Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

A Moayyeri; YH Hsu; D Karasik; Karol Estrada Gil; SM Xiao; C Nielson; P Srikanth; S Giroux; SG Wilson; HF Zheng; AV Smith; SR Pye; PJ Leo; A Teumer; JY Hwang; C Ohlsson; F McGuigan; RL Minster; C Hayward; JM Olmos; LP Lyytikainen; JR Lewis; KMA Swart; L Masi; C Oldmeadow; EG Holliday; SL Cheng; NM Schoor; NC Harvey; M van der Kruk; M Greco; W Igl; O Trummer; E Grigoriou; R Luben; CT Liu; YH Zhou; Ling Oei - Oei; C Medina-Gomez; J Zmuda; G Tranah; SJ Brown; FM Williams; N Soranzo; J Jakobsdottir; K Siggeirsdottir; KL Holliday; A Hannemann; MJ Go; M Garcia; O Polasek; M Laaksonen; K Zhu; Anke Enneman; M McEvoy; R Peel; PC Sham; M Jaworski; A Johansson; AA Hicks; P Pludowski; R Scott; RAM Dhonukshe-Rutten; Nathalie van der Velde; M Kahonen; JS Viikari; H Sievanen; OT Raitakari; J Gonzalez-Macias; JL Hernandez; D Mellstroom; O Ljunggren; YS Cho; U Volker; M Nauck; G Homuth; H Volzke; R Haring; MA Brown; E McCloskey; GC Nicholson; R Eastell; JA Eisman; G Jones; IR Reid; EM Dennison; J Wark; S Boonen; D Vanderschueren; FCW Wu; T Aspelund; JB Richards; D Bauer; Bert Hofman; KT Khaw; G Dedoussis; B Obermayer-Pietsch; U Gyllensten; PP Pramstaller; RS Lorenc; C Cooper; AWC Kung; P Lips; M Alen; J Attia; ML Brandi; LCPGM (Lisette) de Groot; T Lehtimaki; JA Riancho; H Campbell; YM Liu; TB Harris; K Akesson; M Karlsson; JY Lee; H Wallaschofski; EL Duncan; TW O'Neill; V Gudnason; TD Spector; F Rousseau; E Orwoll; SR Cummings; NJ Wareham; Fernando Rivadeneira; André Uitterlinden; RL Prince; DP Kiel; J Reeve; SK Kaptoge

doi:10.1093/hmg/ddt675

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

A Moayyeri, YH Hsu, D Karasik, Karol Estrada Gil, SM Xiao, C Nielson, P Srikanth, S Giroux, SG Wilson, HF Zheng, AV Smith, SR Pye, PJ Leo, A Teumer, JY Hwang, C Ohlsson, F McGuigan, RL Minster, C Hayward, JM OlmosLP Lyytikainen, JR Lewis, KMA Swart, L Masi, C Oldmeadow, EG Holliday, SL Cheng, NM Schoor, NC Harvey, M van der Kruk, M Greco, W Igl, O Trummer, E Grigoriou, R Luben, CT Liu, YH Zhou, Ling Oei - Oei, C Medina-Gomez, J Zmuda, G Tranah, SJ Brown, FM Williams, N Soranzo, J Jakobsdottir, K Siggeirsdottir, KL Holliday, A Hannemann, MJ Go, M Garcia, O Polasek, M Laaksonen, K Zhu, Anke Enneman, M McEvoy, R Peel, PC Sham, M Jaworski, A Johansson, AA Hicks, P Pludowski, R Scott, RAM Dhonukshe-Rutten, Nathalie van der Velde, M Kahonen, JS Viikari, H Sievanen, OT Raitakari, J Gonzalez-Macias, JL Hernandez, D Mellstroom, O Ljunggren, YS Cho, U Volker, M Nauck, G Homuth, H Volzke, R Haring, MA Brown, E McCloskey, GC Nicholson, R Eastell, JA Eisman, G Jones, IR Reid, EM Dennison, J Wark, S Boonen, D Vanderschueren, FCW Wu, T Aspelund, JB Richards, D Bauer, Bert Hofman, KT Khaw, G Dedoussis, B Obermayer-Pietsch, U Gyllensten, PP Pramstaller, RS Lorenc, C Cooper, AWC Kung, P Lips, M Alen, J Attia, ML Brandi, LCPGM (Lisette) de Groot, T Lehtimaki, JA Riancho, H Campbell, YM Liu, TB Harris, K Akesson, M Karlsson, JY Lee, H Wallaschofski, EL Duncan, TW O'Neill, V Gudnason, TD Spector, F Rousseau, E Orwoll, SR Cummings, NJ Wareham, Fernando Rivadeneira, André Uitterlinden, RL Prince, DP Kiel, J Reeve, SK Kaptoge

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

89 Citations (Scopus)

Abstract

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Original language	Undefined/Unknown
Pages (from-to)	3054-3068
Number of pages	15
Journal	Human Molecular Genetics
Volume	23
Issue number	11
DOIs	https://doi.org/10.1093/hmg/ddt675
Publication status	Published - 2014

Research programs

EMC MM-01-39-09-A
EMC NIHES-01-64-02
EMC OR-01-39-08

Access to Document

10.1093/hmg/ddt675

Cite this

Moayyeri, A., Hsu, YH., Karasik, D., Estrada Gil, K., Xiao, SM., Nielson, C., Srikanth, P., Giroux, S., Wilson, SG., Zheng, HF., Smith, AV., Pye, SR., Leo, PJ., Teumer, A., Hwang, JY., Ohlsson, C., McGuigan, F., Minster, RL., Hayward, C., ... Kaptoge, SK. (2014). Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium. Human Molecular Genetics, 23(11), 3054-3068. https://doi.org/10.1093/hmg/ddt675

@article{f890f071113c4ceebc1cbfafafe20764,

title = "Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium",

abstract = "Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.",

author = "A Moayyeri and YH Hsu and D Karasik and {Estrada Gil}, Karol and SM Xiao and C Nielson and P Srikanth and S Giroux and SG Wilson and HF Zheng and AV Smith and SR Pye and PJ Leo and A Teumer and JY Hwang and C Ohlsson and F McGuigan and RL Minster and C Hayward and JM Olmos and LP Lyytikainen and JR Lewis and KMA Swart and L Masi and C Oldmeadow and EG Holliday and SL Cheng and NM Schoor and NC Harvey and {van der Kruk}, M and M Greco and W Igl and O Trummer and E Grigoriou and R Luben and CT Liu and YH Zhou and {Oei - Oei}, Ling and C Medina-Gomez and J Zmuda and G Tranah and SJ Brown and FM Williams and N Soranzo and J Jakobsdottir and K Siggeirsdottir and KL Holliday and A Hannemann and MJ Go and M Garcia and O Polasek and M Laaksonen and K Zhu and Anke Enneman and M McEvoy and R Peel and PC Sham and M Jaworski and A Johansson and AA Hicks and P Pludowski and R Scott and RAM Dhonukshe-Rutten and {van der Velde}, Nathalie and M Kahonen and JS Viikari and H Sievanen and OT Raitakari and J Gonzalez-Macias and JL Hernandez and D Mellstroom and O Ljunggren and YS Cho and U Volker and M Nauck and G Homuth and H Volzke and R Haring and MA Brown and E McCloskey and GC Nicholson and R Eastell and JA Eisman and G Jones and IR Reid and EM Dennison and J Wark and S Boonen and D Vanderschueren and FCW Wu and T Aspelund and JB Richards and D Bauer and Bert Hofman and KT Khaw and G Dedoussis and B Obermayer-Pietsch and U Gyllensten and PP Pramstaller and RS Lorenc and C Cooper and AWC Kung and P Lips and M Alen and J Attia and ML Brandi and {de Groot}, {LCPGM (Lisette)} and T Lehtimaki and JA Riancho and H Campbell and YM Liu and TB Harris and K Akesson and M Karlsson and JY Lee and H Wallaschofski and EL Duncan and TW O'Neill and V Gudnason and TD Spector and F Rousseau and E Orwoll and SR Cummings and NJ Wareham and Fernando Rivadeneira and Andr{\'e} Uitterlinden and RL Prince and DP Kiel and J Reeve and SK Kaptoge",

year = "2014",

doi = "10.1093/hmg/ddt675",

language = "Undefined/Unknown",

volume = "23",

pages = "3054--3068",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "11",

}

Moayyeri, A, Hsu, YH, Karasik, D, Estrada Gil, K, Xiao, SM, Nielson, C, Srikanth, P, Giroux, S, Wilson, SG, Zheng, HF, Smith, AV, Pye, SR, Leo, PJ, Teumer, A, Hwang, JY, Ohlsson, C, McGuigan, F, Minster, RL, Hayward, C, Olmos, JM, Lyytikainen, LP, Lewis, JR, Swart, KMA, Masi, L, Oldmeadow, C, Holliday, EG, Cheng, SL, Schoor, NM, Harvey, NC, van der Kruk, M, Greco, M, Igl, W, Trummer, O, Grigoriou, E, Luben, R, Liu, CT, Zhou, YH, Oei - Oei, L, Medina-Gomez, C, Zmuda, J, Tranah, G, Brown, SJ, Williams, FM, Soranzo, N, Jakobsdottir, J, Siggeirsdottir, K, Holliday, KL, Hannemann, A, Go, MJ, Garcia, M, Polasek, O, Laaksonen, M, Zhu, K, Enneman, A, McEvoy, M, Peel, R, Sham, PC, Jaworski, M, Johansson, A, Hicks, AA, Pludowski, P, Scott, R, Dhonukshe-Rutten, RAM, van der Velde, N, Kahonen, M, Viikari, JS, Sievanen, H, Raitakari, OT, Gonzalez-Macias, J, Hernandez, JL, Mellstroom, D, Ljunggren, O, Cho, YS, Volker, U, Nauck, M, Homuth, G, Volzke, H, Haring, R, Brown, MA, McCloskey, E, Nicholson, GC, Eastell, R, Eisman, JA, Jones, G, Reid, IR, Dennison, EM, Wark, J, Boonen, S, Vanderschueren, D, Wu, FCW, Aspelund, T, Richards, JB, Bauer, D, Hofman, B, Khaw, KT, Dedoussis, G, Obermayer-Pietsch, B, Gyllensten, U, Pramstaller, PP, Lorenc, RS, Cooper, C, Kung, AWC, Lips, P, Alen, M, Attia, J, Brandi, ML, de Groot, LCPGM, Lehtimaki, T, Riancho, JA, Campbell, H, Liu, YM, Harris, TB, Akesson, K, Karlsson, M, Lee, JY, Wallaschofski, H, Duncan, EL, O'Neill, TW, Gudnason, V, Spector, TD, Rousseau, F, Orwoll, E, Cummings, SR, Wareham, NJ, Rivadeneira, F , Uitterlinden, A, Prince, RL, Kiel, DP, Reeve, J & Kaptoge, SK 2014, 'Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium', Human Molecular Genetics, vol. 23, no. 11, pp. 3054-3068. https://doi.org/10.1093/hmg/ddt675

TY - JOUR

T1 - Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

AU - Moayyeri, A

AU - Hsu, YH

AU - Karasik, D

AU - Estrada Gil, Karol

AU - Xiao, SM

AU - Nielson, C

AU - Srikanth, P

AU - Giroux, S

AU - Wilson, SG

AU - Zheng, HF

AU - Smith, AV

AU - Pye, SR

AU - Leo, PJ

AU - Teumer, A

AU - Hwang, JY

AU - Ohlsson, C

AU - McGuigan, F

AU - Minster, RL

AU - Hayward, C

AU - Olmos, JM

AU - Lyytikainen, LP

AU - Lewis, JR

AU - Swart, KMA

AU - Masi, L

AU - Oldmeadow, C

AU - Holliday, EG

AU - Cheng, SL

AU - Schoor, NM

AU - Harvey, NC

AU - van der Kruk, M

AU - Greco, M

AU - Igl, W

AU - Trummer, O

AU - Grigoriou, E

AU - Luben, R

AU - Liu, CT

AU - Zhou, YH

AU - Oei - Oei, Ling

AU - Medina-Gomez, C

AU - Zmuda, J

AU - Tranah, G

AU - Brown, SJ

AU - Williams, FM

AU - Soranzo, N

AU - Jakobsdottir, J

AU - Siggeirsdottir, K

AU - Holliday, KL

AU - Hannemann, A

AU - Go, MJ

AU - Garcia, M

AU - Polasek, O

AU - Laaksonen, M

AU - Zhu, K

AU - Enneman, Anke

AU - McEvoy, M

AU - Peel, R

AU - Sham, PC

AU - Jaworski, M

AU - Johansson, A

AU - Hicks, AA

AU - Pludowski, P

AU - Scott, R

AU - Dhonukshe-Rutten, RAM

AU - van der Velde, Nathalie

AU - Kahonen, M

AU - Viikari, JS

AU - Sievanen, H

AU - Raitakari, OT

AU - Gonzalez-Macias, J

AU - Hernandez, JL

AU - Mellstroom, D

AU - Ljunggren, O

AU - Cho, YS

AU - Volker, U

AU - Nauck, M

AU - Homuth, G

AU - Volzke, H

AU - Haring, R

AU - Brown, MA

AU - McCloskey, E

AU - Nicholson, GC

AU - Eastell, R

AU - Eisman, JA

AU - Jones, G

AU - Reid, IR

AU - Dennison, EM

AU - Wark, J

AU - Boonen, S

AU - Vanderschueren, D

AU - Wu, FCW

AU - Aspelund, T

AU - Richards, JB

AU - Bauer, D

AU - Hofman, Bert

AU - Khaw, KT

AU - Dedoussis, G

AU - Obermayer-Pietsch, B

AU - Gyllensten, U

AU - Pramstaller, PP

AU - Lorenc, RS

AU - Cooper, C

AU - Kung, AWC

AU - Lips, P

AU - Alen, M

AU - Attia, J

AU - Brandi, ML

AU - de Groot, LCPGM (Lisette)

AU - Lehtimaki, T

AU - Riancho, JA

AU - Campbell, H

AU - Liu, YM

AU - Harris, TB

AU - Akesson, K

AU - Karlsson, M

AU - Lee, JY

AU - Wallaschofski, H

AU - Duncan, EL

AU - O'Neill, TW

AU - Gudnason, V

AU - Spector, TD

AU - Rousseau, F

AU - Orwoll, E

AU - Cummings, SR

AU - Wareham, NJ

AU - Rivadeneira, Fernando

AU - Uitterlinden, André

AU - Prince, RL

AU - Kiel, DP

AU - Reeve, J

AU - Kaptoge, SK

PY - 2014

Y1 - 2014

N2 - Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

AB - Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

U2 - 10.1093/hmg/ddt675

DO - 10.1093/hmg/ddt675

M3 - Article

C2 - 24430505

SN - 0964-6906

VL - 23

SP - 3054

EP - 3068

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 11

ER -