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

Lei Zhang, HJ Choi, Karol Estrada Gil, PJ Leo, J Li, YF Pei, YP Zhang, Y Lin, H Shen, YZ Liu, YJ Liu, YC Zhao, JG Zhang, Q Tian, YP Wang, YY Han, S Ran, R Hai, XZ Zhu, SY WuH Yan, XG Liu, TL Yang, Y Guo, F Zhang, YF Guo, Y Chen, XD Chen, LJ Tan, LS Zhang, FY Deng, HY Deng, Fernando Rivadeneira, EL Duncan, JY Lee, BG Han, NH Cho, GC Nicholson, E McCloskey, R Eastell, RL Prince, JA Eisman, G Jones, IR Reid, PN Sambrook, EM Dennison, P Danoy, LM Yerges-Armstrong, EA Streeten, T Hu, SL Xiang, CJ Papasian, MA Brown, CS Shin, André Uitterlinden, HW Deng

Research output: Contribution to journalArticleAcademicpeer-review

129 Citations (Scopus)


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 x 10(-8)) level: 14q24.2 (rs227425, P-value 3.98 x 10(-13), SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 x 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.
Original languageEnglish
Pages (from-to)1923-1933
Number of pages11
JournalHuman Molecular Genetics
Issue number7
Publication statusPublished - 2014

Research programs

  • EMC MM-01-39-09-A
  • EMC NIHES-01-64-01


Dive into the research topics of 'Multistage genome-wide association meta-analyses identified two new loci for bone mineral density'. Together they form a unique fingerprint.

Cite this