WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk.
PLoS Genet
; 8(7): e1002745, 2012 Jul.
Article
en En
| MEDLINE
| ID: mdl-22792071
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 â¼2.5 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)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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Osteoporosis
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Densidad Ósea
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Fracturas Óseas
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Proteínas Wnt
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Estudio de Asociación del Genoma Completo
Tipo de estudio:
Etiology_studies
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Prognostic_studies
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Risk_factors_studies
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Systematic_reviews
Límite:
Adolescent
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Adult
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Animals
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Child
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Child, preschool
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Año:
2012
Tipo del documento:
Article