A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function

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A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function


نویسنده	porcu e. ,medici m. ,pistis g. ,volpato c.b. ,wilson s.g. ,cappola a.r. ,bos s.d. ,deelen j. ,den heijer m. ,freathy r.m. ,lahti j. ,liu c. ,lopez l.m. ,nolte i.m. ,o'connell j.r. ,tanaka t. ,trompet s. ,arnold a. ,bandinelli s. ,beekman m. ,böhringer s. ,brown s.j. ,buckley b.m. ,camaschella c. ,de craen a.j.m. ,davies g. ,de visser m.c.h. ,ford i. ,forsen t. ,frayling t.m. ,fugazzola l. ,gögele m. ,hattersley a.t. ,hermus a.r. ,hofman a. ,houwing-duistermaat j.j. ,jensen r.a. ,kajantie e. ,kloppenburg m. ,lim e.m. ,masciullo c. ,mariotti s. ,minelli c. ,mitchell b.d. ,nagaraja r. ,netea-maier r.t. ,palotie a. ,persani l. ,piras m.g. ,psaty b.m. ,räikkönen k. ,richards j.b. ,rivadeneira f. ,sala c. ,sabra m.m. ,sattar n. ,shields b.m. ,soranzo n. ,starr j.m. ,stott d.j. ,sweep f.c.g.j. ,usala g. ,van der klauw m.m. ,van heemst d. ,van mullem a. ,h.vermeulen s. ,visser w.e. ,walsh j.p. ,westendorp r.g.j. ,widen e. ,zhai g. ,cucca f. ,deary i.j. ,eriksson j.g. ,ferrucci l. ,fox c.s. ,jukema j.w. ,kiemeney l.a. ,pramstaller p.p. ,schlessinger d. ,shuldiner a.r. ,slagboom e.p. ,uitterlinden a.g. ,vaidya b. ,visser t.j. ,wolffenbuttel b.h.r. ,meulenbelt i. ,rotter j.i. ,spector t.d. ,hicks a.a. ,toniolo d. ,sanna s. ,peeters r.p. ,naitza s.
منبع	plos genetics - 2013 - دوره : 9 - شماره : 2
چکیده	Thyroid hormone is essential for normal metabolism and development,and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. in addition,even mild alterations in thyroid function are associated with weight changes,atrial fibrillation,osteoporosis,and psychiatric disorders. to identify novel variants underlying thyroid function,we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers tsh and ft4,in up to 26,420 and 17,520 euthyroid subjects,respectively. here we report 26 independent associations,including several novel loci for tsh (pde10a,vegfa,igfbp5,nfia,sox9,prdm11,fgf7,insr,abo,mir1179,nrg1,mbip,itpk1,sash1,glis3) and ft4 (lhx3,foxe1,aadat,neto1/fbxo15,lpcat2/capns2). notably,only limited overlap was detected between tsh and ft4 associated signals,in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. five of the reported loci (pde8b,pde10a,maf/loc440389,neto1/fbxo15,and lpcat2/capns2) show strong gender-specific differences,which offer clues for the known sexual dimorphism in thyroid function and related pathologies. importantly,the tsh-associated loci contribute not only to variation within the normal range,but also to tsh values outside the reference range,suggesting that they may be involved in thyroid dysfunction. overall,our findings explain,respectively,5.64% and 2.30% of total tsh and ft4 trait variance,and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

آدرس	istituto di ricerca genetica e biomedica (irgb),consiglio nazionale delle ricerche,c/o cittadella universitaria di monserrato,monserrato,cagliari,italy,dipartimento di scienze biomediche,università di sassari,sassari, Italy, department of internal medicine,erasmus mc,rotterdam, Netherlands, istituto di ricerca genetica e biomedica (irgb),consiglio nazionale delle ricerche,c/o cittadella universitaria di monserrato,monserrato,cagliari,italy,division of genetics and cell biology,san raffaele research institute,milano,italy,università degli studi di trieste,trieste,italy,dipartimento di scienze biomediche,università di sassari,sassari, Italy, center for biomedicine,european academy bozen/bolzano (eurac),bolzano,italy,affiliated institute of the university of lübeck,lübeck, Germany, department of endocrinology and diabetes,sir charles gairdner hospital,nedlands,wa,australia,department of twin research and genetic epidemiology,king's college london,london,united kingdom,school of medicine and pharmacology,university of western australia,crawley,wa, Australia, university of pennsylvania school of medicine,philadelphia,pa, United States, leiden university medical center,molecular epidemiology,leiden,netherlands,netherlands consortium for healthy ageing,leiden, Netherlands, leiden university medical center,molecular epidemiology,leiden,netherlands,netherlands consortium for healthy ageing,leiden, Netherlands, department of endocrinology,radboud university nijmegen medical centre,nijmegen,netherlands,department of internal medicine,free university medical center,amsterdam, Netherlands, genetics of complex traits,peninsula college of medicine and dentistry,university of exeter,exeter, United Kingdom, institute of behavioural sciences,university of helsinki,helsinki, Finland, center for population studies,national heart,lung,and blood institute,framingham,ma, United States, centre for cognitive ageing and cognitive epidemiology,university of edinburgh,edinburgh,united kingdom,department of psychology,university of edinburgh,edinburgh, United Kingdom, unit of genetic epidemiology and bioinformatics,department of epidemiology,university medical center groningen,university of groningen,groningen, Netherlands, department of medicine,university of maryland medical school,baltimore,md, United States, clinical research branch,national institute on aging,baltimore,md, United States, department of cardiology,leiden university medical center,leiden,netherlands,department of gerontology and geriatrics,leiden university medical center,leiden, Netherlands, cardiovascular health research unit and department of medicine,university of washington,seattle,wa, United States, geriatric unit,azienda sanitaria firenze (asf),florence, Italy, leiden university medical center,molecular epidemiology,leiden,netherlands,netherlands consortium for healthy ageing,leiden, Netherlands, leiden university medical center,medical statistics and bioinformatics,leiden, Netherlands, department of endocrinology and diabetes,sir charles gairdner hospital,nedlands,wa, Australia, department of pharmacology and therapeutics,university college cork,cork, Ireland, division of genetics and cell biology,san raffaele research institute,milano,italy,vita e salute university,san raffaele scientific institute,milano, Italy, department of gerontology and geriatrics,leiden university medical center,leiden, Netherlands, department of psychology,university of edinburgh,edinburgh, United Kingdom, department for health evidence,radboud university medical centre,nijmegen, Netherlands, robertson center for biostatistics,university of glasgow,glasgow, United Kingdom, department of chronic disease prevention,national institute for health and welfare,helsinki,finland,department of general practice and primary health care,university of helsinki,helsinki,finland,helsinki university central hospital,unit of general practice,helsinki,finland,vaasa health care centre,diabetes unit,vaasa, Finland, genetics of complex traits,peninsula college of medicine and dentistry,university of exeter,exeter, United Kingdom, endocrine unit,fondazione ca' granda policlinico and department of clinical sciences and community health,university of milan,milano, Italy, center for biomedicine,european academy bozen/bolzano (eurac),bolzano, Italy, peninsula nihr clinical research facility,peninsula college of medicine and dentistry,university of exeter,exeter, United Kingdom, department of endocrinology,radboud university nijmegen medical centre,nijmegen, Netherlands, department of epidemiology,erasmus mc,rotterdam,netherlands,netherlands genomics initiative (ngi)-sponsored netherlands consortium for healthy aging (ncha),rotterdam, Netherlands, leiden university medical center,medical statistics and bioinformatics,leiden, Netherlands, cardiovascular health research unit and department of medicine,university of washington,seattle,wa, United States, department of chronic disease prevention,national institute for health and welfare,helsinki,finland,hospital for children and adolescents,helsinki university central hospital and university of helsinki,helsinki, Finland, department of clinical epidemiology and rheumatology,leiden university medical center,leiden, Netherlands, department of endocrinology and diabetes,sir charles gairdner hospital,nedlands,wa,australia,pathwest laboratory medicine wa,nedlands,wa, Australia, division of genetics and cell biology,san raffaele research institute,milano, Italy, dipartimento di scienze mediche,università di cagliari,c/o cittadella universitaria di monserrato,monserrato,cagliari, Italy, center for biomedicine,european academy bozen/bolzano (eurac),bolzano, Italy, department of medicine,university of maryland medical school,baltimore,md, United States, laboratory of genetics,national institute on aging,baltimore,md, United States, department of endocrinology,radboud university nijmegen medical centre,nijmegen, Netherlands, wellcome trust sanger institute,wellcome trust genome campus,cambridge,united kingdom,institute for molecular medicine finland (fimm),university of helsinki,helsinki,finland,department of medical genetics,university of helsinki and university central hospital,helsinki, Finland, department of clinical sciences and community health,university of milan,milano,italy,division of endocrinology and metabolic diseases,irccs ospedale san luca,milan, Italy, istituto di ricerca genetica e biomedica (irgb),consiglio nazionale delle ricerche,c/o cittadella universitaria di monserrato,monserrato,cagliari, Italy, cardiovascular health research unit,departments of medicine,epidemiology,and health services,university of washington,seattle,wa,united states,group health research institute,group health cooperative,seattle,wa, United States, institute of behavioural sciences,university of helsinki,helsinki, Finland, department of twin research and genetic epidemiology,king's college london,london,united kingdom,department of medicine,jewish general hospital,mcgill university,montréal,qc,canada,departments of human genetics,epidemiology,and biostatistics,jewish general hospital,lady davis institute,mcgill university,montréal,qc, Canada, department of internal medicine,erasmus mc,rotterdam,netherlands,department of epidemiology,erasmus mc,rotterdam,netherlands,netherlands genomics initiative (ngi)-sponsored netherlands consortium for healthy aging (ncha),rotterdam, Netherlands, division of genetics and cell biology,san raffaele research institute,milano, Italy, memorial sloan kettering cancer center,medicine-endocrinology,new york,ny, United States, bhf glasgow cardiovascular research centre,faculty of medicine,glasgow, United Kingdom, peninsula nihr clinical research facility,peninsula college of medicine and dentistry,university of exeter,exeter, United Kingdom, wellcome trust sanger institute,wellcome trust genome campus,cambridge, United Kingdom, centre for cognitive ageing and cognitive epidemiology,university of edinburgh,edinburgh,united kingdom,alzheimer scotland dementia research centre,university of edinburgh,edinburgh, United Kingdom, academic section of geriatric medicine,faculty of medicine,university of glasgow,glasgow, United Kingdom, department of laboratory medicine,radboud university nijmegen medical center,nijmegen, Netherlands, istituto di ricerca genetica e biomedica (irgb),consiglio nazionale delle ricerche,c/o cittadella universitaria di monserrato,monserrato,cagliari, Italy, lifelines cohort study,university medical center groningen,university of groningen,groningen,netherlands,department of endocrinology,university medical center groningen,university of groningen,groningen, Netherlands, leiden university medical center,gerontology and geriatrics,leiden, Netherlands, department of internal medicine,erasmus mc,rotterdam, Netherlands, department for health evidence,radboud university medical centre,nijmegen, Netherlands, department of internal medicine,erasmus mc,rotterdam, Netherlands, department of endocrinology and diabetes,sir charles gairdner hospital,nedlands,wa,australia,school of medicine and pharmacology,university of western australia,crawley,wa, Australia, leiden university medical center,gerontology and geriatrics,leiden, Netherlands, institute for molecular medicine finland (fimm),university of helsinki,helsinki, Finland, department of twin research and genetic epidemiology,king's college london,london,united kingdom,discipline of genetics,faculty of medicine,memorial university of newfoundland,st. johns,nl, Canada, istituto di ricerca genetica e biomedica (irgb),consiglio nazionale delle ricerche,c/o cittadella universitaria di monserrato,monserrato,cagliari,italy,dipartimento di scienze biomediche,università di sassari,sassari, Italy, centre for cognitive ageing and cognitive epidemiology,university of edinburgh,edinburgh,united kingdom,department of psychology,university of edinburgh,edinburgh, United Kingdom, department of chronic disease prevention,national institute for health and welfare,helsinki,finland,department of general practice and primary health care,university of helsinki,helsinki,finland,helsinki university central hospital,unit of general practice,helsinki,finland,folkhalsan research centre,helsinki,finland,vasa central hospital,vasa, Finland, clinical research branch,national institute on aging,baltimore,md, United States, division of intramural research,national heart,lung,and blood institute,framingham,ma,united states,division of endocrinology,hypertension,and metabolism,brigham and women's hospital and harvard medical school,boston,ma, United States, department of cardiology,leiden university medical center,leiden,netherlands,durrer center for cardiogenetic research,amsterdam,netherlands,interuniversity cardiology institute of the netherlands,utrecht, Netherlands, department for health evidence,radboud university medical centre,nijmegen,netherlands,department of urology,radboud university medical centre,nijmegen, Netherlands, center for biomedicine,european academy bozen/bolzano (eurac),bolzano,italy,department of neurology,general central hospital,bolzano,italy,department of neurology,university of lübeck,lübeck, Germany, laboratory of genetics,national institute on aging,baltimore,md, United States, department of medicine,university of maryland medical school,baltimore,md,united states,geriatric research and education clinical center,veterans administration medical center,baltimore,md, United States, leiden university medical center,molecular epidemiology,leiden,netherlands,netherlands consortium for healthy ageing,leiden, Netherlands, department of internal medicine,erasmus mc,rotterdam,netherlands,department of epidemiology,erasmus mc,rotterdam,netherlands,netherlands genomics initiative (ngi)-sponsored netherlands consortium for healthy aging (ncha),rotterdam, Netherlands, diabetes,endocrinology and vascular health centre,royal devon and exeter nhs foundation trust,exeter, United Kingdom, department of internal medicine,erasmus mc,rotterdam, Netherlands, lifelines cohort study,university medical center groningen,university of groningen,groningen,netherlands,department of endocrinology,university medical center groningen,university of groningen,groningen, Netherlands, leiden university medical center,molecular epidemiology,leiden,netherlands,netherlands consortium for healthy ageing,leiden, Netherlands, medical genetics institute,cedars-sinai medical center,los angeles,ca, United States, department of twin research and genetic epidemiology,king's college london,london, United Kingdom, center for biomedicine,european academy bozen/bolzano (eurac),bolzano, Italy, division of genetics and cell biology,san raffaele research institute,milano,italy,institute of molecular genetics-cnr,pavia, Italy, istituto di ricerca genetica e biomedica (irgb),consiglio nazionale delle ricerche,c/o cittadella universitaria di monserrato,monserrato,cagliari, Italy, department of internal medicine,erasmus mc,rotterdam, Netherlands, istituto di ricerca genetica e biomedica (irgb),consiglio nazionale delle ricerche,c/o cittadella universitaria di monserrato,monserrato,cagliari, Italy



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