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 Svensson; Stella 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

doi:10.1136/jmedgenet-2013-102064

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 journal › Article › peer-review

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Abstract

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 language	English
Pages (from-to)	122-131
Number of pages	10
Journal	Journal of Medical Genetics
Volume	51
Issue number	2
Early online date	16 Dec 2013
DOIs	https://doi.org/10.1136/jmedgenet-2013-102064
Publication status	Published - Feb 2014

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10.1136/jmedgenet-2013-102064

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Oei, L., Hsu, Y-H., Styrkarsdottir, U., Eussen, B. H., de Klein, A., Peters, M. J., Halldorsson, B., Liu, C-T., Alonso, N., Kaptoge, S. K., Thorleifsson, G., Hallmans, G., Hocking, L. J., Husted, L. B., Jameson, K. A., Kruk, M., Lewis, J. R., Patel, M. S., Scollen, S., ... Estrada, K. (2014). A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. Journal of Medical Genetics, 51(2), 122-131. https://doi.org/10.1136/jmedgenet-2013-102064

Oei, Ling ; Hsu, Yi-Hsiang ; Styrkarsdottir, Unnur ; Eussen, Bert H. ; de Klein, Annelies ; Peters, Marjolein J. ; Halldorsson, Bjarni ; Liu, Ching-Ti ; Alonso, Nerea ; Kaptoge, Stephen K. ; Thorleifsson, Gudmar ; Hallmans, Göran ; Hocking, Lynne J. ; Husted, Lise Bjerre ; Jameson, Karen A. ; Kruk, Marcin ; Lewis, Joshua R. ; Patel, Millan S. ; Scollen, Serena ; Svensson, Olle ; Trompet, Stella ; van Schoor, Natasja M. ; Zhu, Kun ; Buckley, Brendan M. ; Cooper, Cyrus ; Ford, Ian ; Goltzman, David ; Gonzalez-Macias, Jesus ; Langdahl, Bente Lomholt ; Leslie, William D. ; Lips, Paul ; Lorenc, Roman S. ; Olmos, Jose M. ; Pettersson-Kymmer, Ulrika ; Reid, David M. ; Riancho, Jose A. ; Slagboom, P. Eline ; Garcia-Ibarbia, Carmen ; Ingvarsson, Thorvaldur ; Johannsdottir, Hrefna ; Luben, Robert ; Medina-Gomez, Carolina ; Arp, Pascal ; Nandakumar, Kannabiran ; Palsson, Stefan Th ; Sigurdsson, Gunnar ; van Meurs, Joyce B. J. ; Zhou, Yanhua ; Hofman, Albert ; Jukema, J. Wouter ; Pols, Huibert A. P. ; Prince, Richard L. ; Cupples, L. Adrienne ; Marshall, Christian R. ; Pinto, Dalila ; Sato, Daisuke ; Scherer, Stephen W. ; Reeve, Jonathan ; Thorsteinsdottir, Unnur ; Karasik, David ; Richards, J. Brent ; Stefansson, Kari ; Uitterlinden, Andr G. ; Ralston, Stuart H. ; Ioannidis, John P. A. ; Kiel, Douglas P. ; Rivadeneira, Fernando ; Estrada, Karol. / A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. In: Journal of Medical Genetics. 2014 ; Vol. 51, No. 2. pp. 122-131.

@article{7dba14054a3d49b88fbc968a5a830cc4,

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

abstract = "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.",

keywords = "Osteoporosis, Copy-Number, Calcium and Bone, Genetic Epidemiology, Genome-Wide, BONE-MINERAL DENSITY, RISK, ROTTERDAM, VARIANTS, DISEASE, BMD, METAANALYSIS, TYPE-1, GENE, HIP",

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

year = "2014",

month = feb,

doi = "10.1136/jmedgenet-2013-102064",

language = "English",

volume = "51",

pages = "122--131",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "2",

}

Oei, L, Hsu, Y-H, Styrkarsdottir, U, Eussen, BH, de Klein, A, Peters, MJ, Halldorsson, B, Liu, C-T, Alonso, N, Kaptoge, SK, Thorleifsson, G, Hallmans, G, Hocking, LJ, Husted, LB, Jameson, KA, Kruk, M, Lewis, JR, Patel, MS, Scollen, S, Svensson, O, Trompet, S, van Schoor, NM, Zhu, K, Buckley, BM, Cooper, C, Ford, I, Goltzman, D, Gonzalez-Macias, J, Langdahl, BL, Leslie, WD, Lips, P, Lorenc, RS, Olmos, JM, Pettersson-Kymmer, U, Reid, DM, Riancho, JA, Slagboom, PE, Garcia-Ibarbia, C, Ingvarsson, T, Johannsdottir, H, Luben, R, Medina-Gomez, C, Arp, P, Nandakumar, K, Palsson, ST, Sigurdsson, G, van Meurs, JBJ, Zhou, Y, Hofman, A, Jukema, JW, Pols, HAP, Prince, RL, Cupples, LA, Marshall, CR, Pinto, D, Sato, D, Scherer, SW, Reeve, J, Thorsteinsdottir, U, Karasik, D, Richards, JB, Stefansson, K, Uitterlinden, AG, Ralston, SH, Ioannidis, JPA, Kiel, DP, Rivadeneira, F & Estrada, K 2014, 'A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus', Journal of Medical Genetics, vol. 51, no. 2, pp. 122-131. https://doi.org/10.1136/jmedgenet-2013-102064

A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. / Oei, Ling; Hsu, Yi-Hsiang; Styrkarsdottir, Unnur; Eussen, Bert H.; de Klein, Annelies; Peters, Marjolein J.; Halldorsson, Bjarni; Liu, Ching-Ti; Alonso, Nerea; Kaptoge, Stephen K.; Thorleifsson, Gudmar; Hallmans, Göran ; Hocking, Lynne J.; Husted, Lise Bjerre; Jameson, Karen A.; Kruk, Marcin; Lewis, Joshua R.; Patel, Millan S.; Scollen, Serena; Svensson, Olle; Trompet, Stella; van Schoor, Natasja M.; Zhu, Kun; Buckley, Brendan M.; Cooper, Cyrus; Ford, Ian; Goltzman, David; Gonzalez-Macias, Jesus; Langdahl, Bente Lomholt; Leslie, William D.; Lips, Paul; Lorenc, Roman S.; Olmos, Jose M.; Pettersson-Kymmer, Ulrika; Reid, David M.; Riancho, Jose A.; Slagboom, P. Eline; Garcia-Ibarbia, Carmen; Ingvarsson, Thorvaldur; Johannsdottir, Hrefna; Luben, Robert; Medina-Gomez, Carolina; Arp, Pascal; Nandakumar, Kannabiran; Palsson, Stefan Th; Sigurdsson, Gunnar; van Meurs, Joyce B. J.; Zhou, Yanhua; Hofman, Albert; Jukema, J. Wouter; Pols, Huibert A. P.; Prince, Richard L.; Cupples, L. Adrienne; Marshall, Christian R.; Pinto, Dalila; Sato, Daisuke; Scherer, Stephen W.; Reeve, Jonathan; Thorsteinsdottir, Unnur; Karasik, David; Richards, J. Brent; Stefansson, Kari; Uitterlinden, Andr G.; Ralston, Stuart H.; Ioannidis, John P. A.; Kiel, Douglas P.; Rivadeneira, Fernando; Estrada, Karol.

In: Journal of Medical Genetics, Vol. 51, No. 2, 02.2014, p. 122-131.

Research output: Contribution to journal › Article › peer-review

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 -

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

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