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WNT16 Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk

Author

Listed:
  • 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

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 ∼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

Suggested Citation

  • 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 Rai, 2012. "WNT16 Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk," PLOS Genetics, Public Library of Science, vol. 8(7), pages 1-13, July.
  • Handle: RePEc:plo:pgen00:1002745
    DOI: 10.1371/journal.pgen.1002745
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