kung, A.W.C., Lips, P., Alen, M., Attia, J., Brandi, M.L., de Groot, L.C.P.G.M., Lehtimäki, T., Riancho, J.A., Campbell, H., Liu, Y., Harris, T.B., Akesson, K., Karlsson, M., Jong-Lee, Y., 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. (2014) Genetic determinants of heel bone properties: Genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium. Human Molecular Genetics, 23(11), pp. 3054-3068.

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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 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.

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ID Code: 89071
Item Type: Journal Article
Refereed: Yes
Keywords: article, bone density, calcaneus fracture, chromosome 11q, computer model, dual energy X ray absorptiometry, echography, genetic association, genetic epidemiology, genetic susceptibility, genotype, human, osteoporosis, pathophysiology, priority journal, risk assessment, single nucleotide polymorphism, adult, aged, calcaneus, cohort analysis, female, fracture, genetic predisposition, genetics, male, meta analysis, metabolism, middle aged, physiology, very elderly, young adult, Aged, 80 and over, Cohort Studies, Fractures, Bone, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide
DOI: 10.1093/hmg/ddt675
ISSN: 0964-6906
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 15 Oct 2015 04:22
Last Modified: 26 Jun 2017 00:01

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