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Multiple loci are associated with white blood cell phenotypes
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نویسنده
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nalls m.a. ,couper d.j. ,tanaka t. ,van rooij f.j.a. ,chen m.-h. ,smith a.v. ,toniolo d. ,zakai n.a. ,yang q. ,greinacher a. ,wood a.r. ,garcia m. ,gasparini p. ,liu y. ,lumley t. ,folsom a.r. ,reiner a.p. ,gieger c. ,lagou v. ,felix j.f. ,völzke h. ,gouskova n.a. ,biffi a. ,döring a. ,völker u. ,chong s. ,wiggins k.l. ,rendon a. ,dehghan a. ,moore m. ,taylor k. ,wilson j.g. ,lettre g. ,hofman a. ,bis j.c. ,pirastu n. ,fox c.s. ,meisinger c. ,sambrook j. ,arepalli s. ,nauck m. ,prokisch h. ,stephens j. ,glazer n.l. ,cupples l.a. ,okada y. ,takahashi a. ,kamatani y. ,matsuda k. ,tsunoda t. ,tanaka t. ,kubo m. ,nakamura y. ,yamamoto k. ,kamatani n. ,stumvoll m. ,tönjes a. ,prokopenko i. ,illig t. ,patel k.v. ,garner s.f. ,kuhnel b. ,mangino m. ,oostra b.a. ,thein s.l. ,coresh j. ,wichmann h.-e. ,menzel s. ,lin j. ,pistis g. ,uitterlinden a.g. ,spector t.d. ,teumer a. ,eiriksdottir g. ,gudnason v. ,bandinelli s. ,frayling t.m. ,chakravarti a. ,van duijn c.m. ,melzer d. ,ouwehand w.h. ,levy d. ,boerwinkle e. ,singleton a.b. ,hernandez d.g. ,longo d.l. ,soranzo n. ,witteman j.c.m. ,psaty b.m. ,ferrucci l. ,harris t.b. ,o'donnell c.j. ,ganesh s.k.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 6
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چکیده
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White blood cell (wbc) count is a common clinical measure from complete blood count assays,and it varies widely among healthy individuals. total wbc count and its constituent subtypes have been shown to be moderately heritable,with the heritability estimates varying across cell types. we studied 19,509 subjects from seven cohorts in a discovery analysis,and 11,823 subjects from ten cohorts for replication analyses,to determine genetic factors influencing variability within the normal hematological range for total wbc count and five wbc subtype measures. cohort specific data was supplied by the charge,heamgen,and ingi consortia,as well as independent collaborative studies. we identified and replicated ten associations with total wbc count and five wbc subtypes at seven different genomic loci (total wbc count-6p21 in the hla region,17q21 near ormdl3,and csf3; neutrophil count-17q21; basophil count-3p21 near rpn1 and c3orf27; lymphocyte count-6p21,19p13 at eps15l1; monocyte count-2q31 at itga4,3q21,8q24 an intergenic region,9q31 near edg2),including three previously reported associations and seven novel associations. to investigate functional relationships among variants contributing to variability in the six wbc traits,we utilized gene expression- and pathways-based analyses. we implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses,with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. in addition,collaborative efforts between the groups contributing to this study and related studies conducted by the cogent and riken groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.
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آدرس
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laboratory of neurogenetics,intramural research program,national institute on aging (nia),national institutes of health (nih),bethesda,md, United States, collaborative studies coordinating center,department of biostatistics,university of north carolina at chapel hill,chapel hill,nc, United States, longitudinal studies section,clinical research branch,nia,nih,baltimore,md, United States, department of epidemiology,erasmus mc,rotterdam,netherlands,netherlands consortium for healthy aging (ngi-ncha),the netherlands genomics initiative,leiden, Netherlands, national heart,lung,and blood institute's framingham heart study,framingham,ma,united states,department of neurology,boston university school of medicine,boston,ma, United States, icelandic heart association,kopavogur,iceland,university of iceland,reykjavik, Iceland, division of genetics and cell biology,san raffaele scientific institute,milano,italy,institute of molecular genetics-cnr,pavia, Italy, department of medicine university of vermont college of medicine,burlington,vt,united states,department of pathology university of vermont college of medicine,burlington,vt, United States, national heart,lung,and blood institute's framingham heart study,framingham,ma,united states,department of biostatistics,boston university school of public health,boston,ma, United States, institute of immunology and transfusion medicine,ernst-moritz-arndt-university greifswald,greifswald, Germany, genetics of complex traits,peninsula college of medicine and dentistry,university of exeter, United Kingdom, laboratory for epidemiology,demography,and biometry,nia,nih,bethesda,md, United States, medical genetics,irccs-burlo garofolo/university of trieste,trieste, Italy, department of epidemiology and prevention,division of public health sciences,wake forest university,winston-salem,nc, United States, department of biostatistics,university of washington,seattle,wa, United States, division of epidemiology and community health,university of minnesota,minneapolis,mn, United States, department of epidemiology,university of washington,seattle,wa, United States, institute of genetic epidemiology,helmholtz zentrum münchen,german research center for environmental health,neuherberg, Germany, wellcome trust centre for human genetics,university of oxford,oxford,united kingdom,oxford centre for diabetes,endocrinology and metabolism,university of oxford,oxford, United Kingdom, department of epidemiology,erasmus mc,rotterdam,netherlands,netherlands consortium for healthy aging (ngi-ncha),the netherlands genomics initiative,leiden,netherlands,division of clinical epidemiology and aging research,german cancer research center,heidelberg, Germany, community medicine,ernst-moritz-arndt-university greifswald,greifswald, Germany, university of north carolina,school of public health, United States, center for human genetic research,department of neurology,massachusetts general hospital,boston,ma,united states,program in medical and population genetics,broad institute,cambridge,ma, United States, institute of epidemiology i,helmholtz zentrum münchen,german research center for environmental health,neuherberg,germany,institute of epidemiology ii,helmholtz zentrum münchen,german research center for environmental health,neuherberg, Germany, interfaculty institute for genetics and functional genomics,ernst-moritz-arndt-university greifswald,greifswald, Germany, laboratory of neurogenetics,intramural research program,national institute on aging (nia),national institutes of health (nih),bethesda,md, United States, cardiovascular health resarch unit and department of medicine,university of washington,seattle,wa, United States, department of haematology,university of cambridge and national health service blood and transplant,cambridge, United Kingdom, department of epidemiology,erasmus mc,rotterdam,netherlands,netherlands consortium for healthy aging (ngi-ncha),the netherlands genomics initiative,leiden, Netherlands, laboratory of neurogenetics,intramural research program,national institute on aging (nia),national institutes of health (nih),bethesda,md, United States, medical genetics institute,cedars-sinai medical center,los angeles,ca, United States, department of physiology and biophysics,university of mississippi medical center,jackson,ms, United States, montreal heart institute and universite de montreal,montreal, Canada, department of epidemiology,erasmus mc,rotterdam,netherlands,netherlands consortium for healthy aging (ngi-ncha),the netherlands genomics initiative,leiden, Netherlands, cardiovascular health resarch unit and department of medicine,university of washington,seattle,wa, United States, medical genetics,irccs-burlo garofolo/university of trieste,trieste, Italy, national heart,lung,and blood institute's framingham heart study,framingham,ma,united states,division of endocrinology,brigham and women's hospital and harvard medical school,boston, United States, institute of epidemiology ii,helmholtz zentrum münchen,german research center for environmental health,neuherberg, Germany, department of haematology,university of cambridge and national health service blood and transplant,cambridge, United Kingdom, laboratory of neurogenetics,intramural research program,national institute on aging (nia),national institutes of health (nih),bethesda,md, United States, institute for clinical chemistry and laboratory medicine,ernst-moritz-arndt-university greifswald,greifswald, Germany, institute of human genetics,klinikum rechts der isar,technical university munich,munich,germany,institute of human genetics,helmholtz zentrum münchen,german research center for environmental health,neuherberg, Germany, department of haematology,university of cambridge and national health service blood and transplant,cambridge, United Kingdom, cardiovascular health resarch unit and department of medicine,university of washington,seattle,wa, United States, national heart,lung,and blood institute's framingham heart study,framingham,ma,united states,department of biostatistics,boston university school of public health,boston,ma, United States, laboratory for statistical analysis,center for genomic medicine (cgm),institute of physical and chemical research (riken),yokohama,japan,department of allergy and rheumatology,graduate school of medicine,university of tokyo,tokyo, Japan, laboratory for statistical analysis,center for genomic medicine (cgm),institute of physical and chemical research (riken),yokohama, Japan, centre d'etude du polymorphisme humain (ceph),paris, France, laboratory of molecular medicine,human genome center,institute of medical science,university of tokyo,tokyo, Japan, laboratory for medical informatics,cgm,riken,yokohama, Japan, laboratory for cardiovascular diseases,cgm,riken,yokohama, Japan, laboratory for genotyping development,cgm,riken,yokohama, Japan, laboratory of molecular medicine,human genome center,institute of medical science,university of tokyo,tokyo, Japan, department of allergy and rheumatology,graduate school of medicine,university of tokyo,tokyo, Japan, laboratory for statistical analysis,center for genomic medicine (cgm),institute of physical and chemical research (riken),yokohama, Japan, department of medicine,university of leipzig,leipzig,germany,life study centre,university of leipzig,leipzig, Germany, department of medicine,university of leipzig,leipzig, Germany, wellcome trust centre for human genetics,university of oxford,oxford,united kingdom,oxford centre for diabetes,endocrinology and metabolism,university of oxford,oxford, United Kingdom, unit for molecular epidemiology,helmholtz zentrum münchen,german research center for environmental health,neuherberg, Germany, laboratory for epidemiology,demography,and biometry,nia,nih,bethesda,md, United States, department of haematology,university of cambridge and national health service blood and transplant,cambridge, United Kingdom, institute of genetic epidemiology,helmholtz zentrum münchen,german research center for environmental health,neuherberg, Germany, department of twin research and genetic epidemiology,king's college london,london, United Kingdom, department of epidemiology,erasmus mc,rotterdam,netherlands,netherlands consortium for healthy aging (ngi-ncha),the netherlands genomics initiative,leiden,netherlands,department of clinical genetics,erasmus mc,rotterdam, Netherlands, molecular haematology,king's college london,london, United Kingdom, department of epidemiology,johns hopkins university,baltimore,md, United States, institute of epidemiology i,helmholtz zentrum münchen,german research center for environmental health,neuherberg,germany,institute of medical informatics,biometry and epidemiology,chair of epidemiology,ludwig-maximilians-universität,munich,germany,klinikum grosshadern,munich, Germany, molecular haematology,king's college london,london, United Kingdom, office of biostatistical research,division of cardiovascular sciences,nhlbi,nih,bethesda,md, United States, division of genetics and cell biology,san raffaele scientific institute,milano, Italy, department of epidemiology,erasmus mc,rotterdam,netherlands,netherlands consortium for healthy aging (ngi-ncha),the netherlands genomics initiative,leiden,netherlands,department of internal medicine,erasmus mc,rotterdam, Netherlands, department of twin research and genetic epidemiology,king's college london,london, United Kingdom, interfaculty institute for genetics and functional genomics,ernst-moritz-arndt-university greifswald,greifswald, Germany, icelandic heart association,kopavogur, Iceland, icelandic heart association,kopavogur,iceland,university of iceland,reykjavik, Iceland, geriatric unit asf,firenze, Italy, genetics of complex traits,peninsula college of medicine and dentistry,university of exeter, United Kingdom, mckusick-nathans institute of genetic medicine,johns hopkins university,baltimore,md, United States, department of epidemiology,erasmus mc,rotterdam,netherlands,netherlands consortium for healthy aging (ngi-ncha),the netherlands genomics initiative,leiden, Netherlands, epidemiology and public health,peninsula college of medicine and dentistry,university of exeter,exeter,united kingdom,the european centre for environment and human health,pcmd,truro, United Kingdom, department of haematology,university of cambridge and national health service blood and transplant,cambridge,united kingdom,wellcome trust sanger institute,hinxton, United Kingdom, national heart,lung,and blood institute's framingham heart study,framingham,ma,united states,division of intramural research,national heart,lung,and blood institute (nhlbi),bethesda,md, United States, human genetics center,university of texas health science center,houston,tx, United States, laboratory of neurogenetics,intramural research program,national institute on aging (nia),national institutes of health (nih),bethesda,md, United States, laboratory of neurogenetics,intramural research program,national institute on aging (nia),national institutes of health (nih),bethesda,md,united states,department of molecular neuroscience and reta lila laboratories,institute of neurology,university college london,london, United Kingdom, clinical research branch,national institute on aging,baltimore,md, United States, wellcome trust sanger institute,hinxton, United Kingdom, department of epidemiology,erasmus mc,rotterdam,netherlands,netherlands consortium for healthy aging (ngi-ncha),the netherlands genomics initiative,leiden, Netherlands, departments of epidemiology,medicine and health services,university of washington,seattle,wa,united states,group health research institute,group health,seattle,wa, United States, longitudinal studies section,clinical research branch,nia,nih,baltimore,md, United States, laboratory for epidemiology,demography,and biometry,nia,nih,bethesda,md, United States, national heart,lung,and blood institute's framingham heart study,framingham,ma,united states,division of intramural research,national heart,lung,and blood institute (nhlbi),bethesda,md,united states,cardiology division,massachusetts general hospital,harvard medical school,boston,ma, United States, division of cardiovascular medicine,department of internal medicine,university of michigan,ann arbor,mi, United States
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Authors
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