Multistage genome-wide association meta-analyses identified two new loci for bone mineral density

L. Zhang; H.J. Choi; K. Estrada; P.J. Leo; J. Li; Y.F. Pei; Y. Zhang; Y. Lin; H. Shen; Y.Z. Liu; Y. Liu; Y. Zhao; J.G. Zhang; Q. Tian; Y.p. Wang; Y. Han; S. Ran; R. Hai; X.Z. Zhu; S. Wu; H. Yan; X. Liu; T.L. Yang; Y. Guo; F. Zhang; Y.f. Guo; Y. Chen; X. Chen; L. Tan; F.Y. Deng; H. Deng; F. Rivadeneira; E.L. Duncan; J.Y. Lee; B.G. Han; N.H. Cho; G.C. Nicholson; E. Mccloskey; R. Eastell; Richard Prince; J.A. Eisman; G. Jones; I.R. Reid; P.N. Sambrook; E.M. Dennison; P. Danoy; L.M. Yerges-Armstrong; E.A. Streeten; T. Hu; S. Xiang; C.J. Papasian; M.A. Brown; C.S. Shin; A.G. Uitterlinden; H.W. Deng

doi:10.1093/hmg/ddt575

Multistage genome-wide association meta-analyses identified two new loci for bone mineral density

L. Zhang, H.J. Choi, K. Estrada, P.J. Leo, J. Li, Y.F. Pei, Y. Zhang, Y. Lin, H. Shen, Y.Z. Liu, Y. Liu, Y. Zhao, J.G. Zhang, Q. Tian, Y.p. Wang, Y. Han, S. Ran, R. Hai, X.Z. Zhu, S. WuH. Yan, X. Liu, T.L. Yang, Y. Guo, F. Zhang, Y.f. Guo, Y. Chen, X. Chen, L. Tan, F.Y. Deng, H. Deng, F. Rivadeneira, E.L. Duncan, J.Y. Lee, B.G. Han, N.H. Cho, G.C. Nicholson, E. Mccloskey, R. Eastell, Richard Prince, J.A. Eisman, G. Jones, I.R. Reid, P.N. Sambrook, E.M. Dennison, P. Danoy, L.M. Yerges-Armstrong, E.A. Streeten, T. Hu, S. Xiang, C.J. Papasian, M.A. Brown, C.S. Shin, A.G. Uitterlinden, H.W. Deng

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Abstract

© The Author 2013. Published by Oxford University Press. Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10-8) level: 14q24.2 (rs227425, P-value 3.98 × 10-13, SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10-9, CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n 5 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.

Original language	English
Pages (from-to)	1923-1933
Journal	Human Molecular Genetics
Volume	23
Issue number	7
Early online date	17 Nov 2013
DOIs	https://doi.org/10.1093/hmg/ddt575
Publication status	Published - 2014

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10.1093/hmg/ddt575

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Zhang, L., Choi, H. J., Estrada, K., Leo, P. J., Li, J., Pei, Y. F., Zhang, Y., Lin, Y., Shen, H., Liu, Y. Z., Liu, Y., Zhao, Y., Zhang, J. G., Tian, Q., Wang, Y. P., Han, Y., Ran, S., Hai, R., Zhu, X. Z., ... Deng, H. W. (2014). Multistage genome-wide association meta-analyses identified two new loci for bone mineral density. Human Molecular Genetics, 23(7), 1923-1933. https://doi.org/10.1093/hmg/ddt575

@article{33db487182004f26b4a654fa1a9fa624,

title = "Multistage genome-wide association meta-analyses identified two new loci for bone mineral density",

abstract = "{\textcopyright} The Author 2013. Published by Oxford University Press. Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10-8) level: 14q24.2 (rs227425, P-value 3.98 × 10-13, SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10-9, CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n 5 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.",

author = "L. Zhang and H.J. Choi and K. Estrada and P.J. Leo and J. Li and Y.F. Pei and Y. Zhang and Y. Lin and H. Shen and Y.Z. Liu and Y. Liu and Y. Zhao and J.G. Zhang and Q. Tian and Y.p. Wang and Y. Han and S. Ran and R. Hai and X.Z. Zhu and S. Wu and H. Yan and X. Liu and T.L. Yang and Y. Guo and F. Zhang and Y.f. Guo and Y. Chen and X. Chen and L. Tan and F.Y. Deng and H. Deng and F. Rivadeneira and E.L. Duncan and J.Y. Lee and B.G. Han and N.H. Cho and G.C. Nicholson and E. Mccloskey and R. Eastell and Richard Prince and J.A. Eisman and G. Jones and I.R. Reid and P.N. Sambrook and E.M. Dennison and P. Danoy and L.M. Yerges-Armstrong and E.A. Streeten and T. Hu and S. Xiang and C.J. Papasian and M.A. Brown and C.S. Shin and A.G. Uitterlinden and H.W. Deng",

year = "2014",

doi = "10.1093/hmg/ddt575",

language = "English",

volume = "23",

pages = "1923--1933",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "7",

}

Zhang, L, Choi, HJ, Estrada, K, Leo, PJ, Li, J, Pei, YF, Zhang, Y, Lin, Y, Shen, H, Liu, YZ, Liu, Y, Zhao, Y, Zhang, JG, Tian, Q, Wang, YP, Han, Y, Ran, S, Hai, R, Zhu, XZ, Wu, S, Yan, H, Liu, X, Yang, TL, Guo, Y, Zhang, F, Guo, YF, Chen, Y, Chen, X, Tan, L, Deng, FY, Deng, H, Rivadeneira, F, Duncan, EL, Lee, JY, Han, BG, Cho, NH, Nicholson, GC, Mccloskey, E, Eastell, R, Prince, R, Eisman, JA, Jones, G, Reid, IR, Sambrook, PN, Dennison, EM, Danoy, P, Yerges-Armstrong, LM, Streeten, EA, Hu, T, Xiang, S, Papasian, CJ, Brown, MA, Shin, CS, Uitterlinden, AG & Deng, HW 2014, 'Multistage genome-wide association meta-analyses identified two new loci for bone mineral density', Human Molecular Genetics, vol. 23, no. 7, pp. 1923-1933. https://doi.org/10.1093/hmg/ddt575

TY - JOUR

T1 - Multistage genome-wide association meta-analyses identified two new loci for bone mineral density

AU - Zhang, L.

AU - Choi, H.J.

AU - Estrada, K.

AU - Leo, P.J.

AU - Li, J.

AU - Pei, Y.F.

AU - Zhang, Y.

AU - Lin, Y.

AU - Shen, H.

AU - Liu, Y.Z.

AU - Liu, Y.

AU - Zhao, Y.

AU - Zhang, J.G.

AU - Tian, Q.

AU - Wang, Y.p.

AU - Han, Y.

AU - Ran, S.

AU - Hai, R.

AU - Zhu, X.Z.

AU - Wu, S.

AU - Yan, H.

AU - Liu, X.

AU - Yang, T.L.

AU - Guo, Y.

AU - Zhang, F.

AU - Guo, Y.f.

AU - Chen, Y.

AU - Chen, X.

AU - Tan, L.

AU - Deng, F.Y.

AU - Deng, H.

AU - Rivadeneira, F.

AU - Duncan, E.L.

AU - Lee, J.Y.

AU - Han, B.G.

AU - Cho, N.H.

AU - Nicholson, G.C.

AU - Mccloskey, E.

AU - Eastell, R.

AU - Prince, Richard

AU - Eisman, J.A.

AU - Jones, G.

AU - Reid, I.R.

AU - Sambrook, P.N.

AU - Dennison, E.M.

AU - Danoy, P.

AU - Yerges-Armstrong, L.M.

AU - Streeten, E.A.

AU - Hu, T.

AU - Xiang, S.

AU - Papasian, C.J.

AU - Brown, M.A.

AU - Shin, C.S.

AU - Uitterlinden, A.G.

AU - Deng, H.W.

PY - 2014

Y1 - 2014

N2 - © The Author 2013. Published by Oxford University Press. Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10-8) level: 14q24.2 (rs227425, P-value 3.98 × 10-13, SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10-9, CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n 5 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.

AB - © The Author 2013. Published by Oxford University Press. Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10-8) level: 14q24.2 (rs227425, P-value 3.98 × 10-13, SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10-9, CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n 5 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.

U2 - 10.1093/hmg/ddt575

DO - 10.1093/hmg/ddt575

M3 - Article

C2 - 24249740

VL - 23

SP - 1923

EP - 1933

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 7

ER -

Multistage genome-wide association meta-analyses identified two new loci for bone mineral density

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