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

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

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1
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Abstract

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

PMID:
24343915
DOI:
10.1136/jmedgenet-2013-102064
[Indexed for MEDLINE]
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