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WNT16 influences bone mineral density,cortical bone thickness,bone strength,and osteoporotic fracture risk
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نویسنده
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zheng h.-f. ,tobias j.h. ,duncan e. ,evans d.m. ,eriksson j. ,paternoster l. ,yerges-armstrong l.m. ,lehtimäki t. ,bergström u. ,kähönen m. ,leo p.j. ,raitakari o. ,laaksonen m. ,nicholson g.c. ,viikari j. ,ladouceur m. ,lyytikäinen l.-p. ,medina-gomez c. ,rivadeneira f. ,prince r.l. ,sievanen h. ,leslie w.d. ,mellström d. ,eisman j.a. ,movérare-skrtic s. ,goltzman d. ,hanley d.a. ,jones g. ,st. pourcain b. ,xiao y. ,timpson n.j. ,smith g.d. ,reid i.r. ,ring s.m. ,sambrook p.n. ,karlsson m. ,dennison e.m. ,kemp j.p. ,danoy p. ,sayers a. ,wilson s.g. ,nethander m. ,mccloskey e. ,vandenput l. ,eastell r. ,liu j. ,spector t. ,mitchell b.d. ,streeten e.a. ,brommage r. ,pettersson-kymmer u. ,brown m.a. ,ohlsson c. ,richards j.b. ,lorentzon m.
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منبع
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plos genetics - 2012 - دوره : 8 - شماره : 7
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چکیده
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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. © 2012 zheng et al.
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آدرس
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department of medicine,human genetics,mcgill university,montreal,canada,department of epidemiology and biostatistics,lady davis institute for medical research,jewish general hospital,montreal, Canada, musculoskeletal research unit,school of clinical sciences,university of bristol,bristol, United Kingdom, human genetics group,university of queensland diamantina institute,princess alexandra hospital,university of queensland,brisbane,australia,endocrinology,royal brisbane and women's hospital,brisbane, Australia, medical research council centre for causal analyses in translational epidemiology,university of bristol,bristol,united kingdom,school of social and community medicine,university of bristol,bristol, United Kingdom, center for bone and arthritis research,institute of medicine,sahlgrenska academy,university of gothenburg,gothenburg, Sweden, medical research council centre for causal analyses in translational epidemiology,university of bristol,bristol,united kingdom,school of social and community medicine,university of bristol,bristol, United Kingdom, department of medicine,division of endocrinology,diabetes,and nutrition,university of maryland school of medicine,baltimore,md, United States, department of clinical chemistry,fimlab,university of tampere school of medicine and tampere university hospital,tampere, Finland, surgical and perioperative sciences,umeå university,umeå, Sweden, department of clinical physiology,university of tampere school of medicine and tampere university hospital,tampere, Finland, human genetics group,university of queensland diamantina institute,princess alexandra hospital,university of queensland,brisbane, Australia, research centre of applied and preventive cardiovascular medicine,department of clinical physiology and nuclear medicine,university of turku and turku university hospital,turku, Finland, department of food and environmental sciences,university of helsinki,helsinki, Finland, rural clinical school,the university of queensland,toowoomba, Australia, department of medicine,university of turku and turku university hospital,turku, Finland, montreal heart institute,research institute,montreal, Canada, department of clinical chemistry,fimlab,university of tampere school of medicine and tampere university hospital,tampere, Finland, department of internal medicine,erasmus university medical center,rotterdam,netherlands,department of epidemiology,erasmus university medical center,rotterdam, Netherlands, department of internal medicine,erasmus university medical center,rotterdam,netherlands,department of epidemiology,erasmus university medical center,rotterdam, Netherlands, endocrinology and diabetes,sir charles gairdner hospital,perth,australia,school of medicine and pharmacology,university of western australia,perth, Australia, bone research group,ukk institute,tampere, Finland, department of internal medicine,university of manitoba,winnipeg, Canada, center for bone and arthritis research,institute of medicine,sahlgrenska academy,university of gothenburg,gothenburg, Sweden, garvan institute of medical research,university of new south wales,sydney, Australia, center for bone and arthritis research,institute of medicine,sahlgrenska academy,university of gothenburg,gothenburg, Sweden, department of medicine,mcgill university,montreal, Canada, department of medicine,university of calgary,calgary, Canada, menzies research institute,university of tasmania,hobart, Australia, school of social and community medicine,university of bristol,bristol, United Kingdom, centre for bone and periodontal research,mcgill university,montreal, Canada, medical research council centre for causal analyses in translational epidemiology,university of bristol,bristol,united kingdom,school of social and community medicine,university of bristol,bristol, United Kingdom, medical research council centre for causal analyses in translational epidemiology,university of bristol,bristol,united kingdom,school of social and community medicine,university of bristol,bristol, United Kingdom, department of medicine,university of auckland,auckland, New Zealand, school of social and community medicine,university of bristol,bristol, United Kingdom, kolling institute,royal north shore hospital,university of sydney,sydney, Australia, clinical and molecular osteoporosis research unit,department of orthopaedics,skane university hospital,lund university,malmö, Sweden, medical research council lifecourse epidemiology unit,university of southampton,southampton, United Kingdom, medical research council centre for causal analyses in translational epidemiology,university of bristol,bristol,united kingdom,school of social and community medicine,university of bristol,bristol, United Kingdom, human genetics group,university of queensland diamantina institute,princess alexandra hospital,university of queensland,brisbane, Australia, musculoskeletal research unit,school of clinical sciences,university of bristol,bristol, United Kingdom, endocrinology and diabetes,sir charles gairdner hospital,perth,australia,school of medicine and pharmacology,university of western australia,perth,australia,twin research and genetic epidemiology,king's college london,london, United Kingdom, genomics core facility,university of gothenburg,gothenburg, Sweden, academic unit of bone metabolism,metabolic bone centre,university of sheffield,sheffield,united kingdom,nihr musculoskeletal biomedical research unit,sheffield teaching hospitals,sheffield, United Kingdom, center for bone and arthritis research,institute of medicine,sahlgrenska academy,university of gothenburg,gothenburg, Sweden, academic unit of bone metabolism,metabolic bone centre,university of sheffield,sheffield, United Kingdom, lexicon pharmaceuticals,the woodlands,tx, United States, twin research and genetic epidemiology,king's college london,london, United Kingdom, department of medicine,division of endocrinology,diabetes,and nutrition,university of maryland school of medicine,baltimore,md, United States, department of medicine,division of endocrinology,diabetes,and nutrition,university of maryland school of medicine,baltimore,md,united states,geriatric research and education clinical center (grecc),veterans administration medical center,baltimore,md, United States, lexicon pharmaceuticals,the woodlands,tx, United States, department of pharmacology and neuroscience,umeå university,umeå,sweden,department of public health and clinical medicine,umeå unviersity,umeå, Sweden, human genetics group,university of queensland diamantina institute,princess alexandra hospital,university of queensland,brisbane, Australia, center for bone and arthritis research,institute of medicine,sahlgrenska academy,university of gothenburg,gothenburg, Sweden, department of medicine,human genetics,mcgill university,montreal,canada,department of epidemiology and biostatistics,lady davis institute for medical research,jewish general hospital,montreal,canada,twin research and genetic epidemiology,king's college london,london, United Kingdom, center for bone and arthritis research,institute of medicine,sahlgrenska academy,university of gothenburg,gothenburg, Sweden
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Authors
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