Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk

Duncan, Emma L., Danoy, P., Kemp, J. P., Leo, P. J., McCloskey, E., Nicholson, G. C., Eastell, R., Prince, R. L., Eisman, J. A., Jones, G., Sambrook, P. N., Reid, I. R., Dennison, E. M., Wark, J., Richards, J. B., Uitterlinden, A. G., Spector, T. D., Esapa, C., Cox, R. D., Brown, S. D. M., Thakker, R. V., Addison, K. A., Bradbury, L. A., Center, J. R., Cooper, C., Cremin, C., Estrada, K., Felsenberg, D., Glüer, C. C., Hadler, J., Henry, M. J., Hofman, A., Kotowicz, M. A., Makovey, J., Nguyen, S. C., Nguyen, T. V., Pasco, J. A., Pryce, K., Reid, D. M., Rivadeneira, F., Roux, C., Stefansson, K., Styrkarsdottir, U., Thorleifsson, G., Tichawangana, R., Evans, D. M., & Brown, Matthew A. (2011) Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genetics, 7(4).

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Abstract

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or -4.0 to -1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD-associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies. © 2011 Duncan et al.

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ID Code: 87608
Item Type: Journal Article
Refereed: Yes
Keywords: adult, aged, animal experiment, article, bone density, bone mass, CLCN7 gene, controlled study, female, fragility fracture, GALNT3 gene, gene, gene identification, genetic association, hip, human, IBSP gene, loss of function mutation, LTBP3 gene, mouse, nonhuman, postmenopause, quantitative trait, Rspo3 gene, single nucleotide polymorphism, Sox4 gene, animal, animal model, case control study, cohort analysis, disease model, fracture, genetics, genotype, human chromosome, male, middle aged, mutation, postmenopause osteoporosis, bone sialoprotein, chloride channel, CLCN7 protein, human, IBSP protein, human, latent transforming growth factor beta binding protein, LTBP3 protein, human, n acetylgalactosaminyltransferase, polypeptide n acetylgalactosaminyltransferase, polypeptide N-acetylgalactosaminyltransferase, proteoglycan, RSPO3 protein, human, SOX4 protein, human, thrombospondin, transcription factor Sox, transforming growth factor beta receptor, transforming growth factor beta receptor 3, Aged, 80 and over, Animals, Case-Control Studies, Chloride Channels, Chromosomes, Human, Cohort Studies, Disease Models, Animal, Fractures, Bone, Genome-Wide Association Study, Humans, Integrin-Binding Sialoprotein, Latent TGF-beta Binding Proteins, Mice, Models, Animal, N-Acetylgalactosaminyltransferases, Osteoporosis, Postmenopausal, Polymorphism, Single Nucleotide, Proteoglycans, Receptors, Transforming Growth Factor beta, SOXC Transcription Factors, Thrombospondins
DOI: 10.1371/journal.pgen.1001372
ISSN: 1553-7390
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: The authors
Deposited On: 21 Sep 2015 07:22
Last Modified: 24 Nov 2016 02:16

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