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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, Jose A.; Prince, Richard L. and van Schoor, Natasja M., et al. (2014) In Bone 59. p.20-27
Abstract
Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fracture 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 >55 years; 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... (More)
Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fracture 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 >55 years; 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 x 10(-8). In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 x 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% Cl: 0.98-1.14; p = 0.17), displaying high degree of heterogeneity (I-2= 57%; Q(het)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. (C) 2013 Elsevier Inc. All rights reserved. (Less)
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Genome-wide association study, Vertebral fracture risk, Genetics of, osteoporosis, GEFOS consortium, FOXC2
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Bone
volume
59
pages
20 - 27
publisher
Elsevier
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  • pmid:24513584
  • wos:000329558600004
  • scopus:84887568962
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1873-2763
DOI
10.1016/j.bone.2013.10.015
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English
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http://www.ncbi.nlm.nih.gov/pubmed/24513584?dopt=Abstract
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2014-03-03 07:57:01
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@article{1de5da30-dc43-48a6-95ac-8d9cc8b31b55,
  abstract     = {Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fracture 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 &gt;55 years; 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&lt;5 x 10(-8). In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 x 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% Cl: 0.98-1.14; p = 0.17), displaying high degree of heterogeneity (I-2= 57%; Q(het)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 &gt;1.25) may still be consistent with an effect size &lt;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. (C) 2013 Elsevier Inc. All rights reserved.},
  author       = {Oei, Ling and Estrada, Karol and Duncan, Emma L. and Christiansen, Claus and Liu, Ching-Ti and Langdahl, Bente L. and Obermayer-Pietsch, Barbara and Riancho, Jose A. and Prince, Richard L. and van Schoor, Natasja M. and McCloskey, Eugene and Hsu, Yi-Hsiang and Evangelou, Evangelos and Ntzani, Evangelia and Evans, David M. and Alonso, Nerea and Husted, Lise B. and Valero, Carmen and Hernandez, Jose L. and Lewis, Joshua R. and Kaptoge, Stephen K. and Zhu, Kun and Cupples, L. Adrienne and Medina-Gomez, Carolina and Vandenput, Liesbeth and Kim, Ghi Su and Lee, Seung Hun and Castano-Betancourt, Martha C. and Oei, Edwin H. G. and Martinez, Josefina and Daroszewska, Anna and van der Klift, Marjolein and Mellstrom, Dan and Herrera, Lizbeth and Karlsson, Magnus and Hofman, Albert and Ljunggren, Osten and Pols, Huibert A. P. and Stolk, Lisette and van Meurs, Joyce B. J. and Ioannidis, John P. A. and Zillikens, M. Carola and Lips, Paul and Karasik, David and Uitterlinden, Andre G. and Styrkarsdottir, Unnur and Brown, Matthew A. and Koh, Jung-Min and Richards, J. Brent and Reeve, Jonathan and Ohlsson, Claes and Ralston, Stuart H. and Kiel, Douglas P. and Rivadeneira, Fernando},
  issn         = {1873-2763},
  keyword      = {Genome-wide association study,Vertebral fracture risk,Genetics of,osteoporosis,GEFOS consortium,FOXC2},
  language     = {eng},
  pages        = {20--27},
  publisher    = {Elsevier},
  series       = {Bone},
  title        = {Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus},
  url          = {http://dx.doi.org/10.1016/j.bone.2013.10.015},
  volume       = {59},
  year         = {2014},
}