학술논문
WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk.
Document Type
article
Author
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
Source
PLoS Genetics, Vol 8, Iss 7, p e1002745 (2012)
Subject
Language
English
ISSN
1553-7390
1553-7404
1553-7404
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