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

Zheng, Hou-Feng, Tobias, Jon, Duncan, Emma, Evans, David, Eriksson, Joel, Paternoster, Lavinia, Yerges-Armstrong, Laura, Lehtimaki, Terho, Bergstrom, Ulrica, Brown, Matthew, & other, and (2012) WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk. PLoS Genetics, 8(7), Article number: e1002745 1-13.

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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.

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ID Code:

87610

Item Type:

Contribution to Journal (Journal Article)

Refereed:

Yes

ORCID iD:

Duncan, Emma	orcid.org/0000-0002-8143-4403
Brown, Matthew	orcid.org/0000-0003-0538-8211

Measurements or Duration:

13 pages

Keywords:

Adolescent, Animals, Bone, Bone and Bones, Child, Femur, Forearm, Fractures, Genome-Wide Association Study, Humans, Mice, Middle Aged, Mus, Osteoporosis, Polymorphism, Preschool, Risk Factors, Single Nucleotide, WNT16 gene, Wnt Proteins, 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

DOI:

10.1371/journal.pgen.1002745

ISSN:

1553-7390

Pure ID:

32407763

Divisions:

Past > QUT Faculties & Divisions > Faculty of Health
Past > Institutes > Institute of Health and Biomedical Innovation

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Deposited On:

21 Sep 2015 07:15

Last Modified:

16 Jul 2024 21:01

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