WNT16 Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk
Copyright policy )WNT16 Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk
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)
- University of Bristol United Kingdom
- University of Western Australia Australia
- University of Melbourne Australia
- University of Southampton United Kingdom
- UNSW Sydney Australia
Male, genetic association, 1105 Ecology, Fractures, Bone, Mice, Femoral-neck, 1306 Cancer Research, Child, Genetic-factors, FREE TESTOSTERONE, adult, Mus, risk assessment, Folkhälsovetenskap, global hälsa och socialmedicin, Forearm, risk factor, Genetics, developmental biology, physiology, Child, Preschool, GENETIC-FACTORS, Evolution, 610, fragility fracture, Orthopaedics, Bone and Bones, animal tissue, 618, 1311 Genetics, 616, 1312 Molecular Biology, Genetics, Humans, human, Polymorphism, GENOME-WIDE ASSOCIATION, mouse, gene location, ta3121, Public Health, Global Health and Social Medicine, Wnt Proteins, gene function, Orthopedics, cortical bone thickness, Hip-fractures, Osteoporosis, FEMORAL-NECK, Clinical Medicine, musculoskeletal system parameters, SWEDISH MEN, QH426-470, Free testosterone, Receptor-related protein-5, single nucleotide polymorphism, Bone Density, Risk Factors, genetic variability, Femur, Imputed data, Genome-wide association, Swedish men, HIP-FRACTURES, IMPUTED DATA, article, bone density, Single Nucleotide, WNT16 gene, Middle Aged, female, Female, wild type, Research Article, Adult, 2716 Genetics (clinical), gene locus, Adolescent, bone strength, gene frequency, MASS, Polymorphism, Single Nucleotide, male, Behavior and Systematics, Bmd, BMD, Animals, controlled study, Bone, Preschool, gene, gene identification, nonhuman, gene deletion, missense mutation, Klinisk medicin, Mass, RECEPTOR-RELATED PROTEIN-5, Fractures, Genome-Wide Association Study
Male, genetic association, 1105 Ecology, Fractures, Bone, Mice, Femoral-neck, 1306 Cancer Research, Child, Genetic-factors, FREE TESTOSTERONE, adult, Mus, risk assessment, Folkhälsovetenskap, global hälsa och socialmedicin, Forearm, risk factor, Genetics, developmental biology, physiology, Child, Preschool, GENETIC-FACTORS, Evolution, 610, fragility fracture, Orthopaedics, Bone and Bones, animal tissue, 618, 1311 Genetics, 616, 1312 Molecular Biology, Genetics, Humans, human, Polymorphism, GENOME-WIDE ASSOCIATION, mouse, gene location, ta3121, Public Health, Global Health and Social Medicine, Wnt Proteins, gene function, Orthopedics, cortical bone thickness, Hip-fractures, Osteoporosis, FEMORAL-NECK, Clinical Medicine, musculoskeletal system parameters, SWEDISH MEN, QH426-470, Free testosterone, Receptor-related protein-5, single nucleotide polymorphism, Bone Density, Risk Factors, genetic variability, Femur, Imputed data, Genome-wide association, Swedish men, HIP-FRACTURES, IMPUTED DATA, article, bone density, Single Nucleotide, WNT16 gene, Middle Aged, female, Female, wild type, Research Article, Adult, 2716 Genetics (clinical), gene locus, Adolescent, bone strength, gene frequency, MASS, Polymorphism, Single Nucleotide, male, Behavior and Systematics, Bmd, BMD, Animals, controlled study, Bone, Preschool, gene, gene identification, nonhuman, gene deletion, missense mutation, Klinisk medicin, Mass, RECEPTOR-RELATED PROTEIN-5, Fractures, Genome-Wide Association Study
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