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

By Hou-Feng Zheng, Jon H. Tobias, Emma Duncan, David M. Evans, Joel Eriksson, Lavinia Paternoster, Laura M. Yerges-Armstrong, Terho Lehtimaki, Ulrica Bergstrom, Mika Kahonen, Paul J. Leo, Olli Raitakari, Marika Laaksonen, Geoffrey C. Nicholson, Jorma Viikari, Martin Ladouceur, Leo-Pekka Lyytikainen, Carolina Medina-Gomez, Fernando Rivadeneira, Richard L. Prince, Harri Sievanen, William D. Leslie, Dan Mellstrom, John A. Eisman, Sofia Moverare-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 and 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 similar to 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 = 6.2x10(-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 = 2.3x10(-12), and -0.16 SD per G allele, P = 1.2x10(-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 = 7.3x10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9x10(-6) and rs2707466: OR = 1.22, P = 7.2x10(-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% (6.5x10(-13)<P<5.9x10(-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

Topics: Orthopedics
Publisher: 'Public Library of Science (PLoS)'
Year: 2012
DOI identifier: 10.1371/journal.pgen.1002745
OAI identifier: oai:lup.lub.lu.se:0ebc8750-d375-4130-ae8f-203e3ce5f26f
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