WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk

Zheng, H. F., Tobias, J. H., Duncan, Emma L., Evans, D. M., Eriksson, J., Paternoster, L., Yerges-Armstrong, L. M., Lehtimäki, T., Bergström, U., Kähönen, M., Leo, P. J., Raitakari, O., Laaksonen, M., Nicholson, G. C., Viikari, J., Ladouceur, M., Lyytikäinen, L. P., Medina-Gomez, C., Rivadeneira, F., Prince, R. L., Sievanen, H., Leslie, W. D., Mellström, D., Eisman, J. A., Movérare-Skrtic, S., Goltzman, D., Hanley, D. A., Jones, G., St. Pourcain, B., Xiao, Y., Timpson, N. J., Smith, G. D., Reid, I. R., Ring, S. M., Sambrook, P. N., Karlsson, M., Dennison, E. M., Kemp, J. P., Danoy, P., Sayers, A., Wilson, S. G., Nethander, M., McCloskey, E., Vandenput, L., Eastell, R., Liu, J., Spector, T., Mitchell, B. D., Streeten, E. A., Brommage, R., Pettersson-Kymmer, U., Brown, Matthew A., Ohlsson, C., Richards, J. B., & Lorentzon, M. (2012) WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk. PLoS ONE, 8(7), e1002745.

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Abstract

We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ~2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2×10-9). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3×10-12, and -0.16 SD per G allele, P = 1.2×10-15, respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10-9), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10-6 and rs2707466: OR = 1.22, P = 7.2×10-6). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16-/- mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5×10-13<P<5.9×10-4) at both femur and tibia, compared with their wild-type littermates. Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture. © 2012 Zheng et al.

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ID Code: 87610
Item Type: Journal Article
Refereed: Yes
Keywords: adult, animal tissue, article, bone density, bone strength, controlled study, cortical bone thickness, female, fragility fracture, gene, gene deletion, gene frequency, gene function, gene identification, gene location, gene locus, genetic association, genetic variability, human, male, missense mutation, mouse, musculoskeletal system parameters, nonhuman, risk assessment, risk factor, single nucleotide polymorphism, wild type, WNT16 gene, Adolescent, Animals, Bone and Bones, Child, Child, Preschool, Femur, Forearm, Fractures, Bone, Genome-Wide Association Study, Humans, Mice, Middle Aged, Osteoporosis, Polymorphism, Single Nucleotide, Risk Factors, Wnt Proteins, Mus
DOI: 10.1371/journal.pgen.1002745
ISSN: 1553-7390
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2012 Zheng et al.
Copyright Statement: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Deposited On: 21 Sep 2015 07:15
Last Modified: 17 Nov 2016 05:42

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