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

PLoS genetics | Jul 13, 2012

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)

Pubmed ID: 22792071 RIS Download

Mesh terms: Adolescent | Adult | Animals | Bone Density | Bone and Bones | Child | Child, Preschool | Female | Femur | Forearm | Fractures, Bone | Genome-Wide Association Study | Humans | Male | Mice | Middle Aged | Osteoporosis | Polymorphism, Single Nucleotide | Risk Factors | Wnt Proteins

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Associated grants

  • Agency: NIAMS NIH HHS, Id: F32AR059469
  • Agency: NIAMS NIH HHS, Id: R01 AR046838
  • Agency: Medical Research Council, Id: ref: 74882
  • Agency: Medical Research Council, Id: G0600705
  • Agency: Medical Research Council, Id: G0800582
  • Agency: Wellcome Trust, Id: 092731
  • Agency: NIA NIH HHS, Id: R01 AG18728
  • Agency: Medical Research Council, Id: MRC G0800582
  • Agency: NHLBI NIH HHS, Id: U01 HL084756
  • Agency: Wellcome Trust, Id: WT083431MA
  • Agency: Canadian Institutes of Health Research, Id: P30 DK072488
  • Agency: NIDDK NIH HHS, Id: R01AR046838
  • Agency: NIAMS NIH HHS, Id: R01HL088119
  • Agency: NHLBI NIH HHS, Id: F32 AR059469
  • Agency: NIAMS NIH HHS, Id: R01 AG018728
  • Agency: NIA NIH HHS, Id: P30DK072488
  • Agency: NIDDK NIH HHS, Id: ref: 076467
  • Agency: Wellcome Trust, Id: R01 HL088119
  • Agency: NHLBI NIH HHS, Id:

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