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A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus
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2014 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 51, no 2, 122-131 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BMJ Publishing Group , 2014. Vol. 51, no 2, 122-131 p.
Keyword [en]
Osteoporosis, Copy-Number, Calcium and Bone, Genetic Epidemiology, Genome-Wide
National Category
Orthopedics Medical Genetics Genetics
URN: urn:nbn:se:umu:diva-84732DOI: 10.1136/jmedgenet-2013-102064ISI: 000331191300008PubMedID: 24343915OAI: diva2:688879
Available from: 2014-01-17 Created: 2014-01-17 Last updated: 2015-04-22Bibliographically approved

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Hallmans, GöranSvensson, OllePettersson-Kymmer, Ulrika
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Nutritional ResearchDepartment of Biobank ResearchOrthopaedicsClinical PharmacologyDepartment of Public Health and Clinical Medicine
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Journal of Medical Genetics
OrthopedicsMedical GeneticsGenetics

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