Genome-wide association study for radiographic vertebral fractures: a potential role for the 16q24 BMD locus

Oei, Ling, Estrada, Karol, Duncan, Emma L., Christiansen, Claus, Liu, Ching-Ti, Langdahl, Bente L., Obermayer-Pietsch, Barbara, Riancho, José A., Prince, Richard L., van Schoor, Natasja M., McCloskey, Eugene, Hsu, Yi-Hsiang, Evangelou, Evangelos, Ntzani, Evangelia, Evans, David M., Alonso, Nerea, Husted, Lise B., Valero, Carmen, Hernandez, Jose L., Lewis, Joshua R., Kaptoge, Stephen K., Zhu, Kun, Cupples, L. Adrienne, Medina-Gómez, Carolina, Vandenput, Liesbeth, Kim, Ghi Su, Lee, Seung Hun, Castaño-Betancourt, Martha C., Oei, Edwin H. G., Martinez, Josefina, Daroszewska, Anna, van der Klift, Marjolein, Mellström, Dan, Herrera, Lizbeth, Karlsson, Magnus K., Hofman, Albert, Ljunggren, Östen, Pols, Huibert A. P., Stolk, Lisette, van Meurs, Joyce B. J., Ioannidis, John P. A., Zillikens, M. Carola, Lips, Paul, Karasik, David, Uitterlinden, André G., Styrkarsdottir, Unnur, Brown, Matthew A., Koh, Jung-Min, Richards, J. Brent, Reeve, Jonathan, Ohlsson, Claes, Ralston, Stuart H., Kiel, Douglas P. and Rivadeneira, Fernando (2014) Genome-wide association study for radiographic vertebral fractures: a potential role for the 16q24 BMD locus. Bone, 59 20-27. doi:10.1016/j.bone.2013.10.015

Author Oei, Ling
Estrada, Karol
Duncan, Emma L.
Christiansen, Claus
Liu, Ching-Ti
Langdahl, Bente L.
Obermayer-Pietsch, Barbara
Riancho, José A.
Prince, Richard L.
van Schoor, Natasja M.
McCloskey, Eugene
Hsu, Yi-Hsiang
Evangelou, Evangelos
Ntzani, Evangelia
Evans, David M.
Alonso, Nerea
Husted, Lise B.
Valero, Carmen
Hernandez, Jose L.
Lewis, Joshua R.
Kaptoge, Stephen K.
Zhu, Kun
Cupples, L. Adrienne
Medina-Gómez, Carolina
Vandenput, Liesbeth
Kim, Ghi Su
Lee, Seung Hun
Castaño-Betancourt, Martha C.
Oei, Edwin H. G.
Martinez, Josefina
Daroszewska, Anna
van der Klift, Marjolein
Mellström, Dan
Herrera, Lizbeth
Karlsson, Magnus K.
Hofman, Albert
Ljunggren, Östen
Pols, Huibert A. P.
Stolk, Lisette
van Meurs, Joyce B. J.
Ioannidis, John P. A.
Zillikens, M. Carola
Lips, Paul
Karasik, David
Uitterlinden, André G.
Styrkarsdottir, Unnur
Brown, Matthew A.
Koh, Jung-Min
Richards, J. Brent
Reeve, Jonathan
Ohlsson, Claes
Ralston, Stuart H.
Kiel, Douglas P.
Rivadeneira, Fernando
Title Genome-wide association study for radiographic vertebral fractures: a potential role for the 16q24 BMD locus
Journal name Bone   Check publisher's open access policy
ISSN 8756-3282
Publication date 2014-02-01
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.bone.2013.10.015
Volume 59
Start page 20
End page 27
Total pages 8
Editor Sundeep Khosla
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Language eng
Subject 1314 Physiology
2712 Endocrinology, Diabetes and Metabolism
2722 Histology
Formatted abstract
Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5×10-8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6×10-8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98-1.14; p=0.17), displaying high degree of heterogeneity (I2=57%; Qhet p=0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.
Keyword Genome-wide association study
Vertebral fracture risk
Genetics of osteoporosis
GEFOS consortium
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online 26 October 2013

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
UQ Diamantina Institute Publications
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