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

Zhang, L., Choi, H.J., Estrada, K., Leo, P.J., 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., Zhang, L., Deng, F.Y., Deng, H., Rivadeneira, F., Duncan, E.L., Lee, J.Y., Han, B.G., Cho, N.H., Nicholson, G.C., McCloskey, E., Eastell, R., Prince, R.L., Eisman, J.A., Jones, G., Reid, I.R., Sambrook, P.N., Dennison, E.M., Danoy, P., Yerges-Armstrong, L.M., Streeten, E.A., Hu, T., Xiang, S., Papasian, C.J., Brown, M.A., Shin, C.S., Uitterlinden, A.G., & Deng, H.W. (2013) Multistage genome-wide association meta-analyses identified two new loci for bone mineral density. Human Molecular Genetics, 23(7), pp. 1923-1933.

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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. © The Author 2013. Published by Oxford University Press.

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ID Code: 94199
Item Type: Journal Article
Refereed: No
Additional Information: Cited By :29
Export Date: 14 March 2016
Correspondence Address: Deng, H.-W.; Center for Bioinformatics and Genomics, School of Public Health and Tropical Medicine, Tulane University, 1440 Canal Street, Suite 2001, United States
Chemicals/CAS: fibroblast growth factor receptor, 153424-51-2; osteoclast differentiation factor, 200145-93-3
Funding Details: N01WH22110, HHS, U.S. Department of Health and Human Services
Funding Details: N01WH24152, HHS, U.S. Department of Health and Human Services
Funding Details: N01WH32100-2, HHS, U.S. Department of Health and Human Services
Funding Details: N01WH32105-6, HHS, U.S. Department of Health and Human Services
Funding Details: N01WH32108-9, HHS, U.S. Department of Health and Human Services
Funding Details: N01WH32111-13, HHS, U.S. Department of Health and Human Services
Funding Details: N01WH32115, HHS, U.S. Department of Health and Human Services
Funding Details: N01WH32118-32119, HHS, U.S. Department of Health and Human Services
Funding Details: N01WH32122, HHS, U.S. Department of Health and Human Services
Funding Details: N01WH42107-26, HHS, U.S. Department of Health and Human Services
Funding Details: N01WH42129-32, HHS, U.S. Department of Health and Human Services
Funding Details: N01WH44221, HHS, U.S. Department of Health and Human Services
Funding Details: U01HG004790, NHGRI, U.S. Department of Health and Human Services
Funding Details: NHLBI, U.S. Department of Health and Human Services
Funding Details: R01AR/AG 41398, NIH, U.S. Department of Health and Human Services
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Keywords: bone morphogenetic protein, calcium binding protein, claudin, claudin 14, fibroblast growth factor receptor, fibroblast growth factor receptor like 1, low density lipoprotein receptor related protein 5, matrix extracellular phosphoglycoprotein, osteoclast differentiation factor, secreted modular calcium binding protein 1, transcription factor Sox6, unclassified drug, adult, aged, Article, bone density, bone development, bone metabolism, computer model, controlled study, female, femur neck, gene expression, gene function, gene identification, gene locus, genetic analysis, genetic association, heredity, hip, human, lumbar spine, major clinical study, male, osteoblast, osteoporosis, single nucleotide polymorphism, validation study
DOI: 10.1093/hmg/ddt575
ISSN: 09646906 (ISSN)
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 22 Mar 2016 22:32
Last Modified: 24 Mar 2016 03:54

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