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Full-text held externally
- DOI: 10.1093/hmg/ddt675
- PMID: 24430505
- UKPMCID: 24430505
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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, JosĂ© M; Lyytikäinen, Leo-Pekka; Lewis, Joshua R; Swart, Karin M A; 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, Asa; Hicks, Andrew A; Pludowski, Pawel; Scott, Rodney; Dhonukshe-Rutten, Rosalie A M; van der Velde, Nathalie; Kähönen, Mika; Viikari, Jorma S; Sievänen, Harri; Raitakari, Olli T; González-MacĂas, JesĂşs; 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 C W; 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 C P G M; Lehtimäki, Terho; Riancho, JosĂ© 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
Human molecular genetics. 2014;23(11):3054-3068.
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Full-text held externally
- DOI: 10.1093/hmg/ddt675
- PMID: 24430505
- UKPMCID: 24430505
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 Ă— 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 Ă— 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 Ă— 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.
Bibliographic metadata
- 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 M A
- 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, Asa
- Hicks, Andrew A
- Pludowski, Pawel
- Scott, Rodney
- Dhonukshe-Rutten, Rosalie A M
- van der Velde, Nathalie
- Kähönen, Mika
- Viikari, Jorma S
- Sievänen, Harri
- Raitakari, Olli T
- González-MacĂas, JesĂşs
- 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 C W
- 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 C P G M
- 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