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Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.
- Moayyeri, Alireza;
- Hsu, Yi-Hsiang;
- Karasik, David;
- Estrada, Karol;
- Xiao, Su-Mei;
- Nielson, Carrie;
- Srikanth, Priya;
- Giroux, Sylvie;
- Wilson, Scott G;
- Zheng, Hou-Feng;
- Smith, Albert V;
- Pye, Stephen R;
- Leo, Paul J;
- Teumer, Alexander;
- Hwang, Joo-Yeon;
- Ohlsson, Claes;
- McGuigan, Fiona;
- Minster, Ryan L;
- Hayward, Caroline;
- Olmos, José M;
- Lyytikäinen, Leo-Pekka;
- Lewis, Joshua R;
- Swart, Karin MA;
- Masi, Laura;
- Oldmeadow, Chris;
- Holliday, Elizabeth G;
- Cheng, Sulin;
- van Schoor, Natasja M;
- Harvey, Nicholas C;
- Kruk, Marcin;
- del Greco M, Fabiola;
- Igl, Wilmar;
- Trummer, Olivia;
- Grigoriou, Efi;
- Luben, Robert;
- Liu, Ching-Ti;
- Zhou, Yanhua;
- Oei, Ling;
- Medina-Gomez, Carolina;
- Zmuda, Joseph;
- Tranah, Greg;
- Brown, Suzanne J;
- Williams, Frances M;
- Soranzo, Nicole;
- Jakobsdottir, Johanna;
- Siggeirsdottir, Kristin;
- Holliday, Kate L;
- Hannemann, Anke;
- Go, Min Jin;
- Garcia, Melissa;
- Polasek, Ozren;
- Laaksonen, Marika;
- Zhu, Kun;
- Enneman, Anke W;
- McEvoy, Mark;
- Peel, Roseanne;
- Sham, Pak Chung;
- Jaworski, Maciej;
- Johansson, Åsa;
- Hicks, Andrew A;
- Pludowski, Pawel;
- Scott, Rodney;
- Dhonukshe-Rutten, Rosalie AM;
- van der Velde, Nathalie;
- Kähönen, Mika;
- Viikari, Jorma S;
- Sievänen, Harri;
- Raitakari, Olli T;
- González-Macías, Jesús;
- Hernández, Jose L;
- Mellström, Dan;
- Ljunggren, Osten;
- Cho, Yoon Shin;
- Völker, Uwe;
- Nauck, Matthias;
- Homuth, Georg;
- Völzke, Henry;
- Haring, Robin;
- Brown, Matthew A;
- McCloskey, Eugene;
- Nicholson, Geoffrey C;
- Eastell, Richard;
- Eisman, John A;
- Jones, Graeme;
- Reid, Ian R;
- Dennison, Elaine M;
- Wark, John;
- Boonen, Steven;
- Vanderschueren, Dirk;
- Wu, Frederick CW;
- Aspelund, Thor;
- Richards, J Brent;
- Bauer, Doug;
- Hofman, Albert;
- Khaw, Kay-Tee;
- Dedoussis, George;
- Obermayer-Pietsch, Barbara;
- Gyllensten, Ulf;
- Pramstaller, Peter P;
- Lorenc, Roman S;
- Cooper, Cyrus;
- Kung, Annie Wai Chee;
- Lips, Paul;
- Alen, Markku;
- Attia, John;
- Brandi, Maria Luisa;
- de Groot, Lisette CPGM;
- Lehtimäki, Terho;
- Riancho, José A;
- Campbell, Harry;
- Liu, Yongmei;
- Harris, Tamara B;
- Akesson, Kristina;
- Karlsson, Magnus;
- Lee, Jong-Young;
- Wallaschofski, Henri;
- Duncan, Emma L;
- O'Neill, Terence W;
- Gudnason, Vilmundur;
- Spector, Timothy D;
- Rousseau, François;
- Orwoll, Eric;
- Cummings, Steven R;
- Wareham, Nick J;
- Rivadeneira, Fernando;
- Uitterlinden, Andre G;
- Prince, Richard L;
- Kiel, Douglas P;
- Reeve, Jonathan;
- Kaptoge, Stephen K
- et al.
Published Web Location
https://doi.org/10.1093/hmg/ddt675Abstract
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.
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