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

Ling Oei, Yi-Hsiang Hsu, Unnur Styrkarsdottir, Bert H. Eussen, Annelies de Klein, Marjolein J. Peters, Bjarni Halldorsson, Ching-Ti Liu, Nerea Alonso, Stephen K. Kaptoge, Gudmar Thorleifsson, Göran Hallmans, Lynne J. Hocking, Lise Bjerre Husted, Karen A. Jameson, Marcin Kruk, Joshua R. Lewis, Millan S. Patel, Serena Scollen, Olle SvenssonStella Trompet, Natasja M. van Schoor, Kun Zhu, Brendan M. Buckley, Cyrus Cooper, Ian Ford, David Goltzman, Jesus Gonzalez-Macias, Bente Lomholt Langdahl, William D. Leslie, Paul Lips, Roman S. Lorenc, Jose M. Olmos, Ulrika Pettersson-Kymmer, David M. Reid, Jose A. Riancho, P. Eline Slagboom, Carmen Garcia-Ibarbia, Thorvaldur Ingvarsson, Hrefna Johannsdottir, Robert Luben, Carolina Medina-Gomez, Pascal Arp, Kannabiran Nandakumar, Stefan Th Palsson, Gunnar Sigurdsson, Joyce B. J. van Meurs, Yanhua Zhou, Albert Hofman, J. Wouter Jukema, Huibert A. P. Pols, Richard L. Prince, L. Adrienne Cupples, Christian R. Marshall, Dalila Pinto, Daisuke Sato, Stephen W. Scherer, Jonathan Reeve, Unnur Thorsteinsdottir, David Karasik, J. Brent Richards, Kari Stefansson, Andr G. Uitterlinden, Stuart H. Ralston, John P. A. Ioannidis, Douglas P. Kiel, Fernando Rivadeneira, Karol Estrada

    Research output: Contribution to journalArticlepeer-review

    26 Citations (Scopus)


    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%) 210kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69x10(-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.

    Original languageEnglish
    Pages (from-to)122-131
    Number of pages10
    JournalJournal of Medical Genetics
    Issue number2
    Early online date16 Dec 2013
    Publication statusPublished - Feb 2014


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