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

Zheng, Hou-Feng; Tobias, Jon H.; Duncan, Emma; Evans, David M.; Eriksson, Joel; Paternoster, Lavinia; Yerges-Armstrong, Laura M.; Lehtimaki, Terho; Bergstrom, Ulrica and Kahonen, Mika, et al. (2012) In PLoS Genetics 8(7).
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... (More)
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. (Less)
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PLoS Genetics
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8
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7
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Public Library of Science
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  • wos:000306840400004
  • scopus:84863888921
ISSN
1553-7404
DOI
10.1371/journal.pgen.1002745
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English
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@article{0ebc8750-d375-4130-ae8f-203e3ce5f26f,
  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&gt;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&gt;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&lt;0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5x10(-13)&lt;P&lt;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.},
  author       = {Zheng, Hou-Feng and Tobias, Jon H. and Duncan, Emma and Evans, David M. and Eriksson, Joel and Paternoster, Lavinia and Yerges-Armstrong, Laura M. and Lehtimaki, Terho and Bergstrom, Ulrica and Kahonen, Mika and Leo, Paul J. and Raitakari, Olli and Laaksonen, Marika and Nicholson, Geoffrey C. and Viikari, Jorma and Ladouceur, Martin and Lyytikainen, Leo-Pekka and Medina-Gomez, Carolina and Rivadeneira, Fernando and Prince, Richard L. and Sievanen, Harri and Leslie, William D. and Mellstrom, Dan and Eisman, John A. and Moverare-Skrtic, Sofia and Goltzman, David and Hanley, David A. and Jones, Graeme and Pourcain, Beate St. and Xiao, Yongjun and Timpson, Nicholas J. and Smith, George Davey and Reid, Ian R. and Ring, Susan M. and Sambrook, Philip N. and Karlsson, Magnus and Dennison, Elaine M. and Kemp, John P. and Danoy, Patrick and Sayers, Adrian and Wilson, Scott G. and Nethander, Maria and McCloskey, Eugene and Vandenput, Liesbeth and Eastell, Richard and Liu, Jeff and Spector, Tim and Mitchell, Braxton D. and Streeten, Elizabeth A. and Brommage, Robert and Pettersson-Kymmer, Ulrika and Brown, Matthew A. and Ohlsson, Claes and Richards, J. Brent and Lorentzon, Mattias},
  issn         = {1553-7404},
  language     = {eng},
  number       = {7},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {WNT16 Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1002745},
  volume       = {8},
  year         = {2012},
}