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

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

Research output: Contribution to journalArticle

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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 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 languageEnglish
Pages (from-to)1923-1933
Number of pages11
JournalHuman Molecular Genetics
Volume23
Issue number7
DOIs
StatePublished - 1 Jan 2014

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Genome-Wide Association Study
Bone Density
Single Nucleotide Polymorphism
Meta-Analysis
Osteoporosis
Genome
Bone and Bones
Femur Neck
Computer Simulation
Hip
Spine
Gene Expression
Genes

Cite this

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, Elaine 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. ; Deng, Hong Wen. / Multistage genome-wide association meta-analyses identified two new loci for bone mineral density. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 7. pp. 1923-1933.
@article{559738cf0eae4112b5ed39849a12bf72,
title = "Multistage genome-wide association meta-analyses identified two new loci for bone mineral density",
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 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 = "Lei Zhang and Choi, {Hyung Jin} and Karol Estrada and Leo, {Paul J.} and Jian Li and Pei, {Yu Fang} and Yinping Zhang and Yong Lin and Hui Shen and Liu, {Yao Zhong} and Yongjun Liu and Yingchun Zhao and Zhang, {Ji Gang} and Qing Tian and Wang, {Yu ping} and Yingying Han and Shu Ran and Rong Hai and Zhu, {Xue Zhen} and Shuyan Wu and Han Yan and Xiaogang Liu and Yang, {Tie Lin} and Yan Guo and Feng Zhang and Guo, {Yan fang} and Yuan Chen and Xiangding Chen and Lijun Tan and Lishu Zhang and Deng, {Fei Yan} and Hongyi Deng and Fernando Rivadeneira and Duncan, {Emma L.} and Lee, {Jong Young} and Han, {Bok Ghee} and Cho, {Nam H.} and Nicholson, {Geoffrey C.} and Eugene McCloskey and Richard Eastell and Prince, {Richard L.} and Eisman, {John A.} and Graeme Jones and Reid, {Ian R.} and Sambrook, {Philip N.} and Dennison, {Elaine M.} and Patrick Danoy and Yerges-Armstrong, {Laura M.} and Streeten, {Elizabeth A.} and Tian Hu and Shuanglin Xiang and Papasian, {Christopher J.} and Brown, {Matthew A.} and Shin, {Chan Soo} and Uitterlinden, {Andr{\'e} G.} and Deng, {Hong Wen}",
year = "2014",
month = "1",
day = "1",
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",

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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, Zhang, L, Deng, FY, Deng, H, Rivadeneira, F, Duncan, EL, Lee, JY, Han, BG, Cho, NH, Nicholson, GC, McCloskey, E, Eastell, R, Prince, RL, 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

Multistage genome-wide association meta-analyses identified two new loci for bone mineral density. / 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, Elaine 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.; Deng, Hong Wen.

In: Human Molecular Genetics, Vol. 23, No. 7, 01.01.2014, p. 1923-1933.

Research output: Contribution to journalArticle

TY - JOUR

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

AU - Zhang, Lei

AU - Choi, Hyung Jin

AU - Estrada, Karol

AU - Leo, Paul J.

AU - Li, Jian

AU - Pei, Yu Fang

AU - Zhang, Yinping

AU - Lin, Yong

AU - Shen, Hui

AU - Liu, Yao Zhong

AU - Liu, Yongjun

AU - Zhao, Yingchun

AU - Zhang, Ji Gang

AU - Tian, Qing

AU - Wang, Yu ping

AU - Han, Yingying

AU - Ran, Shu

AU - Hai, Rong

AU - Zhu, Xue Zhen

AU - Wu, Shuyan

AU - Yan, Han

AU - Liu, Xiaogang

AU - Yang, Tie Lin

AU - Guo, Yan

AU - Zhang, Feng

AU - Guo, Yan fang

AU - Chen, Yuan

AU - Chen, Xiangding

AU - Tan, Lijun

AU - Zhang, Lishu

AU - Deng, Fei Yan

AU - Deng, Hongyi

AU - Rivadeneira, Fernando

AU - Duncan, Emma L.

AU - Lee, Jong Young

AU - Han, Bok Ghee

AU - Cho, Nam H.

AU - Nicholson, Geoffrey C.

AU - McCloskey, Eugene

AU - Eastell, Richard

AU - Prince, Richard L.

AU - Eisman, John A.

AU - Jones, Graeme

AU - Reid, Ian R.

AU - Sambrook, Philip N.

AU - Dennison, Elaine M.

AU - Danoy, Patrick

AU - Yerges-Armstrong, Laura M.

AU - Streeten, Elizabeth A.

AU - Hu, Tian

AU - Xiang, Shuanglin

AU - Papasian, Christopher J.

AU - Brown, Matthew A.

AU - Shin, Chan Soo

AU - Uitterlinden, André G.

AU - Deng, Hong Wen

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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 - 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.

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U2 - 10.1093/hmg/ddt575

DO - 10.1093/hmg/ddt575

M3 - Article

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AN - SCOPUS:84897861546

VL - 23

SP - 1923

EP - 1933

JO - Human molecular genetics

JF - Human molecular genetics

SN - 0964-6906

IS - 7

ER -