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 - Kruk, Marcin
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 - Gonzalez-Macias, Jesus
AU - Langdahl, Bente Lomholt
AU - Leslie, William D.
AU - Lips, Paul
AU - Lorenc, Roman S.
AU - Olmos, Jose M.
AU - Pettersson-Kymmer, Ulrika
AU - Reid, David M.
AU - Riancho, Jose A.
AU - Slagboom, P. Eline
AU - Garcia-Ibarbia, Carmen
AU - Ingvarsson, Thorvaldur
AU - Johannsdottir, Hrefna
AU - Luben, Robert
AU - Medina-Gomez, 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 - Jukema, J. Wouter
AU - Pols, Huibert A. P.
AU - Prince, Richard L.
AU - Cupples, L. Adrienne
AU - Marshall, Christian R.
AU - Pinto, Dalila
AU - Sato, Daisuke
AU - Scherer, Stephen W.
AU - Reeve, Jonathan
AU - Thorsteinsdottir, Unnur
AU - Karasik, David
AU - Richards, J. Brent
AU - Stefansson, Kari
AU - Uitterlinden, Andr 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%) 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.
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%) 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.
KW - Osteoporosis
KW - Copy-Number
KW - Calcium and Bone
KW - Genetic Epidemiology
KW - Genome-Wide
KW - BONE-MINERAL DENSITY
KW - RISK
KW - ROTTERDAM
KW - VARIANTS
KW - DISEASE
KW - BMD
KW - METAANALYSIS
KW - TYPE-1
KW - GENE
KW - HIP
U2 - 10.1136/jmedgenet-2013-102064
DO - 10.1136/jmedgenet-2013-102064
M3 - Article
C2 - 24343915
VL - 51
SP - 122
EP - 131
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
SN - 0022-2593
IS - 2
ER -