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

PLoS Genet. 2011 Apr;7(4):e1001372. doi: 10.1371/journal.pgen.1001372. Epub 2011 Apr 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • CLCN7 protein, human
  • Chloride Channels
  • IBSP protein, human
  • Integrin-Binding Sialoprotein
  • LTBP3 protein, human
  • Latent TGF-beta Binding Proteins
  • Proteoglycans
  • RSPO3 protein, human
  • Receptors, Transforming Growth Factor beta
  • SOX4 protein, human
  • SOXC Transcription Factors
  • Thrombospondins
  • betaglycan
  • N-Acetylgalactosaminyltransferases