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

Ling Oei - Oei; YH Hsu; U Styrkarsdottir; BH Eussen; Annelies de Klein; Marjolein Peters; B Halldorsson; CT Liu; N Alonso; SK Kaptoge; G Thorleifsson; G Hallmans; LJ Hocking; LB Husted; KA Jameson; M van der Kruk; JR Lewis; MS Patel; S Scollen; O Svensson; S Trompet; NM Schoor; K Zhu; BM Buckley; C Cooper; I Ford; D Goltzman; J Gonzalez-Macias; BL Langdahl; WD Leslie; P Lips; RS Lorenc; JM Olmos; U Pettersson-Kymmer; DM Reid; JA Riancho; PE (Eline) Slagboom; C Garcia-Ibarbia; T Ingvarsson; H Johannsdottir; R Luben; C Medina-Gomez; Pascal Arp; K Nandakumar; ST Palsson; G Sigurdsson; Joyce van Meurs; YH Zhou; Bert Hofman; JW Jukema; Huib Pols; RL Prince; LA Cupples; CR Marshall; D Pinto; D Sato; SW Scherer; J Reeve; U Thorsteinsdottir; D Karasik; JB Richards; K Stefansson; André Uitterlinden; SH Ralston; JPA Ioannidis; DP Kiel; Fernando Rivadeneira; Karol Estrada Gil

doi:10.1136/jmedgenet-2013-102064

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

Ling Oei - Oei, YH Hsu, U Styrkarsdottir, BH Eussen, Annelies de Klein, Marjolein Peters, B Halldorsson, CT Liu, N Alonso, SK Kaptoge, G Thorleifsson, G Hallmans, LJ Hocking, LB Husted, KA Jameson, M van der Kruk, JR Lewis, MS Patel, S Scollen, O SvenssonS Trompet, NM Schoor, K Zhu, BM Buckley, C Cooper, I Ford, D Goltzman, J Gonzalez-Macias, BL Langdahl, WD Leslie, P Lips, RS Lorenc, JM Olmos, U Pettersson-Kymmer, DM Reid, JA Riancho, PE (Eline) Slagboom, C Garcia-Ibarbia, T Ingvarsson, H Johannsdottir, R Luben, C Medina-Gomez, Pascal Arp, K Nandakumar, ST Palsson, G Sigurdsson, Joyce van Meurs, YH Zhou, Bert Hofman, JW Jukema, Huib Pols, RL Prince, LA Cupples, CR Marshall, D Pinto, D Sato, SW Scherer, J Reeve, U Thorsteinsdottir, D Karasik, JB Richards, K Stefansson, André Uitterlinden, SH Ralston, JPA Ioannidis, DP Kiel, Fernando Rivadeneira, Karol Estrada Gil

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

28 Citations (Scopus)

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	Undefined/Unknown
Pages (from-to)	122-131
Number of pages	10
Journal	Journal of Medical Genetics
Volume	51
Issue number	2
DOIs	https://doi.org/10.1136/jmedgenet-2013-102064
Publication status	Published - 2014

Research programs

EMC MGC-02-96-01
EMC MM-01-39-09-A
EMC NIHES-01-64-01

Access to Document

10.1136/jmedgenet-2013-102064

http://hdl.handle.net/1765/67366

Cite this

Oei - Oei, L., Hsu, YH., Styrkarsdottir, U., Eussen, BH., de Klein, A., Peters, M., Halldorsson, B., Liu, CT., Alonso, N., Kaptoge, SK., Thorleifsson, G., Hallmans, G., Hocking, LJ., Husted, LB., Jameson, KA., van der Kruk, M., Lewis, JR., Patel, MS., Scollen, S., ... Estrada Gil, 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

@article{58e19d4f46374abe8608c094c6e8e8e9,

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.",

author = "{Oei - Oei}, Ling and YH Hsu and U Styrkarsdottir and BH Eussen and {de Klein}, Annelies and Marjolein Peters and B Halldorsson and CT Liu and N Alonso and SK Kaptoge and G Thorleifsson and G Hallmans and LJ Hocking and LB Husted and KA Jameson and {van der Kruk}, M and JR Lewis and MS Patel and S Scollen and O Svensson and S Trompet and NM Schoor and K Zhu and BM Buckley and C Cooper and I Ford and D Goltzman and J Gonzalez-Macias and BL Langdahl and WD Leslie and P Lips and RS Lorenc and JM Olmos and U Pettersson-Kymmer and DM Reid and JA Riancho and Slagboom, {PE (Eline)} and C Garcia-Ibarbia and T Ingvarsson and H Johannsdottir and R Luben and C Medina-Gomez and Pascal Arp and K Nandakumar and ST Palsson and G Sigurdsson and {van Meurs}, Joyce and YH Zhou and Bert Hofman and JW Jukema and Huib Pols and RL Prince and LA Cupples and CR Marshall and D Pinto and D Sato and SW Scherer and J Reeve and U Thorsteinsdottir and D Karasik and JB Richards and K Stefansson and Andr{\'e} Uitterlinden and SH Ralston and JPA Ioannidis and DP Kiel and Fernando Rivadeneira and {Estrada Gil}, Karol",

year = "2014",

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

language = "Undefined/Unknown",

volume = "51",

pages = "122--131",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "2",

}

Oei - Oei, L, Hsu, YH, Styrkarsdottir, U, Eussen, BH, de Klein, A, Peters, M, Halldorsson, B, Liu, CT, Alonso, N, Kaptoge, SK, Thorleifsson, G, Hallmans, G, Hocking, LJ, Husted, LB, Jameson, KA, van der Kruk, M, Lewis, JR, Patel, MS, Scollen, S, Svensson, O, Trompet, S, 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, J, Zhou, YH, Hofman, B, Jukema, JW, Pols, H, Prince, RL, Cupples, LA, Marshall, CR, Pinto, D, Sato, D, Scherer, SW, Reeve, J, Thorsteinsdottir, U, Karasik, D, Richards, JB, Stefansson, K, Uitterlinden, A, Ralston, SH, Ioannidis, JPA, Kiel, DP, Rivadeneira, F & Estrada Gil, 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

TY - JOUR

T1 - A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus

AU - Oei - Oei, Ling

AU - Hsu, YH

AU - Styrkarsdottir, U

AU - Eussen, BH

AU - de Klein, Annelies

AU - Peters, Marjolein

AU - Halldorsson, B

AU - Liu, CT

AU - Alonso, N

AU - Kaptoge, SK

AU - Thorleifsson, G

AU - Hallmans, G

AU - Hocking, LJ

AU - Husted, LB

AU - Jameson, KA

AU - van der Kruk, M

AU - Lewis, JR

AU - Patel, MS

AU - Scollen, S

AU - Svensson, O

AU - Trompet, S

AU - Schoor, NM

AU - Zhu, K

AU - Buckley, BM

AU - Cooper, C

AU - Ford, I

AU - Goltzman, D

AU - Gonzalez-Macias, J

AU - Langdahl, BL

AU - Leslie, WD

AU - Lips, P

AU - Lorenc, RS

AU - Olmos, JM

AU - Pettersson-Kymmer, U

AU - Reid, DM

AU - Riancho, JA

AU - Slagboom, PE (Eline)

AU - Garcia-Ibarbia, C

AU - Ingvarsson, T

AU - Johannsdottir, H

AU - Luben, R

AU - Medina-Gomez, C

AU - Arp, Pascal

AU - Nandakumar, K

AU - Palsson, ST

AU - Sigurdsson, G

AU - van Meurs, Joyce

AU - Zhou, YH

AU - Hofman, Bert

AU - Jukema, JW

AU - Pols, Huib

AU - Prince, RL

AU - Cupples, LA

AU - Marshall, CR

AU - Pinto, D

AU - Sato, D

AU - Scherer, SW

AU - Reeve, J

AU - Thorsteinsdottir, U

AU - Karasik, D

AU - Richards, JB

AU - Stefansson, K

AU - Uitterlinden, André

AU - Ralston, SH

AU - Ioannidis, JPA

AU - Kiel, DP

AU - Rivadeneira, Fernando

AU - Estrada Gil, Karol

PY - 2014

Y1 - 2014

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.

U2 - 10.1136/jmedgenet-2013-102064

DO - 10.1136/jmedgenet-2013-102064

M3 - Article

C2 - 24343915

SN - 0022-2593

VL - 51

SP - 122

EP - 131

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 2

ER -