PLoS Genetics (Jul 2012)

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

  • Hou-Feng Zheng,
  • Jon H Tobias,
  • Emma Duncan,
  • David M Evans,
  • Joel Eriksson,
  • Lavinia Paternoster,
  • Laura M Yerges-Armstrong,
  • Terho Lehtimäki,
  • Ulrica Bergström,
  • Mika Kähönen,
  • Paul J Leo,
  • Olli Raitakari,
  • Marika Laaksonen,
  • Geoffrey C Nicholson,
  • Jorma Viikari,
  • Martin Ladouceur,
  • Leo-Pekka Lyytikäinen,
  • Carolina Medina-Gomez,
  • Fernando Rivadeneira,
  • Richard L Prince,
  • Harri Sievanen,
  • William D Leslie,
  • Dan Mellström,
  • John A Eisman,
  • Sofia Movérare-Skrtic,
  • David Goltzman,
  • David A Hanley,
  • Graeme Jones,
  • Beate St Pourcain,
  • Yongjun Xiao,
  • Nicholas J Timpson,
  • George Davey Smith,
  • Ian R Reid,
  • Susan M Ring,
  • Philip N Sambrook,
  • Magnus Karlsson,
  • Elaine M Dennison,
  • John P Kemp,
  • Patrick Danoy,
  • Adrian Sayers,
  • Scott G Wilson,
  • Maria Nethander,
  • Eugene McCloskey,
  • Liesbeth Vandenput,
  • Richard Eastell,
  • Jeff Liu,
  • Tim Spector,
  • Braxton D Mitchell,
  • Elizabeth A Streeten,
  • Robert Brommage,
  • Ulrika Pettersson-Kymmer,
  • Matthew A Brown,
  • Claes Ohlsson,
  • J Brent Richards,
  • Mattias Lorentzon

DOI
https://doi.org/10.1371/journal.pgen.1002745
Journal volume & issue
Vol. 8, no. 7
p. e1002745

Abstract

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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.