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Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk
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نویسنده
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duncan e.l. ,danoy p. ,kemp j.p. ,leo p.j. ,mccloskey e. ,nicholson g.c. ,eastell r. ,prince r.l. ,eisman j.a. ,jones g. ,sambrook p.n. ,reid i.r. ,dennison e.m. ,wark j. ,richards j.b. ,uitterlinden a.g. ,spector t.d. ,esapa c. ,cox r.d. ,brown s.d.m. ,thakker r.v. ,addison k.a. ,bradbury l.a. ,center j.r. ,cooper c. ,cremin c. ,estrada k. ,felsenberg d. ,glüer c.-c. ,hadler j. ,henry m.j. ,hofman a. ,kotowicz m.a. ,makovey j. ,nguyen s.c. ,nguyen t.v. ,pasco j.a. ,pryce k. ,reid d.m. ,rivadeneira f. ,roux c. ,stefansson k. ,styrkarsdottir u. ,thorleifsson g. ,tichawangana r. ,evans d.m. ,brown m.a.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 4
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چکیده
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Osteoporotic fracture is a major cause of morbidity and mortality worldwide. low bone mineral density (bmd) is a major predisposing factor to fracture and is known to be highly heritable. site-,gender-,and age-specific genetic effects on bmd are thought to be significant,but have largely not been considered in the design of genome-wide association studies (gwas) of bmd to date. we report here a gwas using a novel study design focusing on women of a specific age (postmenopausal women,age 55-85 years),with either extreme high or low hip bmd (age- and gender-adjusted bmd z-scores of +1.5 to +4.0,n = 1055,or -4.0 to -1.5,n = 900),with replication in cohorts of women drawn from the general population (n = 20,898). the study replicates 21 of 26 known bmd-associated genes. additionally,we report suggestive association of a further six new genetic associations in or around the genes clcn7,galnt3,ibsp,ltbp3,rspo3,and sox4,with replication in two independent datasets. a novel mouse model with a loss-of-function mutation in galnt3 is also reported,which has high bone mass,supporting the involvement of this gene in bmd determination. in addition to identifying further genes associated with bmd,this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies. © 2011 duncan et al.
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آدرس
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university of queensland diamantina institute,university of queensland,princess alexandra hospital,brisbane, Australia, university of queensland diamantina institute,university of queensland,princess alexandra hospital,brisbane, Australia, medical research council centre for causal analyses in translational epidemiology,university of bristol,bristol, United Kingdom, university of queensland diamantina institute,university of queensland,princess alexandra hospital,brisbane, Australia, academic unit of bone metabolism,metabolic bone centre,university of sheffield,sheffield, United Kingdom, the university of melbourne,department of clinical and biomedical sciences: barwon health,geelong, Australia, academic unit of bone metabolism,metabolic bone centre,university of sheffield,sheffield, United Kingdom, school of medicine and pharmacology,university of western australia,perth,australia,department of endocrinology and diabetes,sir charles gairdner hospital,perth, Australia, garvan institute of medical research,sydney,australia,st. vincent's clinical school,st. vincent's hospital campus,university of new south wales,sydney, Australia, menzies research institute,university of tasmania,hobart, Australia, kolling institute,royal north shore hospital,university of sydney,sydney, Australia, department of medicine,university of auckland,auckland, New Zealand, medical research council lifecourse epidemiology unit,southampton, United Kingdom, university of melbourne department of medicine and bone and mineral service,royal melbourne hospital,melbourne, Australia, departments of medicine,human genetics,epidemiology and biostatistics,lady davis institute,jewish general hospital,mcgill university,montreal,canada,department of twin research and genetic epidemiology,king's college london,london, United Kingdom, department of internal medicine and epidemiology,erasmus medical center,rotterdam, Netherlands, department of twin research and genetic epidemiology,king's college london,london, United Kingdom, medical research council mammalian genetics unit,harwell science and innovation campus,harwell,oxfordshire,united kingdom,academic endocrine unit,nuffield department of clinical medicine,oxford centre for diabetes,endocrinology,and metabolism,university of oxford,churchill hospital,headington,oxford, United Kingdom, medical research council mammalian genetics unit,harwell science and innovation campus,harwell,oxfordshire, United Kingdom, medical research council mammalian genetics unit,harwell science and innovation campus,harwell,oxfordshire, United Kingdom, academic endocrine unit,nuffield department of clinical medicine,oxford centre for diabetes,endocrinology,and metabolism,university of oxford,churchill hospital,headington,oxford, United Kingdom, university of queensland diamantina institute,university of queensland,princess alexandra hospital,brisbane, Australia, university of queensland diamantina institute,university of queensland,princess alexandra hospital,brisbane, Australia, garvan institute of medical research,sydney,australia,st. vincent's clinical school,st. vincent's hospital campus,university of new south wales,sydney, Australia, medical research council lifecourse epidemiology unit,southampton,united kingdom,national institute for health and research biomedical research unit,university of oxford,oxford, United Kingdom, university of queensland diamantina institute,university of queensland,princess alexandra hospital,brisbane, Australia, department of internal medicine and epidemiology,erasmus medical center,rotterdam, Netherlands, centre of muscle and bone research,charité - university medicine berlin,campus benjamin franklin,free and humboldt university,berlin, Germany, medizinische physik,klinik für diagnostische radiologie,universitätsklinikum schleswig-holstein,kiel, Germany, university of queensland diamantina institute,university of queensland,princess alexandra hospital,brisbane, Australia, school of medicine,deakin university,geelong, Australia, department of internal medicine and epidemiology,erasmus medical center,rotterdam, Netherlands, department of endocrinology and diabetes,barwon health,geelong, Australia, institute of bone joint research,university of sydney,royal north shore hospital,sydney, Australia, garvan institute of medical research,sydney,australia,school of public health and community medicine,university of new south wales,sydney, Australia, garvan institute of medical research,sydney,australia,st. vincent's clinical school,st. vincent's hospital campus,university of new south wales,sydney,australia,school of public health and community medicine,university of new south wales,sydney, Australia, school of medicine,deakin university,geelong, Australia, university of queensland diamantina institute,university of queensland,princess alexandra hospital,brisbane, Australia, division of applied medicine,university of aberdeen,aberdeen, United Kingdom, department of internal medicine and epidemiology,erasmus medical center,rotterdam, Netherlands, rheumatology department,ap-hp cochin hospital - paris-descartes university,paris, France, decode genetics,reykjavik,iceland,university of iceland,reykjavik, Iceland, decode genetics,reykjavik, Iceland, decode genetics,reykjavik, Iceland, the university of melbourne,department of clinical and biomedical sciences: barwon health,geelong, Australia, medical research council centre for causal analyses in translational epidemiology,university of bristol,bristol, United Kingdom, university of queensland diamantina institute,university of queensland,princess alexandra hospital,brisbane,australia,national institute for health and research biomedical research unit,university of oxford,oxford, United Kingdom
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Authors
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