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

Multistage genome-wide association meta-analyses identified two new loci for bone mineral density
Multistage genome-wide association meta-analyses identified two new loci for bone mineral density
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 = 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.
1923-1933
Zhang, Lei
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Choi, Hyung Jin
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Estrada, Karol
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Leo, Paul J.
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Li, Jian
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Zhang, Yinping
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Lin, Yong
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Shen, Hui
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Liu, Yao-Zhong
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Liu, Yongjun
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Tian, Qing
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Wang, Yu-ping
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Yan, Han
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Zhang, Feng
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Guo, Yan-fang
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Chen, Xiangding
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Deng, Fei-Yan
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Deng, Hongyi
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Rivadeneira, Fernando
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Duncan, Emma L.
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Lee, Jong Young
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Han, Bok Ghee
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Cho, Nam H.
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Nicholson, Geoffrey C.
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McCloskey, Eugene
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Eastell, Richard
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Prince, Richard L.
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Eisman, John A.
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Jones, Graeme
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Reid, Ian R.
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Sambrook, Philip N.
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Dennison, E.M.
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Danoy, Patrick
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Yerges-Armstrong, Laura M.
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Streeten, Elizabeth A.
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Hu, Tian
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Xiang, Shuanglin
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Papasian, Christopher J.
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Brown, Matthew A.
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Shin, Chan Soo
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Uitterlinden, André G
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Deng, Hong-Wen
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Zhang, Lei
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Choi, Hyung Jin
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Estrada, Karol
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Leo, Paul J.
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Li, Jian
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Pei, Yu-Fang
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Zhang, Yinping
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Lin, Yong
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Shen, Hui
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Liu, Yao-Zhong
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Liu, Yongjun
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Zhao, Yingchun
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Zhang, Ji-Gang
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Tian, Qing
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Wang, Yu-ping
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Han, Yingying
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Ran, Shu
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Hai, Rong
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Zhu, Xue-Zhen
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Wu, Shuyan
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Yan, Han
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Liu, Xiaogang
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Yang, Tie-Lin
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Guo, Yan
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Zhang, Feng
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Guo, Yan-fang
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Chen, Yuan
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Chen, Xiangding
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Tan, Lijun
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Zhang, Lishu
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Deng, Fei-Yan
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Deng, Hongyi
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Rivadeneira, Fernando
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Duncan, Emma L.
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Lee, Jong Young
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Han, Bok Ghee
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Cho, Nam H.
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Nicholson, Geoffrey C.
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McCloskey, Eugene
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Eastell, Richard
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Prince, Richard L.
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Eisman, John A.
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Jones, Graeme
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Reid, Ian R.
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Sambrook, Philip N.
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Dennison, E.M.
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Danoy, Patrick
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Yerges-Armstrong, Laura M.
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Streeten, Elizabeth A.
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Hu, Tian
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Xiang, Shuanglin
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Papasian, Christopher J.
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Brown, Matthew A.
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Shin, Chan Soo
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Uitterlinden, André G
3602fdd2-b484-4be5-91e6-403a281a43f7
Deng, Hong-Wen
51a56591-4119-4ea7-b263-18308b868fa8

Zhang, Lei, Choi, Hyung Jin, Estrada, Karol, Leo, Paul J., Li, Jian, Pei, Yu-Fang, Zhang, Yinping, Lin, Yong, Shen, Hui, Liu, Yao-Zhong, Liu, Yongjun, Zhao, Yingchun, Zhang, Ji-Gang, Tian, Qing, Wang, Yu-ping, Han, Yingying, Ran, Shu, Hai, Rong, Zhu, Xue-Zhen, Wu, Shuyan, Yan, Han, Liu, Xiaogang, Yang, Tie-Lin, Guo, Yan, Zhang, Feng, Guo, Yan-fang, Chen, Yuan, Chen, Xiangding, Tan, Lijun, Zhang, Lishu, Deng, Fei-Yan, Deng, Hongyi, Rivadeneira, Fernando, Duncan, Emma L., Lee, Jong Young, Han, Bok Ghee, Cho, Nam H., Nicholson, Geoffrey C., McCloskey, Eugene, Eastell, Richard, Prince, Richard L., Eisman, John A., Jones, Graeme, Reid, Ian R., Sambrook, Philip N., Dennison, E.M., Danoy, Patrick, Yerges-Armstrong, Laura M., Streeten, Elizabeth A., Hu, Tian, Xiang, Shuanglin, Papasian, Christopher J., Brown, Matthew A., Shin, Chan Soo, Uitterlinden, André G and Deng, Hong-Wen (2014) Multistage genome-wide association meta-analyses identified two new loci for bone mineral density. Human Molecular Genetics, 23 (7), 1923-1933. (doi:10.1093/hmg/ddt575). (PMID:24249740)

Record type: Article

Abstract

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 = 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.

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More information

Published date: 1 April 2014
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 366478
URI: http://eprints.soton.ac.uk/id/eprint/366478
PURE UUID: a486cbf7-bf74-458c-95cc-97261527f1f5
ORCID for E.M. Dennison: ORCID iD orcid.org/0000-0002-3048-4961

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Date deposited: 01 Jul 2014 11:28
Last modified: 18 Feb 2021 16:46

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Contributors

Author: Lei Zhang
Author: Hyung Jin Choi
Author: Karol Estrada
Author: Paul J. Leo
Author: Jian Li
Author: Yu-Fang Pei
Author: Yinping Zhang
Author: Yong Lin
Author: Hui Shen
Author: Yao-Zhong Liu
Author: Yongjun Liu
Author: Yingchun Zhao
Author: Ji-Gang Zhang
Author: Qing Tian
Author: Yu-ping Wang
Author: Yingying Han
Author: Shu Ran
Author: Rong Hai
Author: Xue-Zhen Zhu
Author: Shuyan Wu
Author: Han Yan
Author: Xiaogang Liu
Author: Tie-Lin Yang
Author: Yan Guo
Author: Feng Zhang
Author: Yan-fang Guo
Author: Yuan Chen
Author: Xiangding Chen
Author: Lijun Tan
Author: Lishu Zhang
Author: Fei-Yan Deng
Author: Hongyi Deng
Author: Fernando Rivadeneira
Author: Emma L. Duncan
Author: Jong Young Lee
Author: Bok Ghee Han
Author: Nam H. Cho
Author: Geoffrey C. Nicholson
Author: Eugene McCloskey
Author: Richard Eastell
Author: Richard L. Prince
Author: John A. Eisman
Author: Graeme Jones
Author: Ian R. Reid
Author: Philip N. Sambrook
Author: E.M. Dennison ORCID iD
Author: Patrick Danoy
Author: Laura M. Yerges-Armstrong
Author: Elizabeth A. Streeten
Author: Tian Hu
Author: Shuanglin Xiang
Author: Christopher J. Papasian
Author: Matthew A. Brown
Author: Chan Soo Shin
Author: André G Uitterlinden
Author: Hong-Wen Deng

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