TY - JOUR
T1 - Genome-wide association study for radiographic vertebral fractures
T2 - A potential role for the 16q24 BMD locus
AU - Oei, Ling
AU - Estrada, Karol
AU - Duncan, Emma L.
AU - Christiansen, Claus
AU - Liu, Ching Ti
AU - Langdahl, Bente L.
AU - Obermayer-Pietsch, Barbara
AU - Riancho, José A.
AU - Prince, Richard L.
AU - van Schoor, Natasja M.
AU - McCloskey, Eugene
AU - Hsu, Yi Hsiang
AU - Evangelou, Evangelos
AU - Ntzani, Evangelia
AU - Evans, David M.
AU - Alonso, Nerea
AU - Husted, Lise B.
AU - Valero, Carmen
AU - Hernandez, Jose L.
AU - Lewis, Joshua R.
AU - Kaptoge, Stephen K.
AU - Zhu, Kun
AU - Cupples, L. Adrienne
AU - Medina-Gómez, Carolina
AU - Vandenput, Liesbeth
AU - Kim, Ghi Su
AU - Lee, Seung Hun
AU - Castaño-Betancourt, Martha C.
AU - Oei, Edwin H.G.
AU - Martinez, Josefina
AU - Daroszewska, Anna
AU - van der Klift, Marjolein
AU - Mellström, Dan
AU - Herrera, Lizbeth
AU - Karlsson, Magnus K.
AU - Hofman, Albert
AU - Ljunggren, Östen
AU - Pols, Huibert A.P.
AU - Stolk, Lisette
AU - van Meurs, Joyce B.J.
AU - Ioannidis, John P.A.
AU - Zillikens, M. Carola
AU - Lips, Paul
AU - Karasik, David
AU - Uitterlinden, André G.
AU - Styrkarsdottir, Unnur
AU - Brown, Matthew A.
AU - Koh, Jung Min
AU - Richards, J. Brent
AU - Reeve, Jonathan
AU - Ohlsson, Claes
AU - Ralston, Stuart H.
AU - Kiel, Douglas P.
AU - Rivadeneira, Fernando
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
KW - FOXC2
KW - GEFOS consortium
KW - Genetics of osteoporosis
KW - Genome-wide association study
KW - Vertebral fracture risk
UR - https://www.scopus.com/pages/publications/84887568962
U2 - 10.1016/j.bone.2013.10.015
DO - 10.1016/j.bone.2013.10.015
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C2 - 24516880
AN - SCOPUS:84887568962
SN - 8756-3282
VL - 59
SP - 20
EP - 27
JO - Bone
JF - Bone
ER -
SDG 3 Good Health and Well-being