eCite Digital Repository

Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk


Duncan, EL and Danoy, P and Kemp, JP and Leo, PJ and McCloskey, E and Nicholson, GC and Eastell, R and Prince, RL and Eisman, JA and Jones, G and Sambrook, PN and Reid, IR and Dennison, EM and Wark, J and Richards, JB and Uitterlinden, AG and Spector, TD and Esapa, C and Cox, RD and Brown, SDM and Thakker, RV and Addison, KA and Bradbury, LA and Center, JR and Cooper, C and Cremin, C and Estrada, K and Felsenberg, D and Gluer, CC and Hadler, J and Henry, MJ and Hofman, A and Kotowicz, MA and Makovey, J and Nguyen, SC and Nguyen, TV and Pasco, JA and Pryce, K and Reid, DM and Rivadeneira, F and Roux, C and Stefansson, K and Styrkarsdottir, U and Thorleifsson, G and Tichawangana, R and Evans, DM and Brown, MA, Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk, PLoS Genetics, 7, (4) Article e1001372. ISSN 1553-7390 (2011) [Refereed Article]


Copyright Statement

Licensed under Creative Commons Attribution 2.5 Generic (CC BY 2.5)

DOI: doi:10.1371/journal.pgen.1001372


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 zscores of +1.5 to +4.0, n = 1055, or 24.0 to 21.5, 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.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Clinical sciences
Research Field:Rheumatology and arthritis
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Jones, G (Professor Graeme Jones)
ID Code:76220
Year Published:2011
Web of Science® Times Cited:178
Deposited By:Menzies Institute for Medical Research
Deposited On:2012-03-02
Last Modified:2017-11-02
Downloads:552 View Download Statistics

Repository Staff Only: item control page