학술논문
Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.
Document Type
article
Author
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
Source
Human molecular genetics. 23(11)
Subject
Language
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.