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

Citation

Zheng, HF and Tobias, JH and Duncan, E and Evans, DM and Eriksson, J and Paternoster, L and Yerges-Armstrong, LM and Lehtimaki, T and Bergstrom, U and Kahonen, M and Leo, PJ and Raitakari, O and Laaksonen, M and Nicholson, GC and Viikari, J and Ladouceur, M and Lyytikainen, L-P and Medina-Gomez, C and Rivadeneira, F and Prince, RL and Sievanen, H and Leslie, WD and Mellstrom, D and Eisman, JA and Moverare-Skrtic, S and Goltzman, D and Hanley, DA and Jones, G and St Pourcain, B and Xiao, Y and Timpson, NJ and Smith, GD and Reid, IR and Ring, SM and Sambrook, PN and Karlsson, M and Dennison, EM and Kemp, JP and Danoy, P and Sayers, A and Wilson, SG and Nethander, M and McCloskey, E and Vandenput, L and Eastell, R and Liu, J and Spector, T and Mitchell, BD and Streeten, EA and Brommage, R and Pettersson-Kymmer, U and Brown, MA and Ohlsson, C and Richards, JB and Lorentzon, M, WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk, PLoS Genetics, 8, (7) Article e1002745. ISSN 1553-7404 (2012) [Refereed Article]


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Licenced under Creative Commons Attribution 2.5 Generic (CC BY 2.5) http://creativecommons.org/licenses/by/2.5/

DOI: doi:10.1371/journal.pgen.1002745

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 x 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 x 10-12, and -0.16 SD per G allele, P =  1.2 x 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 x 10-9), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9 x 10-6 and rs2707466: OR =  1.22, P = 7.2 x 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 x 10-13 < P < 5.9 x 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.

Item Details

Item Type:Refereed Article
Keywords:genome-wide association, receptor-related protein-5, free testosterone, genetic factors, hip-fractures, femoral neck, imputed data, Swedish men, BMD, mass
Research Division:Biomedical and Clinical Sciences
Research Group:Clinical sciences
Research Field:Rheumatology and arthritis
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Jones, G (Professor Graeme Jones)
ID Code:79265
Year Published:2012
Web of Science® Times Cited:191
Deposited By:Menzies Institute for Medical Research
Deposited On:2012-08-29
Last Modified:2017-11-02
Downloads:363 View Download Statistics

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