TY - JOUR
T1 - A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus
AU - Oei, Ling
AU - Hsu, Yi Hsiang
AU - Styrkarsdottir, Unnur
AU - Eussen, Bert H.
AU - de Klein, Annelies
AU - Peters, Marjolein J.
AU - Halldorsson, Bjarni
AU - Liu, Ching Ti
AU - Alonso, Nerea
AU - Kaptoge, Stephen K.
AU - Thorleifsson, Gudmar
AU - Hallmans, Göran
AU - Hocking, Lynne J.
AU - Husted, Lise Bjerre
AU - Jameson, Karen A.
AU - Kingdom, Marcin Kr United
AU - Lewis, Joshua R.
AU - Patel, Millan S.
AU - Scollen, Serena
AU - Svensson, Olle
AU - Trompet, Stella
AU - van Schoor, Natasja M.
AU - Zhu, Kun
AU - Buckley, Brendan M.
AU - Cooper, Cyrus
AU - Ford, Ian
AU - Goltzman, David
AU - González-Macías, Jesús
AU - Langdahl, Bente Lomholt
AU - Leslie, William D.
AU - Lips, Paul
AU - Lorenc, Roman S.
AU - Olmos, José M.
AU - Pettersson-Kymmer, Ulrika
AU - Reid, David M.
AU - Riancho, José A.
AU - Slagboom, P. Eline
AU - Garcia-Ibarbia, Carmen
AU - Ingvarsson, Thorvaldur
AU - Johannsdottir, Hrefna
AU - Luben, Robert
AU - Medina-Gómez, Carolina
AU - Arp, Pascal
AU - Nandakumar, Kannabiran
AU - Palsson, Stefan Th
AU - Sigurdsson, Gunnar
AU - van Meurs, Joyce B.J.
AU - Zhou, Yanhua
AU - Hofman, Albert
AU - Jukeme, J. Wouter
AU - Pols, Huibert A.P.
AU - Prince, Richard L.
AU - Cupples, L. Adrienne
AU - Marshall, Christian R.
AU - Pinto, Dalila
AU - Sato, Dais United Kingdome
AU - Scherer, Stephen W.
AU - Reeve, Jonathan
AU - Thorsteinsdottir, Unnur
AU - Karasik, David
AU - Richards, J. Brent
AU - Stefansson, Kari
AU - Uitterlinden, André G.
AU - Ralston, Stuart H.
AU - Ioannidis, John P.A.
AU - Kiel, Douglas P.
AU - Rivadeneira, Fernando
AU - Estrada, Karol
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84894028523&partnerID=8YFLogxK
U2 - 10.1136/jmedgenet-2013-102064
DO - 10.1136/jmedgenet-2013-102064
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C2 - 24343915
AN - SCOPUS:84894028523
SN - 0022-2593
VL - 51
SP - 122
EP - 131
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 2
ER -