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

Citation

Moayyeri, A and Hsu, Y-H and Karasik, D and Estrada, K and Xiao, S-M and Nielson, C and Srikanth, P and Giroux, S and Wilson, SG and Zheng, H-F and Smith, AV and Pye, SR and Leo, PJ and Teumer, A and Hwang, J-Y and Ohlsson, C and McGuigan, F and Minster, RL and Hayward, C and Olmos, JM and Lyytikainen, LP and Lewis, JR and Swart, KMA and Masi, L and Oldmeadow, C and Holliday, EG and Cheng, S and Van Schoor, NM and Harvey, NC and Kruk, M and Del Greco, FM and Igl, W and Trummer, O and Grigoriou, E and Luben, R and Liu, C-T and Zhou, Y and Oei, L and Medina-Gomez, C and Zmuda, J and Tranah, G and Brown, SJ and Williams, FM and Soranzo, N and Jakobsdottir, J and Siggeirsdottir, K and Holliday, KL and Hannemann, A and Go, MJ and Garcia, M and Polasek, O and Laaksonen, M and Zhu, K and Enneman, AW and McEvoy, M and Pee, R and Sham, PC and Jaworski, M and Johansson, A and Hicks, AA and Pludowski, P and Scott, R and Dhonukshe-Rutten, RAM and Van Der Velde, NV and Kaohonen, M and Viikari, JS and Sievaonen, H and Raitakari, OT and Gonzalez-Macias, J and Hernandez, JL and Mellstrom, D and Ljunggren, O and Cho, Y-S and Volker, U and Nauck, M and Homuth, G and Volzke, H and Haring, R and Brown, MA and McCloskey, E and Nicholson, GC and Eastell, R and Eisman, JA and Jones, G and Reid, IR and Dennison, EM and Wark, J and Boonen, S and Vanderschueren, D and Wu, FCW and Aspelund, T and Richards, JB and Bauer, D and Hofman, A and Khaw, K-T and Dedoussis, G and Obermayer-Pietsch, B and Gyllensten, U and Pramstaller, PP and Lorenc, RS and Cooper, C and Kung, AWC and Lips, P and Alen, M and Attia, J and Brandi, ML and de Groot, LCPGM and Lehtimaki, T and Riancho, JA and Campbell, H and Liu, Y and Harris, TB and Akesson, K and Karlsson, M and Jong-Lee, Y and Wallaschofski, H and Duncan, EL and O'Neill, TW and Gudnason, V and Spector, TD and Rousseau, F and Orwoll, E and Cummings, SR and Wareham, NJ and Rivadeneira, F and Uitterlinden, AG and Prince, RL and Kiel, DP and Reeve, J and Kaptoge, SK, 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. ISSN 0964-6906 (2014) [Refereed Article]

Copyright Statement

Copyright 2014 The Author

DOI: doi:10.1093/hmg/ddt675

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 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.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Clinical Sciences
Research Field:Rheumatology and Arthritis
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Skeletal System and Disorders (incl. Arthritis)
Author:Jones, G (Professor Graeme Jones)
ID Code:98015
Year Published:2014
Web of Science® Times Cited:31
Deposited By:Menzies Institute for Medical Research
Deposited On:2015-01-28
Last Modified:2015-04-21
Downloads:0

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