1.1www.00271

LETTERdoi:10.
1038/nature11401FTOgenotypeisassociatedwithphenotypicvariabilityofbodymassindexAlistofauthorsandtheiraffiliationsappearsattheendofthepaper.
Thereisevidenceacrossseveralspeciesforgeneticcontrolofphenotypicvariationofcomplextraits1–4,suchthatthevarianceamongphenotypesisgenotypedependent.
Understandinggeneticcontrolofvariabilityisimportantinevolutionarybiology,agricul-turalselectionprogrammesandhumanmedicine,yetforcomplextraits,noindividualgeneticvariantsassociatedwithvariance,asopposedtothemean,havebeenidentified.
Hereweperformameta-analysisofgenome-wideassociationstudiesofphenotypicvariationusing170,000samplesonheightandbodymassindex(BMI)inhumanpopulations.
Wereportevidencethatthesinglenucleotidepolymorphism(SNP)rs7202116attheFTOgenelocus,whichisknowntobeassociatedwithobesity(asmeasuredbymeanBMIforeachrs7202116genotype)5–7,isalsoassociatedwithphenotypicvariability.
Weshowthattheresultsarenotduetoscaleeffectsorotherartefacts,andfindnootherexperiment-wisesignificantevidenceforeffectsonvariability,eitheratlociotherthanFTOforBMIoratanylocusforheight.
ThedifferenceinvarianceforBMIamongindividualswithoppositehomozygousgenotypesattheFTOlocusisapproximately7%,correspondingtoadifferenceof0.
5kilogramsinthestandarddeviationofweight.
Ourresultsindicatethatgeneticvariantscanbediscoveredthatareassociatedwithvariability,andthatbetween-personvariabilityinobesitycanpartlybeexplainedbythegenotypeattheFTOlocus.
TheresultsareconsistentwithreportedFTObyenvironmentinteractionsforBMI8,possiblymediatedbyDNAmethylation9,10.
OurBMIresultsforotherSNPsandourheightresultsforallSNPssuggestthatmostgeneticvariants,includingthosethatinfluencemeanheightormeanBMI,arenotassociatedwithphenotypicvariance,orthattheireffectsonvariabilityaretoosmalltodetectevenwithsamplessizesgreaterthan100,000.
Geneticstudiesofcomplextraitsusuallyfocusonquantifyinganddissectingphenotypicvariationwithinpopulations,bycontrastingmeandifferencesinphenotypesbetweengenotypes.
Forexample,inassociationstudiesthedifferencebetweentheaveragephenotype(P)ofeachgenotypeistested.
Inaddition,thephenotypicvarianceamongindividualsofthesamegenotype(G)canvaryacrossgenotypes,sothatphenotypicvarianceconditionalongenotype,var(PjG),isnotcon-stant.
Phenotypicvariancegivenaparticulargenotypedoesnotneedtobeduetosensitivitytoexternalenvironmentalfactorsbutcan,forexample,becausedbydevelopmentalfluctuationoftheinternalmicro-environmentinagenotype-dependentmanner1.
Forexample,geneticcontrolofstochasticvariationindevelopmentorinhomeo-staticcontrol1,4.
Thedifferencebetweengenotypescanalsodependonexternalfactors,forexample,ontheenvironmentinwhichtheyarereared,inwhichcasethereisagenotypebyenvironment(G3E)interaction.
Inspeciesinwhichthesamegenotypecanbemeasuredacrossdefinedenvironments,suchasinplantoranimalpopulations,thedifferenceinmeanphenotypeforeachgenotypecanbequantifiedexperimentally,andisknownasthereactionnormofthegenotype11,12.
However,anyenvironmentislikelytobeheterogeneous,sothattheenvironmentexperiencedbyeachindividualdiffers,althoughthesedifferencesarenotformallyrecognizedbytheexperimenter.
Inthissituation,ifaG3Einteractionexistsitmaymanifestasdifferencesinenvironmentalsensitivitysothatgenotypesdifferinphenotypicvari-ance.
Therefore,eveniftheenvironments,internalorexternal,arenotdirectlymeasured,evidenceforgeneticcontrolofvariationcanbequantifiedthroughananalysisofvariability.
Thereisempiricalevidenceforgeneticcontrolofphenotypicvari-ationinseveralspecies1,includingDrosophila13,snails14,maize15andchickens3,andspecificquantitativetraitlociwithaneffectonvariancehavebeenreportedforyeast2andArabidopsis4.
Manytheoriesandmethodstoidentifygeneticlociresponsibleforphenotypicvariabilityhavebeenproposed1,16–18.
Inhumans,therehavebeenreportsthatvariabilityofserumcholesterolandtriglyceridelevelswithinmono-zygotictwinpairsdependsontheirgenotypeattheMNbloodgroupsystem19.
Inclinicalpractice,knowledgeofphenotypicvariabilityasafunctionofgenotypemaybeimportantwhenthephenotypesareriskfactorsfordiseaseortreatmentresponse,inparticularwhentherearenomeandifferencesbetweengenotypesinthepopulation19.
Detectionofgeneticvariationinenvironmentalorphenotypicvari-ancerequireslargesamplesizesbecauserelativetotheirexpectedvalues,thevariancehasalargersamplingerrorthanthemean16,20.
Weperformedameta-analysisofgenome-wideassociationstudies(GWAS)ofphenotypicvariationforheightandBMIinhumanpopu-lationsonapproximately170,000samplescomprising133,154inadiscoverysetand36,727forinsilicoreplication,andreportasinglelocuswithagenome-widesignificanteffectonvariabilityinBMI.
HeightandBMIwerechosenbecausegeneticeffectsonvariabilityinheightandsizetraitshavebeenreportedinotherspecies,andbecauseverylargesamplesofgenotypedandphenotypedindividualsareavail-ablethroughexistingresearchconsortia.
Weperformedadiscoverymeta-analysisof38studiesconsistingof133,154individuals(60%females)ofrecentEuropeandecenttoidentifySNPsthatareassociatedwiththevariabilityofheightorBMI.
Ineachstudy,,2.
44milliongenotypedandimputedautosomalSNPswereincludedintheanalysisafterapplyingquality-controlfilters.
WeadjustedheightandBMIphenotypesforpossiblecovariatessuchasage,sexandcase-controlstatus,andstandardizedthemtozscoresbyaninverse-normaltransformation.
Wethenregressedthesquaredzscores(z2),whichareameasureofvariance20,onthegeno-typeindicatorvariableofeachSNPtotestforassociationoftheSNPwithtraitvariability.
Theassociationstatisticswerecorrectedbythegenomiccontrolmethod21inindividualstudiesandthencombinedbyaninverse-variancemeta-analysisacrossallofthestudies(seeMethods).
Weselected42SNPsat6lociforheightand51SNPsat7lociforBMIwithP,531026forinsilicoreplication(SupplementaryFig.
1).
WeexaminedthetoptwoSNPsateachofthe6lociforheightand7lociforBMIinafurthersampleof36,727individuals(54%females)ofEuropeanancestryfrom13studies(Methods).
ForBMI,onlyrs7202116attheFTOlocus(Fig.
1)andrs7151545attheRCOR1locus(SupplementaryFig.
2)werereplicatedatgenome-widesignifi-cancelevel,withP52.
931024andP53.
631023inthevalidationsetandP52.
4310210andP54.
131028inthecombinedset,respectively(Table1).
NoneoftheheightSNPswasreplicated(Table1).
Weshowbyanapproximateconditionalanalysisusingsummarystatisticsfromthediscoverymeta-analysisandestimated00MONTH2012|VOL000|NATURE|1MacmillanPublishersLimited.
Allrightsreserved2012linkagedisequilibriumstructurefromtheAtherosclerosisRiskInCommunities(ARIC)cohortthatthereisnosecondaryassociatedSNPintheFTOregionwhenconditioningonrs7202116(Supplemen-taryFig.
3).
Theestimateoftheeffectassociatedwithrs7202116onBMIz2wasslightlylargerinmen(0.
041,standarderror(SE)50.
009)thaninwomen(0.
033,SE50.
007)inthecombinedsetbutthediffer-encewasnotsignificant(P50.
670).
TheRCOR1SNPonlyjustpassedthegenome-widesignificancelevel(531028),however,itdidnotreachtheexperiment-wisesignificancelevel(2.
531028)consideringthattwoindependenttraitsweretested.
Therewereseveralcase-controlstudiesincludedinthemeta-analysisthatwereascertainedfordiseasesthatmaybecorrelatedwithBMI.
Weperformedafurthermeta-analysisinthecombinedsetexcludingthesecase-controlstudies,andtheFTOSNPrs7202116remainedgenome-widesignificantwithP52.
8310211buttheRCOR1SNPdidnotwithP53.
631025(SupplementaryTable1).
WethereforefocusontheFTOlocusinthemaintextandprovidetheresultsfortheRCOR1locusintheSupplementaryInformation.
OnthescaleonwhichBMIismeasured,thepredictedper-alleleeffectoftheGallele(theotheralleleisA)ofrs7202116onthemeandifferenceis0.
37kgm22inmenand0.
43kgm22inwomen22,andtheeffectonthevariancedifferenceis0.
79kg2m24inmenand1.
09kg2m24inwomen,reflectingthelargerstandarddeviationofBMIinwomencomparedwithmen(SupplementaryTable2).
Assuminganadditivemodel,themeandifferencebetweentheGGandAAgeno-typesis0.
74kgm22inmenand0.
86kgm22inwomen,withavari-ancedifferencebetweenthetwogenotypesof1.
58kg2m24inmenand2.
18kg2m24inwomen,whichis7.
2%ofthephenotypicvarianceofBMIinbothmenandwomen.
Toprovideanillustrationoftheeffectofrs7202116onBMIvariance,wedidanapproximatecalculationofitseffectonthevarianceofweight.
Ifwetakethemeanheightof1.
78mformenand1.
65mforwomen,thedifferenceinthevarianceofweightbetweenthetwogenotypegroupsisroughly16kg2inbothmenandwomen(SupplementaryTable2).
Forexample,ifthestandarddevi-ation(SD)ofweightis15kgformen,thepredictedSDofweightinthetwohomozygousgenotypeclassesis14.
73and15.
27kg,respectively.
TheeffectofaSNPonvariancecouldbeowingtoouruseofthez2valueasameasureofvarianceortoageneralrelationshipbetweenmeanandvarianceofBMI1,23.
Belowwepresentevidencethatexcludesthesetwoexplanations.
0246810–log10(Pvalue)020406080100Recombinationrate(cMMb–1)rs72021160.
20.
40.
60.
8r2RBL2AKTIPRPGRIP1LFTOIRX35252.
252.
452.
652.
853Positiononchr16(Mb)PlottedSNPsFigure1|Teststatistics(–log10(Pvalues))forassociationwithBMIvariabilityinthediscoverymeta-analysisofSNPsattheFTOlocusagainsttheirphysicallocation.
TheSNPssurroundingrs7202116arecolour-codedtoreflecttheirlinkagedisequilibriumwithrs7202116.
Therecombinationratesareplottedincyantoreflectlocallinkagedisequilibriumstructure.
Genes,thepositionofexonsandthedirectionoftranscriptionfromtheUniversityofCalifornia,SantaCruz(UCSC)genomebrowserarenoted.
ThePvalueforrs7202116inthecombinedsetisrepresentedbyapurplediamond,andthatfromthediscoverysetbyapurplecircle.
Table1|Associationsofthetop6and7lociwithvarianceofheightandBMI,respectivelyChr.
SNPbpNearestgeneCADiscoveryFreq.
bSEPnHeight1rs642982014,210,915PRDM2G0.
19620.
0350.
00711.
031026129,2002rs6429975143,002,110KYNUT0.
18020.
0360.
00741.
031026129,1962rs674837745,002,877SIX3T0.
17520.
0380.
00754.
031027129,1837rs1048672241,778,433INHBAC0.
3390.
0290.
00601.
031026128,8348rs10268523,577,500CSMD1G0.
44420.
0290.
00591.
031026126,36314rs1289134334,453,301BAZ1AT0.
2270.
0310.
00685.
031026128,725BMI2rs12328474140,638,570LRP1BG0.
26320.
0380.
00781.
231026104,6402rs10932241208,685,200CRYGDC0.
4070.
0280.
00592.
931026127,5974rs11942401188,052,244FATA0.
14020.
0430.
00854.
331027125,0106rs141830482,795,837IBTKG0.
49620.
0260.
00573.
331026127,61114rs12894649102,232,512RCOR1C0.
0570.
0610.
01261.
331026127,08014rs7151545102,247,397RCOR1G0.
0570.
0590.
01262.
431026127,08016rs719314452,368,187FTOC0.
4030.
0300.
00581.
931027127,53716rs720211652,379,116FTOG0.
4020.
0350.
00672.
03102795,96618rs62005237,900,962PIK3C3G0.
3780.
0330.
00691.
63102695,971Thesquaredzscores(z2)wereusedtotestforassociationofthetop6and7SNPswithtraitvariability(heightandBMI,respectively).
Thediscoverysetconsistsof133,154individuals,anddataforinsilicoreplicationarefromanother36,727samples.
AtboththeFTOandRCOR1loci,thesecondtopSNPs(highlightedinbold)inthediscoverysetpassthesingletraitgenome-widesignificancelevel(531028)inthecombinedset.
b,estimateofadditiveeffectonz2;bp,physicalposition;CA,codedallele;chr.
,chromosome;freq.
,frequencyofthecodedallele.
RESEARCHLETTER2|NATURE|VOL000|00MONTH2012MacmillanPublishersLimited.
Allrightsreserved2012IfanSNPhasaneffectonthemean,theteststatisticforassociationoftheSNPwithz2willbeinflated,andthenon-centralityparameter(NCPv0)ofthex2testunderthenullhypothesisofnoeffectonvarianceis:np(12p)(122p)2(a1(122p)d)4,inwhichnisthesamplesize,pisthefrequencyofthecodedallele,andaanddaretheadditiveanddominanceeffects,respectively,onthemeandifference(Supplemen-taryNote).
Weshowbyanalysisandsimulationresultsbasedonanadditiveanddominancegeneticmodelthatsuchinflationisinverselyproportionaltotheminorallelefrequency(MAF)oftheSNP;thatis,SNPswithalowerMAFwilltendtohavehigherteststatisticsunderthenullhypothesis(SupplementaryFig.
4).
However,whenweplottedtheobservedteststatisticsoftheconfirmed180heightloci24and32BMIloci22thathavethelargestreportedeffectsonthemean,wedidnotobservesuchatrend(SupplementaryFig.
5).
WecalculatedtheNCPv0oftheknownheightandBMIlocigiventheeffectsonthemeanfromthepublishedpapers22,24,andtheNCPv0valuesofalltheseknownlociweresmallerthan1(resultsnotshown).
Theobservedgenomicinflationfactorinthediscoverymeta-analysiswas1.
039forheightand1.
033forBMI(SupplementaryFig.
6).
ThissmallinflationcouldbeduetomanySNPsaffectingthemeanandthereforehavingatinyeffectonz2(SupplementaryFig.
7),ormanySNPsthathaveaneffectonthevariancethatistoosmalltobesignificantevenwithourlargesamplesize.
AcrosscommonSNPsinthegenome,variantsattheFTOlocushavethelargesteffectsizeonBMI22.
TheGalleleoftheFTOSNPrs7202116hasapopulationfrequencyof,0.
4andanadditiveeffectonthemeanBMIof,0.
1z-scoreunits5,22.
IfoursignificantresultattheFTOlocusisdueonlytoanalleliceffectonmeanBMI,wewouldexpectanalleliceffectonvariabilityof,0.
002(predictedfromtheequationintheSupplementaryNote),whichisverysmallcomparedwiththeobservedeffectof0.
036.
Forsometraits,thevariancechangesinapredictablemannerasthemeanchanges.
Inthiscase,ascaletransformation,suchasalogarithmictransformation,canremoveeffectsonthevariancewhentheyaresimplyduetoaneffectonthemean1.
WewereinterestedineffectsofSNPonvariabilitythatwouldremainafterascaletransformation,andthereforesoughttoexcludescaleeffectsthatcouldexplainourobservedassociation.
Weper-formedfurtheranalysesinthreedatasetseachwithapproximately20,000individualswithindividual-levelgenotypeandphenotypedataavailabletoverifytheeffectsofrs7202116attheFTOlocusonBMIvariance(MethodsandTable2).
Weusedseveraltests,includingBartlett'steststatistic,totestforthedifferenceinvariancebetweenthethreegenotypes.
TheBartlett'stestPvaluewas,0.
05ineachofthethreedatasets,regardlessofwhetherornottheBMIphenotypeswereadjustedforthemeandifference,logarithmtransformedorinverse-normaltransformed(Table2).
Inthecombinedanalysisofthethreedatasetstotalling60,624individuals,theeffectofrs7202116ontheBMIz2scoreafteradjustingforthemeandifferencewas0.
030(P51.
231024)forinverse-normaltransformedBMI,0.
065(2.
3310212)forlogarithm-transformedBMI,and0.
097(8.
9310216)forBMIwithoutscaletransformation(Table2).
Thedecreaseoftheeffectofrs7202116onBMIz2owingtotheadjustmentofthemeandifferencewas,0.
003,inlinewiththatof,0.
002aspredictedfromthetheoryabove.
Similarconclusionsasabovecanbedrawnfromthefurtheranalysesforrs7151545attheRCOR1locus(SupplementaryTable3).
Weplottedtheteststatisticsandestimatesfortheeffectsonthevariabilityinourdiscoverymeta-analysisagainstthosefortheeffectsonthemeanfromthepublishedGIANTmeta-analysesforheight24andBMI22,anddidnotfindanyapparentcorrela-tionsexceptforafewoutlyingSNPsattheFTOlocus(SupplementaryFig.
7).
TheseresultstogethersuggestthattheobservedeffectoftheFTOSNPonvariabilityisneitheraconsequenceoftheeffectonthemeannorduetothechoiceofscale,andthatourinverse-normaltransformationislikelytobeoverlyconservative.
ResultsfromreportedquantileregressionofuntransformedBMIonamultipleSNPpredictorofBMIandonFTO25areconsistentwithourresultsbutarealsoconsistentwithscaleeffectsduetotheskeweddistributionofuntrans-formedBMI.
WehaveshowninthisstudythattheeffectofFTOonvariabilityisnotduetoascaleeffectand,concordantly,aquantileregressionofbothtransformedanduntransformedBMIz-scoresontheSNPsattheFTOandRCOR1locionBMIon17,974individualsshowsarelationshipbetweeneffectsizeandthequantileofthedistri-bution(SupplementaryFig.
8).
Bycontrast,theuseofuntransformedBMIinduceswidespreadcorrelationbetweenestimatedSNPeffectsonthemeanandonvariance(SupplementaryFig.
9).
Wehavereportedameta-analysisofGWASofsquarednormalizedresidualsfortwoquantitativetraitsinhumanpopulations,andprovideempiricalevidencethattheFTOandRCOR1lociinfluencephenotypicvarianceofobesity.
Conversely,wedidnotobserveanysignificantSNPsforheightoranysignificantSNPsotherthanthoseattheFTOandRCOR1lociforBMItobegenome-widesignificantlyassociatedwithphenotypicvariance(Table1),evenforthoselociknowntohaveeffectsonthemean(SupplementaryFig.
5),whichindicatesthatSNPeffectsonvarianceareuncommonforheightandBMI,andthosepreviouslyidentifiedSNPeffectsonthemean,althoughverysmall,arerobusttoenvironmentalperturbation.
WeprovideevidencethattheassociationbetweentheFTOlocusandBMIvariabilityisnotduetoartefactssuchasscaleorascertainment.
WealsodiscussthatitisimplausiblethattheobservedeffectoftheFTOSNPonvarianceisduetoitsstronglinkagedisequilibrium(D951)withacausalvariantthathasalargeeffectonthemean(SupplementaryNote).
TheFTOInsilicoreplicationCombinedFreq.
bSEPnbSEPn0.
20920.
0020.
01318.
93102132,35520.
0270.
00621.
031025161,5550.
17720.
0020.
01378.
93102132,47220.
0280.
00651.
031025161,6680.
18520.
0060.
01386.
73102131,98820.
0310.
00663.
031026161,1710.
31820.
0050.
01126.
33102132,4160.
0210.
00536.
031025161,2500.
43520.
0040.
01107.
43102131,83720.
0230.
00527.
031026158,2000.
2250.
0120.
01203.
23102136,1500.
0270.
00596.
031026164,8750.
2500.
0350.
01522.
03102232,40320.
0230.
00691.
131023137,0430.
41120.
0060.
01256.
23102128,6410.
0220.
00535.
631025156,2380.
1280.
0030.
01878.
53102128,01620.
0350.
00776.
231026153,0260.
4930.
0040.
01036.
93102136,72120.
0190.
00501.
231024164,3320.
0500.
0580.
02481.
93102232,2980.
0600.
01127.
931028159,3780.
0530.
0830.
02853.
63102328,0400.
0630.
01154.
131028155,1200.
4060.
0200.
01158.
03102232,4490.
0280.
00525.
431028159,9860.
4170.
0390.
01072.
93102435,2670.
0360.
00572.
4310210131,2330.
38220.
0100.
01113.
73102134,6680.
0210.
00593.
531024130,639Table1jContinuedLETTERRESEARCH00MONTH2012|VOL000|NATURE|3MacmillanPublishersLimited.
Allrightsreserved2012SNPsthatareassociatedwithvariancearealsoassociatedwithmeandifferencesinBMI.
Interestingly,thisphenomenonseemstoberestrictedtotheFTOgeneandtoobesity,becausewedidnotobservesucheffectsforheightorforBMIatlociotherthanFTO.
Onepossibleexplanationoftheobservationisadifferentialresponsetophysicalactivity26,becauseinteractionsbetweenFTOgenotypesandphysicalactivityhavebeenreportedforthesameSNPsaswereportinthisstudy:theGallelethatisassociatedwithanincreaseinmeanBMIhasasmallereffectinthegroupofpeoplewithahighlevelofphysicalactivitythanintheabsenceofphysicalactivity8,27,28.
Theremaybeotherunknownlifestylefactors,includingdiet,thatalsointeractwiththeFTOgenotypeandresultintheobservedeffectonvariability.
WedonotprovideamechanismofhowallelesatFTOinfluencevariability(howFTOallelesaffectthemeanisalsonotknown).
However,thefactthattheallelethatincreasesobesityalsoincreasesvariabilitysuggestsabreakdownofhomeostaticcontrol.
DataonmicelackingtheFtogenesuggestthattheobservedeffectsonmeanobesityinhumansmaybeduetoupregulationordysregulationofFTOexpression,resultinginanincreasedsusceptibilitytoobesity29.
IfbothupregulationandimpairmentofFTOexpressionhavearolethenthiscouldprovideamechanismoftheobservedeffectonvariability.
TheFTOproteinaffectsdemethylationofnuclearRNAinvitro29,butwhethertheefficiencyofthisprocessdependsontheFTOgenotypeorhowthismayberelatedtotheobservedeffectsonBMIisnotclear.
Notably,arecentstudyreportedthatrs7202116alleleG,whichispresentontheobesity-susceptibilityhaplotypeattheFTOlocus,createsaCpGsitealongwithothervariantsinperfectlinkagedis-equilibriumwithit9,andthereforeriskalleleshaveincreasedDNAmethylation.
Inaddition,itwasreportedthataCpGsiteinthefirstintronofFTOshowedsignificanthypomethylationintype2diabetescasesrelativetocontrols30,andthattheriskvariantseemstohaveaneffectonmethylationstatusatothergenes10.
DNAmethylationcanbeaffectedbyenvironmentalinfluences,includingdietaryandlifestylefactors,andmayaffectgeneexpression.
Forexample,physicalexercisemayincreasegeneexpressionattheFTOlocus,butlesssoinGGindividualscomparedwithAAindividualsbecausetheirallelesaremoremethylated.
Thisthereforesuggestsapossiblemechanismfortheobservedeffectsonboththemeanandvariability.
However,moreTable2|EffectsoftheFTOSNPrs7202116onBMIBMIlog(BMI)BMI(inv.
norm.
)Unadj.
Adj.
Unadj.
Adj.
Unadj.
Adj.
WGHS(n522,888)b0.
1480.
1420.
1000.
0930.
0460.
040SE0.
0210.
0200.
0150.
0150.
0130.
013P4.
53102134.
03102125.
53102118.
63102106.
8310243.
331023PermutationP,131024,131024,131024,1310249.
0310243.
931023Bartlett'sP1.
13102241.
13102242.
03102112.
03102116.
5310236.
631023MeanAA20.
0700.
020.
0690.
020.
0680.
0MeanAG20.
0010.
020.
0010.
00.
00.
0MeanGG0.
1610.
00.
1590.
00.
1520.
0VarianceAA0.
8950.
9000.
9320.
9370.
9710.
977VarianceAG1.
0021.
0080.
9951.
0010.
9900.
996VarianceGG1.
1941.
2021.
1321.
1381.
0601.
066EPIC(n519,762)b0.
0770.
0760.
0490.
0480.
0270.
026SE0.
0210.
0210.
0170.
0170.
0140.
014P1.
7310242.
1310243.
2310233.
9310236.
1310227.
131022PermutationP,131024,1310244.
9310235.
1310236.
4310227.
131022Bartlett'sP7.
6310277.
6310273.
0310233.
0310231.
2310211.
231021MeanAA20.
0770.
00020.
0760.
00020.
0750.
000MeanAG0.
0120.
0000.
0120.
0000.
0120.
000MeanGG0.
1030.
0000.
1020.
0000.
1000.
000VarianceAA0.
9320.
9360.
9510.
9550.
9670.
970VarianceAG1.
0051.
0091.
0071.
0111.
0101.
013VarianceGG1.
0851.
0891.
0451.
0491.
0131.
017ARIC1QIMR1NHS1HPFS(n517,974)b0.
0700.
0670.
0490.
0460.
0260.
024SE0.
0220.
0220.
0170.
0170.
0150.
015P1.
7310232.
8310233.
6310236.
1310238.
9310221.
231021PermutationP1.
6310232.
6310233.
8310237.
1310238.
7310221.
231021Bartlett'sP1.
2310271.
2310272.
5310242.
5310242.
0310222.
031022MeanAA20.
0670.
020.
0680.
020.
0690.
0MeanAG0.
0060.
00.
0080.
00.
0100.
0MeanGG0.
1220.
00.
1180.
00.
1130.
0VarianceAA0.
9680.
9730.
9780.
9830.
9940.
998VarianceAG0.
9680.
9720.
9740.
9780.
9750.
979VarianceGG1.
1311.
1361.
0931.
0971.
0591.
064Combined(n560,624)b0.
1000.
0970.
0680.
0650.
0340.
030SE0.
0120.
0120.
0090.
0090.
0080.
008P8.
93102178.
93102161.
43102132.
33102122.
4310251.
231024Bartlett'sP1.
33102321.
33102328.
53102158.
63102154.
4310244.
231024MeanAA20.
0710.
020.
0710.
020.
0700.
0MeanAG0.
0050.
00.
0060.
00.
0070.
0MeanGG0.
1290.
00.
1270.
00.
1220.
0VarianceAA0.
930.
930.
950.
960.
980.
98VarianceAG0.
991.
000.
991.
000.
991.
00VarianceGG1.
141.
141.
091.
091.
041.
05TheeffectsoftheFTOSNPrs7202116onthevarianceforBMIandlog(BMI)weretestedinthreesubsetsofdata.
TheBMIphenotypeswerecorrectedforageeffectandstandardizedtozscoresusingthemeanandstandarddeviation,orbyaninverse-normal(inv.
norm.
)transformationineachgendergroupineachcohort.
Phenotypeswereadjusted(adj.
)(orunadjusted(unadj.
))formeandifferenceinthethreegenotypes.
FortheEPICcohort,2,397sampleswereinthemeta-analysis,and17,376werenotpartofthemeta-analysis.
ForthecombinedARIC,QIMR,NHSandHPFScohort,12,741sampleswereinthemeta-analysisand5,233sampleswerenot.
b,theeffectoftheGalleleonz2;Bartlett'sP,PvaluecalculatedfromtheBartlett'stestforvariancedifferenceinthethreegenotypes;EPIC,EuropeanProspectiveInvestigationintoCancer;HPFS,HealthProfessionalsFollow-upStudy;NHS,Nurses'HealthStudy;permutationP,empiricalPvaluecalculatedfrom10,000permutations;QIMR,QueenslandInstituteofMedicalResearch;WGHS,Women'sGenomeHealthStudy.
RESEARCHLETTER4|NATURE|VOL000|00MONTH2012MacmillanPublishersLimited.
Allrightsreserved2012researchisneededtodeterminethemoleculareffectandmechanismofFTOonboththelevelsandvariabilityofobesity.
Overall,ourfindingsareconsistentwithalowheritabilityofpheno-typicvariability1andnocommongeneticvariantsthataccountforalargeproportionofvariationinenvironmentalorphenotypicvariability.
Theyalsoindicateanabsenceofwidespreadgenotype-by-environmentinteractioneffects,atleastforheightandobesityinhumansandwithinteractioneffectslargeenoughtobedetectedinourstudyinwhichspecificenvironmentalfactorswerenotidentified.
Nevertheless,thedemonstrationthatindividualgeneticlociwitheffectsonvariabilitycanbeidentifiedwithsufficientlylargesamplesizesfacilitatesfurtherstudytounderstandthefunctionandevolutionofthegeneticcontrolofvariation.
METHODSSUMMARYWeperformedameta-analysisof51GWASwith169,881individualsofEuropeanancestry,and,2.
44milliongenotypedorimputedSNPsafterqualitycontrol.
Ineachstudy,associationanalysisofeachSNPwithheightandBMIz2wasper-formedafteradjustmentforcovariatesandfollowedbyaninverse-normaltrans-formation.
Wemeta-analysedtheassociationresultsofeachSNPfrom38studieswith133,154individualsasadiscoveryset,andvalidatedthetopSNPsidentifiedinthediscoverysetwithassociationPvalues,531026inaseparatesampleof36,727individualsfrom13studies.
Furtheranalysesusingindividual-levelgeno-typeandphenotypedatatotestfordifferenceinvarianceofBMIbetweenthethreegroupsforthetopSNPsattheFTOandRCOR1lociwereperformedon60,624individuals,including22,598individualswhowerenotpartofthemeta-analysis.
FullMethodsandanyassociatedreferencesareavailableintheonlineversionofthepaper.
Received15January;accepted6July2012.
Publishedonline16September2012.
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SupplementaryInformationisavailableintheonlineversionofthepaper.
AcknowledgementsWeacknowledgefundingfromtheAustralianNationalHealthandMedicalResearchCouncil(NHMRCgrants241944,389875,389891,389892,389938,442915,442981,496739,496688,552485,613672,613601and1011506),theUSNationalInstitutesofHealth(grantsAA07535,AA10248,AA014041,AA13320,AA13321,AA13326,DA12854andGM057091)andtheAustralianResearchCouncil(ARCgrantDP1093502).
AdetailedlistofacknowledgementsbystudyisprovidedintheSupplementaryInformation.
Weapologizetoauthorswhoseworkwecouldnotciteowingtospacerestrictions.
AuthorContributionsP.
M.
V.
,M.
E.
G.
andJ.
Y.
conceivedanddesignedthestudy.
J.
Y.
andP.
M.
V.
derivedtheanalyticaltheory.
J.
Y.
performedthemeta-analysesandsimulations.
J.
Y.
andP.
M.
V.
wrotethefirstdraftofthemanuscript.
J.
Y.
,D.
I.
C.
,J.
H.
Z.
andR.
J.
F.
L.
performedfurtherstatisticalverificationanalyses.
D.
P.
S.
,W.
G.
H.
,R.
J.
F.
L.
,S.
I.
B.
andH.
Sniedercontributedimportantadditionalconceptsandcriticallyreviewedthemanuscriptbeforesubmission.
S.
E.
M.
,P.
A.
F.
M.
,A.
C.
H.
,N.
G.
M.
,D.
R.
N.
andG.
W.
M.
contributedtheindividual-levelgenotypeandphenotypedataoftheQIMRcohort.
T.
M.
F.
,J.
N.
H.
andR.
J.
F.
L.
liaisedwiththeGIANTconsortiumforthisproject.
Thecohort-specificcontributionsofallotherauthorsareprovidedintheSupplementaryInformation.
AuthorInformationReprintsandpermissionsinformationisavailableatwww.
nature.
com/reprints.
Theauthorsdeclarenocompetingfinancialinterests.
Readersarewelcometocommentontheonlineversionofthepaper.
CorrespondenceandrequestsformaterialsshouldbeaddressedtoP.
M.
V.
(peter.
visscher@uq.
edu.
au).
JianYang1,2,RuthJ.
F.
Loos3,4,JosephE.
Powell1,2,SarahE.
Medland2,ElizabethK.
Speliotes5,6,DanielI.
Chasman7,8,LyndaM.
Rose7,GudmarThorleifsson9,ValgerdurSteinthorsdottir9,ReedikMa¨gi10,11,LindsayWaite12,AlbertVernonSmith13,14,LauraM.
Yerges-Armstrong15,KeriL.
Monda16,DavidHadley17,AnubhaMahajan11,GuoLi18,KarenKapur19,20,VeroniqueVitart21,JenniferE.
Huffman21,SophieR.
Wang22,23,24,CameronPalmer23,24,TonuEsko10,KristaFischer10,JingHuaZhao3,AyseDemirkan25,AaronIsaacs25,MaryF.
Feitosa26,Jian'anLuan3,NancyL.
Heard-Costa27,CharlesWhite27,AnneU.
Jackson28,MichaelPreuss29,30,AndreasZiegler30,JoelEriksson31,ZoltanKutalik19,20,FrancescaFrau32,IljaM.
Nolte33,JanaV.
VanVliet-Ostaptchouk34,35,Jouke-JanHottenga36,KevinB.
Jacobs37,NiekVerweij38,AnujGoel11,39,CarolinaMedina-Gomez40,41,42,KarolEstrada40,41,42,JenniferLynnBragg-Gresham43,SerenaSanna44,CarloSidore43,45,JonathanTyrer46,AlexanderTeumer47,IngaProkopenko11,48,MassimoMangino49,CeciliaM.
Lindgren11,ThemistoclesL.
Assimes50,AlanR.
Shuldiner15,51,JennieHui52,53,54,JohnP.
Beilby52,53,WendyL.
McArdle55,PerHall56,TalinHaritunians57,LinaZgaga58,59,IvanaKolcic60,OzrenPolasek60,TatijanaZemunik60,BenA.
Oostra25,M.
JuhaniJunttila61,HenrikGro¨nberg56,StefanSchreiber62,AnnettePeters63,64,AndrewA.
Hicks65,JonathanStephens66,67,NicolaS.
Foad66,67,JaanaLaitinen68,AnneliPouta69,70,MarikaKaakinen71,GonnekeWillemsen36,JacquelineM.
Vink36,SarahH.
Wild58,GerjanNavis72,FolkertW.
Asselbergs73,GeorgHomuth47,UlrichJohn74,CarlosIribarren75,TamaraHarris76,LenoreLauner76,VilmundurGudnason13,14,JeffreyR.
O'Connell15,EricBoerwinkle77,GemmaCadby78,LyleJ.
Palmer78,AlanL.
James79,80,ArthurW.
Musk79,81,ErikIngelsson56,BruceM.
Psaty82,83,JacquesS.
Beckmann19,84,GerardWaeber85,PeterVollenweider85,CarolineHayward21,AlanF.
Wright21,IgorRudan58,60,LeifC.
Groop86,AndresMetspalu10,KayTeeKhaw87,CorneliaM.
vanDuijn25,IngridB.
Borecki26,88,MichaelA.
Province26,88,NicholasJ.
Wareham3,Jean-ClaudeTardif89,90,HeikkiV.
Huikuri61,L.
AdrienneCupples27,91,LarryD.
Atwood27,CarolineS.
Fox91,MichaelBoehnke28,FrancisS.
Collins92,KarenL.
Mohlke93,JeanetteErdmann29,94,HeribertSchunkert29,94,ChristianHengstenberg95,KlausStark95,MattiasLorentzon31,ClaesOhlsson31,DanieleCusi32,JanA.
Staessen96,97,MelanieM.
VanderKlauw34,35,PeterP.
Pramstaller98,99,100,SekarKathiresan91,101,102,103,104,JenniferD.
Jolley66,67,SamuliRipatti105,106,107,LETTERRESEARCH00MONTH2012|VOL000|NATURE|5MacmillanPublishersLimited.
Allrightsreserved2012Marjo-RiittaJarvelin69,71,108,EcoJ.
C.
deGeus36,DorretI.
Boomsma36,BrendaPenninx109,JamesF.
Wilson58,HarryCampbell58,StephenJ.
Chanock110,PimvanderHarst38,AndersHamsten111,112,HughWatkins11,39,AlbertHofman41,42,JacquelineC.
Witteman41,42,M.
CarolaZillikens40,AndreG.
Uitterlinden40,41,42,FernandoRivadeneira40,41,42,M.
CarolaZillikens40,LambertusA.
Kiemeney113,SitaH.
Vermeulen113,GoncaloR.
Abecasis43,DavidSchlessinger114,SabineSchipf115,MichaelStumvoll116,117,AnkeTo¨njes116,117,TimD.
Spector49,KariE.
North118,GuillaumeLettre89,90,MarkI.
McCarthy11,48,119,SonjaI.
Berndt110,AndrewC.
Heath120,PamelaA.
F.
Madden120,DaleR.
Nyholt2,GrantW.
Montgomery2,NicholasG.
Martin2,BarbaraMcKnight121,DavidP.
Strachan17,WilliamG.
Hill122,HaroldSnieder33,35,PaulM.
Ridker7,8,UnnurThorsteinsdottir9,123,KariStefansson9,123,TimothyM.
Frayling124,JoelN.
Hirschhorn22,23,24,MichaelE.
Goddard125,126&PeterM.
Visscher1,2,1271UniversityofQueenslandDiamantinaInstitute,TheUniversityofQueensland,PrincessAlexandraHospital,Brisbane,Queensland4102,Australia.
2QueenslandInstituteofMedicalResearch,300HerstonRoad,Brisbane,Queensland4006,Australia.
3MRCEpidemiologyUnit,InstituteofMetabolicScience,CambridgeCB20QQ,UK.
4MountSinaiSchoolofMedicine,NewYork,NewYork10029,USA.
5DepartmentofInternalMedicine,DivisionofGastroenterology,UniversityofMichigan,AnnArbor,Michigan48109,USA.
6CenterforComputationalMedicineandBioinformatics,UniversityofMichigan,AnnArbor,Michigan48109,USA.
7DivisionofPreventiveMedicine,BrighamandWomen'sHospital,900CommonwealthAvenue,Boston,Massachusetts02215,USA.
8HarvardMedicalSchool,Boston,Massachusetts02215,USA.
9deCODEgenetics,IS-101Reykjavik,Iceland.
10EstonianGenomeCenter,UniversityofTartu,Tartu50410,Estonia.
11WellcomeTrustCentreforHumanGenetics,UniversityofOxford,OxfordOX37BN,UK.
12HudsonAlphaInstituteforBiotechnology,Huntsville,Alabama35806,USA.
13IcelandicHeartAssociation,IS-201Kopavogur,Iceland.
14UniversityofIceland,IS-101Reykjavik,Iceland.
15DepartmentofMedicine,UniversityofMarylandSchoolofMedicine,Baltimore,Maryland21201,USA.
16DepartmentofEpidemiology,TheUniversityofNorthCarolina,ChapelHill,NorthCarolina27514,USA.
17DivisionofPopulationHealthSciences&Education,StGeorge's,UniversityofLondon,LondonSW170RE,UK.
18CardiovascularHealthResearchUnit,DepartmentofMedicine,UniversityofWashington,Seattle,Washington98101,USA.
19DepartmentofMedicalGenetics,UniversityofLausanne,1005Lausanne,Switzerland.
20SwissInstituteofBioinformatics,1005Lausanne,Switzerland.
21MRCHGUattheMRCIGMMattheUniversityofEdinburgh,EdinburghEH89AG,UK.
22DepartmentofGenetics,HarvardMedicalSchool,Boston,Massachusetts02115,USA.
23DivisionsofGeneticsandEndocrinologyandPrograminGenomics,Children'sHospital,Boston,Massachusetts02115,USA.
24MetabolismInitiativeandPrograminMedicalandPopulationGenetics,BroadInstitute,Cambridge,Massachusetts02142,USA.
25DepartmentofEpidemiology,SubdivisonGeneticEpidemiology,ErasmusMC,Rotterdam,TheNetherlands.
26DepartmentofGenetics,WashingtonUniversitySchoolofMedicine,StLouis,Missouri63110,USA.
27BostonUniversity,Boston,Massachusetts02118,USA.
28DepartmentofBiostatisticsandCenterforStatisticalGenetics,UniversityofMichigan,AnnArbor,Michigan48109,USA.
29Universita¨tzuLu¨beck,MedizinischeKlinikII,RatzeburgerAllee160,23538Lu¨beck,Germany.
30Institutfu¨rMedizinischeBiometrieundStatistik,Universita¨tzuLu¨beck,23562Lu¨beck,Germany.
31CenterforBoneandArthritisResearch,InstituteofMedicine,SahlgrenskaAcademy,UniversityofGothenburg,41345Gothenburg,Sweden.
32DepartmentofHealthSciences,UniversityofMilano,20133Milano,Italy.
33UnitofGeneticEpidemiology&Bioinformatics,DepartmentofEpidemiology,UniversityMedicalCenterGroningen,UniversityofGroningen,9700RBGroningen,TheNetherlands.
34DepartmentofEndocrinology,UniversityMedicalCenterGroningen,UniversityofGroningen,POBox30001,9700RBGroningen,TheNetherlands.
35LifeLinesCohortStudy,UniversityMedicalCenterGroningen,UniversityofGroningen,9700RBGroningen,TheNetherlands.
36DepartmentofBiologicalPsychology,VUUniversity,1081BTAmsterdam,TheNetherlands.
37CoreGenotypingFacility,SAIC-Frederick,Inc.
,NCI-Frederick,Frederick,Maryland21702,USA.
38DepartmentofCardiology,UniversityMedicalCenterGroningen,UniversityofGroningen,9700RBGroningen,TheNetherlands.
39CardiovascularMedicine,UniversityofOxford,OxfordOX37BN,UK.
40DepartmentofInternalMedicine,ErasmusMC,Rotterdam3015GE,TheNetherlands.
41DepartmentofEpidemiology,ErasmusMC,Rotterdam3015GE,TheNetherlands.
42NetherlandsGenomicsInitiative(NGI)-sponsoredNetherlandsConsortiumforHealthyAging(NCHA),2300RCLeiden,TheNetherlands.
43Biostatistics-CenterforStatisticalGenetics,UniversityofMichigan,AnnArbor,Michigan48109,USA.
44IstitutodiRicercaGeneticaeBiomedica,CNR,Monserrato09042,Italy.
45DipartimentodiScienzeBiomediche,Universita`diSassari,07100SS,Italy.
46DepartmentofOncology,UniversityofCambridge,CambridgeCB18RN,UK.
47InterfacultyInstituteforGeneticsandFunctionalGenomics,UniversityMedicineGreifswald,17487Greifswald,Germany.
48OxfordCentreforDiabetes,EndocrinologyandMetabolism,UniversityofOxford,OxfordOX37BN,UK.
49DepartmentofTwinResearchandGeneticEpidemiology,King'sCollegeLondon,LambethPalaceRoad,LondonSE17EH,UK.
50DepartmentofMedicine,StanfordUniversitySchoolofMedicine,Stanford94305,California,USA.
51GeriatricResearchandEducationClinicalCenter,VeteransAdministrationMedicalCenter,Baltimore,Maryland21201,USA.
52PathologyandLaboratoryMedicine,UniversityofWesternAustralia,NedlandsWesternAustralia6009,Australia.
53MolecularGenetics,PathWestLaboratoryMedicineWA,UniversityofWesternAustralia,NedlandsWesternAustralia6009,Australia.
54SchoolofPopulationHealth,UniversityofWesternAustralia,NedlandsWesternAustralia6009,Australia.
55SchoolofSocialandCommunityMedicine,UniversityofBristol,BristolBS82BN,UK.
56DepartmentofMedicalEpidemiologyandBiostatistics,KarolinskaInstitutet,Box281,SE-17177Stockholm,Sweden.
57MedicalGeneticsInstitute,Cedars-SinaiMedicalCenter,LosAngeles,California90048,USA.
58CentreforPopulationHealthSciences,TheUniversityofEdinburghMedicalSchool,EdinburghEH164TJ,UK.
59AndrijaStamparSchoolofPublicHealth,MedicalSchoolUniversityofZagreb,Zagreb,Croatia.
60FacultyofMedicine,UniversityofSplit,Soltanska2,21000Split,Croatia.
61InstituteofClinicalMedicine,DepartmentOfInternalMedicine,UniversityofOulu,90014Oulu,Finland.
62Institutfu¨rKlinischeMolekularbiologie,Christian-AlbrechtsUniversita¨t,24098Kiel,Germany.
63InstituteofEpidemiologyII,HelmholtzZentrumMu¨nchen,GermanResearchCenterforEnvironmentalHealth,85764Neuherberg,Germany.
64MunichHeartAlliance,80802Munich,Germany.
65CenterforBiomedicine,EuropeanAcademyBozen/Bolzano(EURAC),39100Bolzano,Italy.
66DepartmentofHaematology,UniversityofCambridge,CambridgeCB20PT,UK.
67NHSBloodandTransplant,Cambridge,CambridgeCB20PT,UK.
68FinnishInstituteofOccupationalHealth,90220Oulu,Finland.
69NationalInstituteforHealthandWelfare,90101Oulu,Finland.
70DepartmentofClinicalSciences/ObstetricsandGynecology,UniversityofOulu,90014Oulu,Finland.
71InstituteofHealthSciences,BiocenterOulu,UniversityofOulu,90014Oulu,Finland.
72DepartmentofInternalMedicine,UniversityMedicalCenterGroningen,UniversityofGroningen,9700RBGroningen,TheNetherlands.
73DepartmentofCardiology,DivisionHeart&Lungs,UniversitymedicalCenterUtrecht,3508GAUtrecht,TheNetherlands.
74InstituteofEpidemiologyandSocialMedicine,UniversityMedicineGreifswald,17475Greifswald,Germany.
75DivisionofResearch,KaiserPermanenteNorthernCalifornia,Oakland,California94612,USA.
76NationalInstitutesonAging,NationalInstitutesofHealth,Bethesda,Maryland20892,USA.
77HumanGeneticsCenterandDivisionofEpidemiology,TheUniversityofTexasHealthScienceCenters,Houston,Texas77030,USA.
78GeneticEpidemiologyandBiostatisticsPlatform,OntarioInstituteforCancerResearch,Toronto,OntarioM5G1L7,Canada.
79MedicineandPharmacology,UniversityofWesternAustralia,NedlandsWesternAustralia6009,Australia.
80PulmonaryPhysiology,SirCharlesGairdnerHospital,UniversityofWesternAustralia,NedlandsWesternAustralia6009,Australia.
81RespiratoryMedicine,SirCharlesGairdnerHospital,UniversityofWesternAustralia,NedlandsWesternAustralia6009,Australia.
82CardiovascularHealthResearchUnit,DepartmentsofMedicine,Epidemiology,andHealthServices,UniversityofWashington,Seattle,Washington98101,USA.
83GroupHealthResearchInstitute,GroupHealthCooperative,Seattle,Washington98101,USA.
84ServiceofMedicalGenetics,CentreHospitalierUniversitaireVaudois(CHUV)UniversityHospital,1011Lausanne,Switzerland.
85DepartmentofInternalMedicine,UniversityHospital,1011Lausanne,Switzerland.
86LundUniversityDiabetesCentre,DepartmentofClinicalSciences,LundUniversity,20502Malmo¨,Sweden.
87DepartmentofPublicHealthandPrimaryCare,UniversityofCambridge,CambridgeCB18RN,UK.
88DivisionofBiostatistics,WashingtonUniversitySchoolofMedicine,StLouis,Missouri63110,USA.
89DepartementdeMedecine,UniversitedeMontreal,Montreal,QuebecH4J1C5,Canada.
90MontrealHeartInstitute,Montreal,QuebecH1T1C8,Canada.
91FraminghamHeartStudyoftheNationalHeart,Lung,andBloodInstituteandBostonUniversity,Framingham,Massachusetts01702,USA.
92NationalHumanGenomeResearchInstitute,NationalInstitutesofHealth,Bethesda,Maryland20892,USA.
93DepartmentofGenetics,UniversityofNorthCarolina,ChapelHill,NorthCarolina27599-7264,USA.
94DeutschesZentrumfu¨rHerz-Kreislauf-Forschung(DZHK),Universita¨tzuLu¨beck,23562Lu¨beck,Germany.
95KlinikundPoliklinikfu¨rInnereMedizinII,93053Regensburg,Germany.
96DepartmentofCardiovascularDiseases,UniversityofLeuven,3000Leuven,Belgium.
97DepartmentofEpidemiology,MaastrichtUniversity,6200MDMaastricht,TheNetherlands.
98CenterforBiomedicine,EuropeanAcademyBozen/Bolzano(EURAC),39100Bolzano,Italy.
99DepartmentofNeurology,GeneralCentralHospital,39100Bolzano,Italy.
100DepartmentofNeurology,UniversityofLu¨beck,23562Lu¨beck,Germany.
101PrograminMedicalandPopulationGenetics,BroadInstituteofHarvardandMassachusettsInstituteofTechnology,Cambridge,Massachusetts02142,USA.
102CenterforHumanGeneticsResearch,MassachusettsGeneralHospital,Boston,Massachusetts02114,USA.
103CardiovascularResearchCenterandCardiologyDivision,MassachusettsGeneralHospital,Boston,Massachusetts02114,USA.
104DepartmentofMedicine,HarvardMedicalSchool,Boston,Massachusetts02115,USA.
105InstituteforMolecularMedicineFinland,FIMM,UniversityofHelsinki,00014Helsinki,Finland.
106PublicHealthGenomicsUnit,NationalInstituteforHealthandWelfare,00271Helsinki,Finland.
107WellcomeTrustSangerInstitute,CambridgeCB101SA,UK.
108DepartmentofEpidemiologyandBiostatistics,MRC-HPACenterforEnvironmentandHealth,ImperialCollegeLondon,LondonW21PG,UK.
109DepartmentofPsychiatry,UniversityMedicalCenterGroningen,UniversityofGroningen,9713GZGroningen,TheNetherlands.
110DivisionofCancerEpidemiology&Genetics,NationalCancerInstitute,NationalInstitutesofHealth,Bethesda,Maryland20852,USA.
111KarolinskaInstitutet,17177Stockholm,Sweden.
112AtherosclerosisResearchUnit,DepartmentofMedicine,Solna,17176Stockholm,Sweden.
113Epidemiology,Biostatistics&HTA,RadboudUniversityNijmegenMedicalCentre,POBox9101,6500HBNijmegen,TheNetherlands.
114NationalInstituteonAging,NationalInstitutesofHealth,Bethesda,Maryland20892,USA.
115InstituteforCommunityMedicine,UniversityMedicineGreifswald,17475Greifswald,Germany.
116DepartmentofMedicine,UniversityofLeipzig,04103Leipzig,Germany.
117IFBAdiposityDiseases,UniversityofLeipzig,04103Leipzig,Germany.
118DepartmentofEpidemiologyandCarolinaCenterforGenomeSciences,TheUniversityofNorthCarolina,ChapelHill,NorthCarolina27514,USA.
119OxfordNationalInstituteforHealthResearchBiomedicalResearchCentre,ChurchillHospital,OldRoadHeadington,OxfordOX37LJ,UK.
120DepartmentofPsychiatry,WashingtonUniversityStLouis,Missouri63110,USA.
121DepartmentofBiostatistics,UniversityofWashington,Seattle,Washington98115,USA.
122InstituteofEvolutionaryBiology,UniversityofEdinburgh,EdinburghEH93JT,UK.
123FacultyofMedicine,UniversityofIceland,IS-101Reykjavik,Iceland.
124GeneticsofComplexTraits,InstituteofBiomedicalandClinicalScience,PeninsulaMedicalSchool,UniversityofExeter,ExeterEX12LU,UK.
125DepartmentofFoodandAgriculturalSystems,UniversityofMelbourne,Victoria3010,Australia.
126BiosciencesResearchDivision,DepartmentofPrimaryIndustries,Bundoora,Victoria3083,Australia.
127QueenslandBrainInstitute,TheUniversityofQueensland,Brisbane,Queensland4072,Australia.
RESEARCHLETTER6|NATURE|VOL000|00MONTH2012MacmillanPublishersLimited.
Allrightsreserved2012METHODSFifty-onestudieswereincludedinthemeta-analysis.
AllindividualswereofrecentEuropeandescent.
Ineachoftheparticipatingstudies,genotypedSNPsthatpassedstandardquality-controlprocesses(missingness,Hardy–WeinbergequilibriumtestandMAF)wereusedtoimputetheungenotypedSNPstotheHapMapIICEUreferencepanel31.
WeexcludedSNPswithimputationqualityscore,0.
4forIMPUTE32and,0.
3otherwise33,34.
Asummaryofsamplesize,genotypingplatform,quality-controlfiltersandtheimputationtoolofalltheparticipatingstudiesisprovidedinSupplementaryTable4.
WefurtherexcludedSNPswithMAF,0.
01ineachstudyorinthemeta-analysis,andretainedabout2.
68millionautosomalSNPsintheanalysis.
Ineachstudy,heightandBMIphenotypeswereadjustedforageandstandardizedtozscorebyaninverse-normaltransformation.
TheanalysisprotocolsuppliedtoallcohortsisgivenasaSupplementaryNote.
ThedescriptivestatisticsofphenotypesofeachstudyareshowninSupplementaryTable5.
Theassociationanalysesofpheno-typicvariabilitywereperformedonasingle-SNPbasisbythefollowingadditivegeneticmodel:y5a1bx1e,inwhichyisz2,aistheintercept,bistheadditiveSNPeffectonz2,xistheallelicdosagecodedas0,1or2forthethreegenotypegroups,andeistheresidual.
Westratifiedtheanalysisbygendergroupand/orcase-controlstatuswhereapplicable.
Weselected38studiesconsistingof133,154individualsasthediscoverysetbythetimewhendatawereavailable.
Wecollectedsummary-levelassociationresultsofalltheSNPsfromthesestudiesandadjustedthestandarderrorsofallSNPsbythegenomiccontrolapproachineachstudy21,thatis,multiplyingthestandarderrorsoftheestimatesofbbythesquarerootofthegenomicinflationfactor21.
WethencombinedtheeffectofeachSNPbyaninverse-variancemeta-analysisimplementedinMETAL35.
Inaregressionanalysis,thesquaredstandarderroroftheestimateofaSNPeffectis:s2/(2p(12p)n),inwhichs2istheresidualvariance,pisthefrequencyofthecodedallele,andnisthesamplesize.
ThisassumesHardy–Weinbergequilibriumofgenotypefrequencies.
Iftheeffectsizeissmall,s2isapproximatelyequaltothevarianceofy,whichis2.
Wecheckedtheoverallqualityofeachstudybyplottingthemedianof1/SEacrossallSNPsagainstthereportedsamplesize,andbyplottingthemedianof2p(12p)nSE2acrossallSNPstoseeifitwascloseto2(SupplementaryFig.
10).
WefurtherestimatedtheeffectivesamplesizeofeachSNPby:n52/(2p(1–p)SE2),usingthesummarystatisticsofthewholediscoveryset,andexcludedSNPswithn,mean(n)22SD(n)andretained,2.
44millionSNPsforbothheightandBMI.
Wecollecteddatafromafurther36,727samplesfrom13cohorts(SupplementaryTables4and5),andvalidatedthetopSNPsat6associatedlociforheightand7forBMI(P,531026)intheseextrasamples.
Weperformedfurtheranalysesinthreedatasetswithatotalsamplesizeof60,624withindividual-levelgenotypeandphenotypedatatoverifyourfindings.
Thesethreedatasetsinclude22,888individualsfromtheWGHScohort,and19,762individualsfromtheEPICcohorts,andacombinedsampleof17,974individualsfromtheARIC,QIMR,NHSandHPFScohorts,with17,365individualsfromtheEPICcohortand5,233individualsfromtheNHSandHPFScohortsnotpartofthemeta-analysis.
Weusedlogarithmorinverse-normaltransformationtoremoveapossiblemean–variancerelationshipofBMIphenotypes,andadjustedthepheno-typefortheeffectofthetopSNPattheFTOorRCOR1locusonthemeanofBMI.
WeperformedpermutationteststoassessthesignificanceoftheeffectofFTOorRCOR1onBMIz2with10,000permutations,andusedtheBartlett'sstatistictotestfordifferenceinvarianceofBMIbetweenthreegenotypesforFTOorRCOR.
TheplotofassociationresultsattheFTOlocusinFig.
1wasgeneratedusingLocusZoom36withtherecombinationratesandpairwiselinkagedisequilibriumr2valuesbetweenSNPsestimatedfromtheHapMapCEUpanel31.
31.
TheInternationalHapMapConsortium.
Asecondgenerationhumanhaplotypemapofover3.
1millionSNPs.
Nature449,851–861(2007).
32.
Marchini,J.
,Howie,B.
,Myers,S.
,McVean,G.
&Donnelly,P.
Anewmultipointmethodforgenom3102wideassociationstudiesbyimputationofgenotypes.
NatureGenet.
39,906–913(2007).
33.
Li,Y.
,Willer,C.
J.
,Ding,J.
,Scheet,P.
&Abecasis,G.
R.
MaCH:usingsequenceandgenotypedatatoestimatehaplotypesandunobservedgenotypes.
Genet.
Epidemiol.
34,816–834(2010).
34.
Aulchenko,Y.
S.
,Ripke,S.
,Isaacs,A.
&vanDuijn,C.
M.
GenABEL:anRlibraryforgenome-wideassociationanalysis.
Bioinformatics23,1294–1296(2007).
35.
Willer,C.
J.
,Li,Y.
&Abecasis,G.
R.
METAL:fastandefficientmeta-analysisofgenomewideassociationscans.
Bioinformatics26,2190–2191(2010).
36.
Pruim,R.
J.
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Bioinformatics26,2336–2337(2010).
LETTERRESEARCHMacmillanPublishersLimited.
Allrightsreserved2012