%0 Journal Article
%T WNT16 Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk
%A Hou-Feng Zheng equal contributor
%A Jon H. Tobias equal contributor
%A Emma Duncan equal contributor
%A David M. Evans equal contributor
%A Joel Eriksson
%A Lavinia Paternoster
%A Laura M. Yerges-Armstrong
%A Terho Lehtim£¿ki
%A Ulrica Bergstr£¿m
%A Mika K£¿h£¿nen
%A Paul J. Leo
%A Olli Raitakari
%A Marika Laaksonen
%A Geoffrey C. Nicholson
%A Jorma Viikari
%A Martin Ladouceur
%A Leo-Pekka Lyytik£¿inen
%A Carolina Medina-Gomez
%A Fernando Rivadeneira
%A Richard L. Prince
%A Harri Sievanen
%A William D. Leslie
%A Dan Mellstr£¿m
%A John A. Eisman
%A Sofia Mov¨¦rare-Skrtic
%A David Goltzman
%A David A. Hanley
%A Graeme Jones
%A Beate St. Pourcain
%A Yongjun Xiao
%A Nicholas J. Timpson
%A George Davey Smith
%A Ian R. Reid
%A Susan M. Ring
%A Philip N. Sambrook
%A Magnus Karlsson
%A Elaine M. Dennison
%A John P. Kemp
%A Patrick Danoy
%A Adrian Sayers
%A Scott G. Wilson
%A Maria Nethander
%A Eugene McCloskey
%A Liesbeth Vandenput
%A Richard Eastell
%A Jeff Liu
%A Tim Spector
%A Braxton D. Mitchell
%A Elizabeth A. Streeten
%A Robert Brommage
%A Ulrika Pettersson-Kymmer
%A Matthew A. Brown
%A Claes Ohlsson £¿
%A J. Brent Richards £¿
%A Mattias Lorentzon £¿
%J PLOS Genetics
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pgen.1002745
%X 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¡Á10£¿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¡Á10£¿12, and £¿0.16 SD per G allele, P = 1.2¡Á10£¿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¡Á10£¿9), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9¡Á10£¿6 and rs2707466: OR = 1.22, P = 7.2¡Á10£¿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%¨C61% (6.5¡Á10£¿13<P<5.9¡Á10£¿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.
%U http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1002745