Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

Ling Oei - Oei; Karol Estrada Gil; EL Duncan; C Christiansen; CT Liu; BL Langdahl; B Obermayer-Pietsch; JA Riancho; RL Prince; NM Schoor; E McCloskey; YH Hsu; E Evangelou; E Ntzani; DM Evans; N Alonso; LB Husted; C Valero; JL Hernandez; JR Lewis; SK Kaptoge; K Zhu; LA Cupples; C Medina-Gomez; L Vandenput; GS Kim; SH Lee; MC Castano-Betancourt; Edwin Oei; J Martinez; A Daroszewska; M Klift; D Mellstrom; L Herrera; MK Karlsson; Bert Hofman; O Ljunggren; Huib Pols; Lisette Stolk; Joyce van Meurs; JPA Ioannidis; M.C. Zillikens; P Lips; D Karasik; André Uitterlinden; U Styrkarsdottir; MA Brown; JM Koh; JB Richards; J Reeve; C Ohlsson; SH Ralston; DP Kiel; Fernando Rivadeneira

doi:10.1016/j.bone.2013.10.015

Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

Ling Oei - Oei, Karol Estrada Gil, EL Duncan, C Christiansen, CT Liu, BL Langdahl, B Obermayer-Pietsch, JA Riancho, RL Prince, NM Schoor, E McCloskey, YH Hsu, E Evangelou, E Ntzani, DM Evans, N Alonso, LB Husted, C Valero, JL Hernandez, JR LewisSK Kaptoge, K Zhu, LA Cupples, C Medina-Gomez, L Vandenput, GS Kim, SH Lee, MC Castano-Betancourt, Edwin Oei, J Martinez, A Daroszewska, M Klift, D Mellstrom, L Herrera, MK Karlsson, Bert Hofman, O Ljunggren, Huib Pols, Lisette Stolk, Joyce van Meurs, JPA Ioannidis, M.C. Zillikens, P Lips, D Karasik, André Uitterlinden, U Styrkarsdottir, MA Brown, JM Koh, JB Richards, J Reeve, C Ohlsson, SH Ralston, DP Kiel, Fernando Rivadeneira

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

27 Citations (Scopus)

Abstract

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fracture applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5 x 10(-8). In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 x 10(-8). However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% Cl: 0.98-1.14; p = 0.17), displaying high degree of heterogeneity (I-2= 57%; Q(het)p = 0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures. (C) 2013 Elsevier Inc. All rights reserved.

Original language	Undefined/Unknown
Pages (from-to)	20-27
Number of pages	8
Journal	Bone
Volume	59
DOIs	https://doi.org/10.1016/j.bone.2013.10.015
Publication status	Published - 2014

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10.1016/j.bone.2013.10.015

Cite this

Oei - Oei, L., Estrada Gil, K., Duncan, EL., Christiansen, C., Liu, CT., Langdahl, BL., Obermayer-Pietsch, B., Riancho, JA., Prince, RL., Schoor, NM., McCloskey, E., Hsu, YH., Evangelou, E., Ntzani, E., Evans, DM., Alonso, N., Husted, LB., Valero, C., Hernandez, JL., ... Rivadeneira, F. (2014). Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus. Bone, 59, 20-27. https://doi.org/10.1016/j.bone.2013.10.015

@article{1935bcb1a9044eea9430aed6028b29e2,

title = "Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus",

abstract = "Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fracture applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5 x 10(-8). In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 x 10(-8). However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% Cl: 0.98-1.14; p = 0.17), displaying high degree of heterogeneity (I-2= 57%; Q(het)p = 0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures. (C) 2013 Elsevier Inc. All rights reserved.",

author = "{Oei - Oei}, Ling and {Estrada Gil}, Karol and EL Duncan and C Christiansen and CT Liu and BL Langdahl and B Obermayer-Pietsch and JA Riancho and RL Prince and NM Schoor and E McCloskey and YH Hsu and E Evangelou and E Ntzani and DM Evans and N Alonso and LB Husted and C Valero and JL Hernandez and JR Lewis and SK Kaptoge and K Zhu and LA Cupples and C Medina-Gomez and L Vandenput and GS Kim and SH Lee and MC Castano-Betancourt and Edwin Oei and J Martinez and A Daroszewska and M Klift and D Mellstrom and L Herrera and MK Karlsson and Bert Hofman and O Ljunggren and Huib Pols and Lisette Stolk and {van Meurs}, Joyce and JPA Ioannidis and M.C. Zillikens and P Lips and D Karasik and Andr{\'e} Uitterlinden and U Styrkarsdottir and MA Brown and JM Koh and JB Richards and J Reeve and C Ohlsson and SH Ralston and DP Kiel and Fernando Rivadeneira",

year = "2014",

doi = "10.1016/j.bone.2013.10.015",

language = "Undefined/Unknown",

volume = "59",

pages = "20--27",

journal = "Bone",

issn = "8756-3282",

publisher = "Elsevier Inc.",

}

Oei - Oei, L, Estrada Gil, K, Duncan, EL, Christiansen, C, Liu, CT, Langdahl, BL, Obermayer-Pietsch, B, Riancho, JA, Prince, RL, Schoor, NM, McCloskey, E, Hsu, YH, Evangelou, E, Ntzani, E, Evans, DM, Alonso, N, Husted, LB, Valero, C, Hernandez, JL, Lewis, JR, Kaptoge, SK, Zhu, K, Cupples, LA, Medina-Gomez, C, Vandenput, L, Kim, GS, Lee, SH, Castano-Betancourt, MC, Oei, E, Martinez, J, Daroszewska, A, Klift, M, Mellstrom, D, Herrera, L, Karlsson, MK, Hofman, B, Ljunggren, O, Pols, H, Stolk, L, van Meurs, J, Ioannidis, JPA, Zillikens, MC, Lips, P, Karasik, D, Uitterlinden, A, Styrkarsdottir, U, Brown, MA, Koh, JM, Richards, JB, Reeve, J, Ohlsson, C, Ralston, SH, Kiel, DP & Rivadeneira, F 2014, 'Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus', Bone, vol. 59, pp. 20-27. https://doi.org/10.1016/j.bone.2013.10.015

TY - JOUR

T1 - Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

AU - Oei - Oei, Ling

AU - Estrada Gil, Karol

AU - Duncan, EL

AU - Christiansen, C

AU - Liu, CT

AU - Langdahl, BL

AU - Obermayer-Pietsch, B

AU - Riancho, JA

AU - Prince, RL

AU - Schoor, NM

AU - McCloskey, E

AU - Hsu, YH

AU - Evangelou, E

AU - Ntzani, E

AU - Evans, DM

AU - Alonso, N

AU - Husted, LB

AU - Valero, C

AU - Hernandez, JL

AU - Lewis, JR

AU - Kaptoge, SK

AU - Zhu, K

AU - Cupples, LA

AU - Medina-Gomez, C

AU - Vandenput, L

AU - Kim, GS

AU - Lee, SH

AU - Castano-Betancourt, MC

AU - Oei, Edwin

AU - Martinez, J

AU - Daroszewska, A

AU - Klift, M

AU - Mellstrom, D

AU - Herrera, L

AU - Karlsson, MK

AU - Hofman, Bert

AU - Ljunggren, O

AU - Pols, Huib

AU - Stolk, Lisette

AU - van Meurs, Joyce

AU - Ioannidis, JPA

AU - Zillikens, M.C.

AU - Lips, P

AU - Karasik, D

AU - Uitterlinden, André

AU - Styrkarsdottir, U

AU - Brown, MA

AU - Koh, JM

AU - Richards, JB

AU - Reeve, J

AU - Ohlsson, C

AU - Ralston, SH

AU - Kiel, DP

AU - Rivadeneira, Fernando

PY - 2014

Y1 - 2014

N2 - Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fracture applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5 x 10(-8). In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 x 10(-8). However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% Cl: 0.98-1.14; p = 0.17), displaying high degree of heterogeneity (I-2= 57%; Q(het)p = 0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures. (C) 2013 Elsevier Inc. All rights reserved.

AB - Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fracture applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5 x 10(-8). In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 x 10(-8). However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% Cl: 0.98-1.14; p = 0.17), displaying high degree of heterogeneity (I-2= 57%; Q(het)p = 0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures. (C) 2013 Elsevier Inc. All rights reserved.

U2 - 10.1016/j.bone.2013.10.015

DO - 10.1016/j.bone.2013.10.015

M3 - Article

SN - 8756-3282

VL - 59

SP - 20

EP - 27

JO - Bone

JF - Bone

ER -