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-Gomez, Carolina, Vandenput, Liesbeth, Kim, Ghi Su, Lee, Seung Hun, Castano-Betancourt, Martha C., Oei, Edwin H.G., Martinez, Josefina, Daroszewska, Anna, van der Klift, Marjolein, Mellström, Dan, Herrera, Lizbeth, Karlsson, Magnus, 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 (2014) Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus. Bone, 59, pp. 20-27.

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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.

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ID Code: 87878
Item Type: Journal Article
Refereed: Yes
Keywords: FOXC2, GEFOS consortium, Genetics of osteoporosis, Genome-wide association study, Vertebral fracture risk, adult, aged, aging, allele, article, bone density, chromosome 16q, controlled study, female, FOXC2 gene, fragility fracture, gene, gene cluster, gene locus, gene mapping, genetic association, genetic risk, genetic susceptibility, genetic trait, genetic variability, genotype, heredity, heterozygote, homozygote, human, major clinical study, male, marker gene, phenotype, radiographic vertebral fracture, scoring system, single nucleotide polymorphism, spine fracture, Chromosomes, Human, Pair 16, Genetic Loci, Humans, Netherlands, Polymorphism, Single Nucleotide, Reproducibility of Results, Spinal Fractures
DOI: 10.1016/j.bone.2013.10.015
ISSN: 8756-3282
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2013 Elsevier Inc.
Deposited On: 01 Oct 2015 02:30
Last Modified: 28 Mar 2016 23:57

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