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


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.

Type Journal
ISBN 1553-7404 (Electronic) 1553-7390 (Linking)
Authors Duncan, E. 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.; Thakker, R. V.; Addison, K. A.; Bradbury, L. A.; Center, J. R.; Cooper, C.; Cremin, C.; Estrada, K.; Felsenberg, D.; Gluer, 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, M. A.;
Publisher Name PLOS GENET
Published Date 2011-01-01
Published Volume 7
Published Issue 4
Published Pages e1001372
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version