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, Kahonen, Mika, Leo, Paul J., Raitakari, Olli, Laaksonen, Marika, Nicholson, Geoffrey C., Viikari, Jorma, Ladouceur, Martin, Lyytikainen, Leo-Pekka, Medina-Gomez, Carolina, Rivadeneira, Fernando, Prince, Richard L., Sievanen, Harri, Leslie, William D., Mellstrom, Dan, Eisman, John A., Moverare-Skrtic, Sofia, Goltzman, David, Hanley, David A., Jones, Graeme, Pourcain, Beate St., Xiao, Yongjun, Timpson, Nicholas J., Smith, George Davey, Reid, Ian R., Ring, Susan M., Sambrook, Philip N., Karlsson, Magnus, Dennison, Elaine M., Kemp, John P., Danoy, Patrick, Sayers, Adrian, Wilson, Scott G., Nethander, Maria, McCloskey, Eugene, Vandenput, Liesbeth, Eastell, Richard, Liu, Jeff, Spector, Tim, Mitchell, Braxton D., Streeten, Elizabeth A., Brommage, Robert, Pettersson-Kymmer, Ulrika, Brown, Matthew A., Ohlsson, Claes, Richards, J. Brent and Lorentzon, Mattias (2012) WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk. Plos Genetics, 8 7: e1002745.1-e1002745.13. doi:10.1371/journal.pgen.1002745

Author Zheng, Hou-Feng
Tobias, Jon H.
Duncan, Emma
Evans, David M.
Eriksson, Joel
Paternoster, Lavinia
Yerges-Armstrong, Laura M.
Lehtimaki, Terho
Bergstrom, Ulrica
Kahonen, Mika
Leo, Paul J.
Raitakari, Olli
Laaksonen, Marika
Nicholson, Geoffrey C.
Viikari, Jorma
Ladouceur, Martin
Lyytikainen, Leo-Pekka
Medina-Gomez, Carolina
Rivadeneira, Fernando
Prince, Richard L.
Sievanen, Harri
Leslie, William D.
Mellstrom, Dan
Eisman, John A.
Moverare-Skrtic, Sofia
Goltzman, David
Hanley, David A.
Jones, Graeme
Pourcain, Beate St.
Xiao, Yongjun
Timpson, Nicholas J.
Smith, George Davey
Reid, Ian R.
Ring, Susan M.
Sambrook, Philip N.
Karlsson, Magnus
Dennison, Elaine M.
Kemp, John P.
Danoy, Patrick
Sayers, Adrian
Wilson, Scott G.
Nethander, Maria
McCloskey, Eugene
Vandenput, Liesbeth
Eastell, Richard
Liu, Jeff
Spector, Tim
Mitchell, Braxton D.
Streeten, Elizabeth A.
Brommage, Robert
Pettersson-Kymmer, Ulrika
Brown, Matthew A.
Ohlsson, Claes
Richards, J. Brent
Lorentzon, Mattias
Title WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk
Journal name Plos Genetics   Check publisher's open access policy
ISSN 1553-7404
Publication date 2012-07
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1002745
Open Access Status DOI
Volume 8
Issue 7
Start page e1002745.1
End page e1002745.13
Total pages 13
Place of publication Oxford, United Kingdom
Publisher John Wiley & Sons
Collection year 2013
Language eng
Formatted 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<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5×10 -13<P<5.9×10 -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.
Keyword Genome-wide association
Receptor-related protein-5
Free testosterone
Imputed data
Swedish men
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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