University Of Tasmania

File(s) under permanent embargo

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

journal contribution
posted on 2023-05-18, 09:55 authored by Zhang, L, Choi, HJ, Estrada, K, Leo, PJ, 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, Wu, S, Yan, H, Liu, X, Yang, T-L, Guo, Y, Zhang, F, Guo, Y-F, Chen, Y, Chen, X, Tan, L, Deng, F-Y, Deng, H, Rivadeneira, F, Duncan, EL, Lee, JY, Han, BG, Cho, NH, Nicholson, GC, McCloskey, E, Eastell, R, Prince, RL, Eisman, JA, Graeme JonesGraeme Jones, 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, H-W
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.


Publication title

Human Molecular Genetics










Menzies Institute for Medical Research


Oxford Univ Press

Place of publication

Great Clarendon St, Oxford, England, Ox2 6Dp

Rights statement

Copyright 2013 The Authors

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

Usage metrics

    University Of Tasmania