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

Citation

Zhang, L and Choi, HJ and Estrada, K and Leo, PJ and Li, J and Pei, Y-F and Zhang, Y and Lin, Y and Shen, H and Liu, Y-Z and Liu, Y and Zhao, Y and Zhang, J-G and Tian, Q and Wang, Y-P and Han, Y and Ran, S and Hai, R and Zhu, X-Z and Wu, S and Yan, H and Liu, X and Yang, T-L and Guo, Y and Zhang, F and Guo, Y-F and Chen, Y and Chen, X and Tan, L and Zhang, L and Deng, F-Y and Deng, H and Rivadeneira, F and Duncan, EL and Lee, JY and Han, BG and Cho, NH and Nicholson, GC and McCloskey, E and Eastell, R and Prince, RL and Eisman, JA and Jones, G and Reid, IR and Sambrook, PN and Dennison, EM and Danoy, P and Yerges-Armstrong, LM and Streeten, EA and Hu, T and Xiang, S and Papasian, CJ and Brown, MA and Shin, CS and Uitterlinden, AG and Deng, H-W, Multistage genome-wide association meta-analyses identified two new loci for bone mineral density, Human Molecular Genetics, 23, (7) pp. 1923-1933. ISSN 0964-6906 (2014) [Refereed Article]

Copyright Statement

Copyright 2013 The Authors

DOI: doi:10.1093/hmg/ddt575

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.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Clinical Sciences
Research Field:Rheumatology and Arthritis
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Skeletal System and Disorders (incl. Arthritis)
Author:Jones, G (Professor Graeme Jones)
ID Code:100412
Year Published:2014
Web of Science® Times Cited:49
Deposited By:Menzies Institute for Medical Research
Deposited On:2015-05-14
Last Modified:2015-08-28
Downloads:0

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