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

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24430505
10.1093/hmg/ddt675
PMC4038791
Human molecular genetics
June 1, 2014
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Young Adult, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Ultrasonography, Male, Adult, Fractures, Bone, Middle Aged, Humans, Female, Bone Density, Cohort Studies, Aged, Osteoporosis, Aged, 80 and over, Calcaneus
G1000143, MR/L003120/1, MC_UU_12015/1, MC_U106179471, MR/K006312/1, G0401527, G0701863, MC_PC_U127561128, MC_UU_12011/1, G0400491, K01 AR062655, MC_UP_A620_1014, RG/08/014/24067, U01 AR066160, R01 AG005407
Xiao SM, Hwang JY, McGuigan F, Minster RL, Masi L, Oldmeadow C, Holliday EG, Kruk M, del Greco M F, Igl W, Trummer O, Grigoriou E, Brown SJ, Holliday KL, Go MJ, Laaksonen M, McEvoy M, Peel R, Sham PC, Jaworski M, Johansson Å, Pludowski P, Sievänen H, González-Macías J, Hernández JL, Cho YS, Nauck M, Nicholson GC, Jones G, Dennison EM, Wark J, Dedoussis G, Obermayer-Pietsch B, Gyllensten U, Lorenc RS, Kung AW, Lips P, Alen M, Attia J, Brandi ML, Kaptoge SK, Williams FM, Harvey NC, McCloskey E, Zhu K, Scott R, Akesson K, Luben R, Garcia M, Hannemann A, Homuth G, Jakobsdottir J, Völker U, Hicks AA, Pramstaller PP, Polasek O, Lyytikäinen LP, Swart KM, Dhonukshe-Rutten RA, Viikari JS, Raitakari OT, Haring R, Lee JY, Wareham NJ, Medina-Gomez C, Wallaschofski H, Campbell H, Hayward C, Kähönen M, Lehtimäki T, Teumer A, Liu Y, Moayyeri A, Giroux S, Leo PJ, Olmos JM, Brown MA, Duncan EL, Rousseau F, Wilson SG, Zheng HF, Estrada K, Lewis JR, Soranzo N, Prince RL, Zhou Y, Oei L, Liu CT, Siggeirsdottir K, Hsu YH, van der Velde N, de Groot LC, Richards JB, van Schoor NM, Enneman AW, Völzke H, Khaw KT, Aspelund T, Smith AV, Karasik D, Gudnason V, Srikanth P, Kiel DP, Pye SR, Boonen S, Vanderschueren D, Wu FC, O'Neill TW, Nielson C, Riancho JA, Karlsson M, Rivadeneira F, Tranah G, Hofman A, Spector TD, Uitterlinden AG, Ohlsson C, Mellström D, Ljunggren O, Reeve J, Harris TB, Eastell R, Cheng S, Reid IR, Orwoll E, Eisman JA, Bauer D, Cooper C, Zmuda J, Cummings SR
Moayyeri A, Hsu YH, Karasik D, Estrada K, Xiao SM, Nielson C, Srikanth P, Giroux S, Wilson SG, Zheng HF, Smith AV, Pye SR, Leo PJ, Teumer A, Hwang JY, Ohlsson C, McGuigan F, Minster RL, Hayward C, Olmos JM, Lyytikäinen LP, Lewis JR, Swart KM, 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 CT, 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 RA, 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 FC, Aspelund T, Richards JB, Bauer D, Hofman A, Khaw KT, Dedoussis G, Obermayer-Pietsch B, Gyllensten U, Pramstaller PP, Lorenc RS, Cooper C, Kung AW, Lips P, Alen M, Attia J, Brandi ML, de Groot LC, Lehtimäki T, Riancho JA, Campbell H, Liu Y, Harris TB, Akesson K, Karlsson M, Lee JY, 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. Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium. Human molecular genetics 2014 Jun 1.

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 × 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.