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 Kr United Kingdom, 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, Jesús González-Macías, Bente Lomholt Langdahl, William D. Leslie, Paul Lips, Roman S. Lorenc, José M. Olmos, Ulrika Pettersson-Kymmer, David M. Reid, José A. Riancho, P. Eline Slagboom, Carmen Garcia-Ibarbia, Thorvaldur Ingvarsson, Hrefna Johannsdottir, Robert Luben, Carolina Medina-Gómez, Pascal Arp, Kannabiran Nandakumar, Stefan Th Palsson, Gunnar Sigurdsson, Joyce B.J. van Meurs, Yanhua Zhou, Albert Hofman, J. Wouter Jukeme, Huibert A.P. Pols, Richard L. Prince, L. Adrienne Cupples, Christian R. Marshall, Dalila Pinto, Dais United Kingdome Sato, Stephen W. Scherer, Jonathan Reeve, Unnur Thorsteinsdottir, David Karasik, J. Brent Richards, Kari Stefansson, André G. Uitterlinden, Stuart H. Ralston, John P.A. Ioannidis, Douglas P. Kiel, Fernando Rivadeneira, Karol Estrada

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27 Scopus citations


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.

Original languageEnglish
Pages (from-to)122-131
Number of pages10
JournalJournal of Medical Genetics
Issue number2
StatePublished - Feb 2014
Externally publishedYes


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