WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk

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dc.contributor.author Zheng, Hou-Feng
dc.contributor.author Tobias, Jon H
dc.contributor.author Duncan, Emma
dc.date.accessioned 2012-10-19T07:53:13Z
dc.date.available 2012-10-19T07:53:13Z
dc.date.issued 2012
dc.identifier.issn 1553-7390 -
dc.identifier.uri http://tampub.uta.fi/handle/10024/66362
dc.description Public Library of Science open access -
dc.description.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. -
dc.language.iso en -
dc.title WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk -
dc.type fi=Artikkeli aikakauslehdessä | en=Journal Article| -
dc.identifier.urn URN:NBN:fi:uta-201210191060 -
dc.identifier.doi 10.1371/journal.pgen.1002745 -
dc.type.version fi=Kustantajan versio | en=Publisher's version| -
dc.subject.okm fi=Oikeuslääketiede ja muut lääketieteet | en=Forensic science and other medical sciences| -
dc.administrativeunit fi=Lääketieteen yksikkö | en=School of Medicine| -
dc.journal.title Plos Genetics -
dc.journal.volume 8 -
dc.journal.number 7 -
dc.journal.volumepagerange 1-13 -
dc.journal.url http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1002745 -
dc.contributor.tayperson Lehtimäki, Terho
dc.contributor.tayperson Kähönen, Mika
dc.contributor.tayperson Lyytikäinen, Leo-Pekka
dc.ismoreauthorsthanlisted 1 -

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