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

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

Authors

  • Zheng HF
  • Tobias JH
  • Duncan E
  • Evans DM
  • Eriksson J
  • Paternoster L
  • Yerges-Armstrong LM
  • Lehtimäki T
  • Bergström U
  • Kähönen M
  • Leo PJ
  • Raitakari O
  • Laaksonen M
  • Nicholson GC
  • Viikari J
  • Ladouceur M
  • Lyytikäinen LP
  • Medina-Gomez C
  • Rivadeneira F
  • Prince RL
  • Sievanen H
  • Leslie WD
  • Mellström D
  • Eisman JA
  • Movérare-Skrtic S
  • Goltzman D
  • Hanley DA
  • Jones G
  • St Pourcain B
  • Xiao Y
  • Timpson NJ
  • Smith GD
  • Reid IR
  • Ring SM
  • Sambrook PN
  • Karlsson M
  • Dennison EM
  • Kemp JP
  • Danoy P
  • Sayers A
  • Wilson SG
  • Nethander M
  • McCloskey E
  • Vandenput L
  • Eastell R
  • Liu J
  • Spector T
  • Mitchell BD
  • Streeten EA
  • Brommage R
  • Pettersson-Kymmer U
  • Brown MA
  • Ohlsson C
  • Richards JB
  • Lorentzon M

Journal

PLoS genetics

Publication Data

July 13, 2012

Associated Grants

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

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