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Multiple independent loci at chromosome 15q25.1 affect smoking quantity: A meta-analysis and comparison with lung cancer and COPD
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نویسنده
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saccone n.l. ,culverhouse r.c. ,schwantes-an t. ,cannon d.s. ,chen x. ,cichon s. ,giegling i. ,han s. ,han y. ,keskitalo-vuokko k. ,kong x. ,landi m.t. ,ma j.z. ,short s.e. ,stephens s.h. ,stevens v.l. ,sun l. ,wang y. ,wenzlaff a.s. ,aggen s.h. ,breslau n. ,broderick p. ,chatterjee n. ,chen j. ,heath a.c. ,heliövaara m. ,hoft n.r. ,hunter d.j. ,jensen m.k. ,martin n.g. ,montgomery g.w. ,niu t. ,payne t.j. ,peltonen l. ,pergadia m.l. ,rice j.p. ,sherva r. ,spitz m.r. ,sun j. ,wang j.c. ,weiss r.b. ,wheeler w. ,witt s.h. ,yang b. ,caporaso n.e. ,ehringer m.a. ,eisen t. ,gapstur s.m. ,gelernter j. ,houlston r. ,kaprio j. ,kendler k.s. ,kraft p. ,leppert m.f. ,li m.d. ,madden p.a.f. ,nöthen m.m. ,pillai s. ,rietschel m. ,rujescu d. ,schwartz a. ,amos c.i. ,bierut l.j.
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منبع
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plos genetics - 2010 - دوره : 6 - شماره : 8
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چکیده
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Recently,genetic association findings for nicotine dependence,smoking behavior,and smoking-related diseases converged to implicate the chromosome 15q25.1 region,which includes the chrna5-chrna3-chrnb4 cholinergic nicotinic receptor subunit genes. in particular,association with the nonsynonymous chrna5 snp rs16969968 and correlates has been replicated in several independent studies. extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence,tagged by rs578776 and rs588765. one goal of the consortium for the genetic analysis of smoking phenotypes (cgasp) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking),lung cancer,and chronic obstructive pulmonary disease (copd). we performed a metaanalysis across 34 datasets of european-ancestry subjects,including 38,617 smokers who were assessed for cigarettes-perday,7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers),and 2,614 copd cases and 3,568 copd-free controls (all smokers). we demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10-35 and <10-8 respectively). because the risk alleles at these loci are negatively correlated,their association with smoking is stronger in the joint model than when each snp is analyzed alone. rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10-6). in models adjusting for cigarettes-perday,we confirm the association between rs16969968 and lung cancer (p<10-20) and observe a nominally significant association with copd (p = 0.01); the other loci are not significantly associated with either lung cancer or copd after adjusting for rs16969968. this study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. this study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these snps have previously been associated with mrna levels of chrna5 in brain and lung tissue.
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آدرس
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department of genetics,washington university school of medicine,st. louis,mo,united states,pharmaceutical research and development,roche pharmaceuticals,nutley,nj, United States, department of internal medicine,washington university school of medicine,st. louis,mo,united states,division of biostatistics,washington university school of medicine,st. louis,mo, United States, department of genetics,washington university school of medicine,st. louis,mo, United States, department of psychiatry,university of utah school of medicine,salt lake city,ut, United States, department of psychiatry,virginia commonwealth university,richmond,va,united states,department of human molecular genetics,virginia commonwealth university,richmond,va, United States, department of genomics,life and brain center,university of bonn,bonn,germany,institute of neuroscience and medicine (inm-1),research center jülich,jülich, Germany, department of psychiatry,university of munich (lmu),munich, Germany, departments of psychiatry,genetics,and neurobiology,yale university school of medicine,new haven,ct, United States, department of epidemiology,university of texas m. d. anderson cancer center,houston, United States, department of public health,university of helsinki,helsinki, Finland, department of quantitative sciences,glaxosmithkline,king of prussia,pa, United States, division of cancer epidemiology and genetics,national institutes of health,bethesda,md, United States, department of public health sciences,university of virginia,charlottesville,va, United States, department of sociology,brown university,providence,ri,united states,environmental and occupational medicine and epidemiology program,harvard school of public health,boston,ma, United States, institute for behavioral genetics,university of colorado,boulder,co, United States, epidemiology research,american cancer society,atlanta,ga, United States, department of psychiatry,washington university school of medicine,st. louis,mo, United States, section of cancer genetics,institute of cancer research,sutton surrey, United Kingdom, karmanos cancer institute,wayne state university,detroit,mi, United States, department of psychiatry,virginia commonwealth university,richmond,va, United States, department of epidemiology,michigan state university,east lansing,mi, United States, section of cancer genetics,institute of cancer research,sutton surrey, United Kingdom, division of cancer epidemiology and genetics,national institutes of health,bethesda,md, United States, department of psychiatry,virginia commonwealth university,richmond,va, United States, department of psychiatry,washington university school of medicine,st. louis,mo, United States, national institute for health and welfare,helsinki, Finland, institute for behavioral genetics,university of colorado,boulder,co, United States, department of epidemiology,harvard school of public health,boston,ma,united states,department of nutrition,harvard school of public health,boston,ma, United States, department of nutrition,harvard school of public health,boston,ma, United States, queensland institute of medical research,brisbane,qld, Australia, queensland institute of medical research,brisbane,qld, Australia, department of psychiatry and neurobehavioral sciences,university of virginia,charlottesville,va, United States, department of otolaryngology and communicative sciences,the university of mississippi medical center,jackson,ms, United States, national institute for health and welfare,helsinki,finland,institute for molecular medicine finland fimm,helsinki,finland,department of medical genetics,university of helsinki,helsinki,finland,wellcome trust sanger institute,cambridge,united kingdom,broad institute of harvard and massachusetts institute of technology,cambridge,ma, United States, department of psychiatry,washington university school of medicine,st. louis,mo, United States, department of genetics,washington university school of medicine,st. louis,mo,united states,division of biostatistics,washington university school of medicine,st. louis,mo,united states,department of psychiatry,washington university school of medicine,st. louis,mo, United States, department of medicine (genetics program),boston university school of medicine,boston,ma, United States, department of epidemiology,university of texas m. d. anderson cancer center,houston, United States, epidemiology research,american cancer society,atlanta,ga, United States, department of psychiatry,washington university school of medicine,st. louis,mo, United States, department of human genetics,eccles institute of human genetics,university of utah school of medicine,salt lake city,ut, United States, information management services,rockville,ma, United States, department of genetic epidemiology in psychiatry,central institute of mental health mannheim,mannheim, Germany, departments of psychiatry,genetics,and neurobiology,yale university school of medicine,new haven,ct, United States, division of cancer epidemiology and genetics,national institutes of health,bethesda,md, United States, institute for behavioral genetics,university of colorado,boulder,co,united states,department of integrative physiology,university of colorado,boulder,co, United States, cambridge biomedical research centre,cambridge, United Kingdom, epidemiology research,american cancer society,atlanta,ga, United States, departments of psychiatry,genetics,and neurobiology,yale university school of medicine,new haven,ct, United States, section of cancer genetics,institute of cancer research,sutton surrey, United Kingdom, department of public health,university of helsinki,helsinki,finland,national institute for health and welfare,helsinki,finland,institute for molecular medicine finland fimm,helsinki, Finland, department of psychiatry,virginia commonwealth university,richmond,va,united states,department of human molecular genetics,virginia commonwealth university,richmond,va, United States, department of epidemiology,harvard school of public health,boston,ma,united states,department of biostatistics,harvard university,boston,co, United States, department of human genetics,eccles institute of human genetics,university of utah school of medicine,salt lake city,ut, United States, department of psychiatry and neurobehavioral sciences,university of virginia,charlottesville,va, United States, department of psychiatry,washington university school of medicine,st. louis,mo, United States, department of genomics,life and brain center,university of bonn,bonn,germany,institute of human genetics,university of bonn,bonn, Germany, glaxo smithkline,research triangle park,north carolina,nc, United States, department of genetic epidemiology in psychiatry,central institute of mental health mannheim,mannheim,germany,department of psychiatry,university of bonn,bonn, Germany, department of psychiatry,university of munich (lmu),munich, Germany, karmanos cancer institute,wayne state university,detroit,mi, United States, department of epidemiology,university of texas m. d. anderson cancer center,houston, United States, department of psychiatry,washington university school of medicine,st. louis,mo, United States
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Authors
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