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 journalArticlepeer-review

96 Scopus citations

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 (US)
Pages (from-to)1923-1933
Number of pages11
JournalHuman molecular genetics
Volume23
Issue number7
DOIs
StatePublished - 2014

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