Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1371/journal.pgen.1001372

Type

Journal article

Journal

PLoS Genetics

Publication Date

21/04/2011

Volume

7

Addresses

University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia.

Keywords

Chromosomes, Human, Animals, Humans, Mice, Osteoporosis, Postmenopausal, Disease Models, Animal, N-Acetylgalactosaminyltransferases, Proteoglycans, Chloride Channels, Thrombospondins, Receptors, Transforming Growth Factor beta, Case-Control Studies, Cohort Studies, Models, Animal, Bone Density, Genotype, Mutation, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Female, Male, Fractures, Bone, Latent TGF-beta Binding Proteins, Genome-Wide Association Study, SOXC Transcription Factors, Integrin-Binding Sialoprotein