Advanced

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. and Zheng, Hou-Feng, et al. (2014) In Human Molecular Genetics 23(11). p.3054-3068
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... (More)
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 x 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 x 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 x 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. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
23
issue
11
pages
3054 - 3068
publisher
Oxford University Press
external identifiers
  • wos:000336483200021
  • scopus:84893613998
ISSN
0964-6906
DOI
10.1093/hmg/ddt675
language
English
LU publication?
yes
id
fb63a1c4-6c5f-4f66-b206-467c0a908ace (old id 4552486)
date added to LUP
2014-08-01 07:39:29
date last changed
2017-10-22 03:00:18
@article{fb63a1c4-6c5f-4f66-b206-467c0a908ace,
  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 &lt; 5 x 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 &lt; 8.23 x 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 &lt; 5 x 10(-6) also had the expected direction of association with any fracture (P &lt; 0.05), including three SNPs with P &lt; 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.},
  author       = {Moayyeri, Alireza and Hsu, Yi-Hsiang and Karasik, David and Estrada, Karol and Xiao, Su-Mei and Nielson, Carrie and Srikanth, Priya and Giroux, Sylvie and Wilson, Scott G. and Zheng, Hou-Feng and Smith, Albert V. and Pye, Stephen R. and Leo, Paul J. and Teumer, Alexander and Hwang, Joo-Yeon and Ohlsson, Claes and McGuigan, Fiona and Minster, Ryan L. and Hayward, Caroline and Olmos, Jose M. and Lyytikaeinen, Leo-Pekka and Lewis, Joshua R. and Swart, Karin M. A. and Masi, Laura and Oldmeadow, Chris and Holliday, Elizabeth G. and Cheng, Sulin and van Schoor, Natasja M. and Harvey, Nicholas C. and Kruk, Marcin and Fabiola Del Greco, M. and Igl, Wilmar and Trummer, Olivia and Grigoriou, Efi and Luben, Robert and Liu, Ching-Ti and Zhou, Yanhua and Oei, Ling and Medina-Gomez, Carolina and Zmuda, Joseph and Tranah, Greg and Brown, Suzanne J. and Williams, Frances M. and Soranzo, Nicole and Jakobsdottir, Johanna and Siggeirsdottir, Kristin and Holliday, Kate L. and Hannemann, Anke and Go, Min Jin and Garcia, Melissa and Polasek, Ozren and Laaksonen, Marika and Zhu, Kun and Enneman, Anke W. and McEvoy, Mark and Peel, Roseanne and Sham, Pak Chung and Jaworski, Maciej and Johansson, Asa and Hicks, Andrew A. and Pludowski, Pawel and Scott, Rodney and Dhonukshe-Rutten, Rosalie A. M. and van der Velde, Nathalie and Kaehoenen, Mika and Viikari, Jorma S. and Sievaenen, Harri and Raitakari, Olli T. and Gonzalez-Macias, Jesus and Hernandez, Jose L. and Mellstroem, Dan and Ljunggren, Oesten and Cho, Yoon Shin and Voelker, Uwe and Nauck, Matthias and Homuth, Georg and Voelzke, Henry and Haring, Robin and Brown, Matthew A. and McCloskey, Eugene and Nicholson, Geoffrey C. and Eastell, Richard and Eisman, John A. and Jones, Graeme and Reid, Ian R. and Dennison, Elaine M. and Wark, John and Boonen, Steven and Vanderschueren, Dirk and Wu, Frederick C. W. and Aspelund, Thor and Richards, J. Brent and Bauer, Doug and Hofman, Albert and Khaw, Kay-Tee and Dedoussis, George and Obermayer-Pietsch, Barbara and Gyllensten, Ulf and Pramstaller, Peter P. and Lorenc, Roman S. and Cooper, Cyrus and Kung, Annie Wai Chee and Lips, Paul and Alen, Markku and Attia, John and Luisa Brandi, Maria and de Groot, Lisette C. P. G. M. and Lehtimaeki, Terho and Riancho, Jose A. and Campbell, Harry and Liu, Yongmei and Harris, Tamara B. and Åkesson, Kristina and Karlsson, Magnus and Lee, Jong-Young and Wallaschofski, Henri and Duncan, Emma L. and O'Neill, Terence W. and Gudnason, Vilmundur and Spector, Timothy D. and Rousseau, Francois and Orwoll, Eric and Cummings, Steven R. and Wareham, Nick J. and Rivadeneira, Fernando and Uitterlinden, Andre G. and Prince, Richard L. and Kiel, Douglas P. and Reeve, Jonathan and Kaptoge, Stephen K.},
  issn         = {0964-6906},
  language     = {eng},
  number       = {11},
  pages        = {3054--3068},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium},
  url          = {http://dx.doi.org/10.1093/hmg/ddt675},
  volume       = {23},
  year         = {2014},
}