A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus

J Med Genet. 2014 Feb;51(2):122-31. doi: 10.1136/jmedgenet-2013-102064. Epub 2013 Dec 16.


Background: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.

Aim: To identify CNVs associated with osteoporotic bone fracture risk.

Method: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.

Results: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.

Conclusions: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

Keywords: Calcium and Bone; Copy-Number; Genetic Epidemiology; Genome-Wide; Osteoporosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Chromosome Breakpoints
  • Chromosomes, Human, Pair 6 / genetics*
  • Cohort Studies
  • DNA Copy Number Variations
  • DNA Mutational Analysis
  • Gene Deletion
  • Gene Dosage
  • Genome-Wide Association Study
  • Humans
  • Markov Chains
  • Middle Aged
  • Osteoporosis / genetics*
  • Osteoporotic Fractures / genetics*