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AUTHORS1

GeorgB.Ehret1,2*,TeresaFerreira3*,DanielI.Chasman4,5,AnneU.Jackson6,7,EllenM.Schmidt8,Toby2

Johnson9,10,GudmarThorleifsson11,Jian'anLuan12,LousieA.Donnelly13,StavroulaKanoni14,Ann-Kristin3

Petersen15,VasylPihur1,RonaJ.Strawbridge16,17,DmitryShungin18,19,20,MariaF.Hughes21,Osorio4

Meirelles22,MarikaKaakinen23,NabilaBouatia-Naji24,25,KatiKristiansson26,27,SoniaShah28,MarcusE.5

Kleber29,XiuqingGuo30,Leo-PekkaLyytikäinen31,32,CristianoFava33,34,NiclasEriksson35,IljaM.Nolte36,6

PatrikK.Magnusson37,EliasL.Salfati38,LoukianosS.Rallidis39,ElizabethTheusch40,AndrewJ.P.Smith41,7

LasseFolkersen16,KateWitkowska9,42,TuneH.Pers43,44,45,46,47,RobyJoehanes48,StuartK.Kim49,Lazaros8

Lataniotis14,RickJansen50,AndrewD.Johnson48,51,HelenWarren9,42,YoungJinKim52,WeiZhao53,Ying9

Wu54,BamideleO.Tayo55,MurielleBochud56,CHARGE-EchoGenconsortium57,CHARGE-HF10

consortium57,WellcomeTrustCaseControlConsortium57,DevinAbsher58,LindaS.Adair59,NajafAmin60,11

DanE.Arking1,TomasAxelsson61,DamianoBaldassarre62,63,BeverleyBalkau64,StefaniaBandinelli65,12

MichaelR.Barnes14,42,InêsBarroso66,67,68,StephenBevan69,JoshuaC.Bis70,GydaBjornsdottir11,Michael13

Boehnke6,7,EricBoerwinkle71,LoriL.Bonnycastle72,DorretI.Boomsma73,StefanR.Bornstein74,MorrisJ.14

Brown75,MichelBurnier76,ClaudiaP.Cabrera9,42,JohnC.Chambers77,78,79,I-ShouChang80,Ching-Yu15

Cheng81,82,83,PeterS.Chines72,Ren-HuaChung84,FrancisS.Collins72,JohnM.Connell85,Angela16

Döring86,87,JeanDallongeville88,JohnDanesh89,66,90,UlfdeFaire91,GracielaDelgado29,AnnaF.17

Dominiczak92,AlexS.F.Doney13,FotiosDrenos41,SarahEdkins66,JohnD.Eicher48,51,RobertoElosua93,18

StefanEnroth94,95,JeanetteErdmann96,97,PerEriksson16,TonuEsko98,99,100,EvangelosEvangelou77,101,19

AlunEvans21,ToveFall102,MartinFarrall3,103,JanineF.Felix104,JeanFerrières105,LuigiFerrucci106,Myriam20

Fornage107,TerrenceForrester108,NoraFranceschini109,OscarH.FrancoDuran104,AndersFranco-21

Cereceda110,RossM.Fraser111,112,SanthiK.Ganesh113,HeGao77,KarlGertow16,17,Francesco22

Gianfagna114,115,BrunaGigante91,FrancoGiulianini4,AnujGoel3,103,AlisonH.Goodall116,117,MarkO.23

Goodarzi118,MathiasGorski119,120,JürgenGräßler121,ChristopherGroves122,VilmundurGudnason123,124,24

UlfGyllensten94,95,GöranHallmans18,Anna-LiisaHartikainen125,126,MaijaHassinen127,AkiS.Havulinna26,25

CarolineHayward128,SergeHercberg129,Karl-HeinzHerzig130,131,132,AndrewA.Hicks133,AroonD.26

Hingorani28,JoelN.Hirschhorn43,44,45,134,AlbertHofman104,135,JosteinHolmen136,OddgeirLingaas27

Holmen136,137,Jouke-JanHottenga73,PhilHoward41,ChaoA.Hsiung84,StevenC.Hunt138,139,M.Arfan28

Ikram104,140,141,ThomasIllig142,143,144,CarlosIribarren145,RichardA.Jensen70,146,MikaKähönen147,Hyun29

Kang6,7,SekarKathiresan148,149,150,45,151,BrendanJ.Keating152,153,Kay-TeeKhaw154,YunKyoungKim52,Eric30

Kim155,MikaKivimaki28,NormanKlopp142,143,GenovefaKolovou156,PirjoKomulainen127,JaspalS.31

Kooner157,78,79,GulumKosova149,148,100,RonaldM.Krauss158,DianaKuh159,ZoltanKutalik160,161,Johanna32

3

Kuusisto162,KirstiKvaløy136,TimoALakka163,127,164,NanetteR.Lee165,166,I-TeLee167,168,Wen-JaneLee169,1

DanielLevy48,170,XiaohuiLi30,Kae-WoeiLiang171,172,HonghuangLin173,48,LiLin2,JaanaLindström26,2

StéphaneLobbens174,175,176,SatuMännistö26,GabrieleMüller177,MartinaMüller-Nurasyid15,178,179,3

FrançoisMach2,HughS.Markus180,EiriniMarouli14,181,MarkI.McCarthy122,ColinA.McKenzie108,Pierre4

Meneton182,CristinaMenni183,AndresMetspalu98,VladanMijatovic184,LeenaMoilanen185,186,MayE.5

Montasser187,AndrewD.Morris13,AlannaC.Morrison188,AntonellaMulas189,RamaiahNagaraja22,6

NarisuNarisu72,KjellNikus190,191,ChristopherJ.O'Donnell192,48,151,PaulF.O'Reilly193,KenK.Ong12,Fred7

Paccaud56,CameronD.Palmer194,195,45,AfshinParsa187,NancyL.Pedersen37,BrendaW.Penninx196,197,198,8

MarkusPerola26,27,98,AnnettePeters87,NeilPoulter199,PeterP.Pramstaller133,200,201,BruceM.9

Psaty70,202,203,204,ThomasQuertermous38,DabeeruC.Rao205,AsifRasheed206,NWilliamN.W.R.10

Rayner122,3,66,FridaRenström19,207,18,RainerRettig208,KennethM.Rice209,RobertRoberts210,211,LyndaM.11

Rose4,JacquesRossouw212,NileshJ.Samani116,213,SerenaSanna189,JoukoSaramies214,Heribert12

Schunkert215,216,217,218,SylvainSebert219,131,164,WayneH.-H.Sheu167,168,220,Young-AhShin52,Xueling13

Sim6,7,221,JohannesH.Smit196,AlbertV.Smith123,124,MariaX.Sosa1,TimD.Spector183,Alena14

Stančáková222,AliceStanton223,KathleenE.Stirrups14,224,HeatherM.Stringham6,7,JohanSundstrom61,15

AmyJ.Swift72,Ann-ChristineSyvänen61,E-ShyongTai225,82,221,ToshikoTanaka106,KirillV.Tarasov226,16

AlexanderTeumer227,UnnurThorsteinsdottir11,124,MartinD.Tobin228,ElenaTremoli62,63,AndreG.17

Uitterlinden104,229,MattiUusitupa230,231,AhmadVaez36,232,DhananjayVaidya233,CorneliaM.van18

Duijn104,234,ErikP.A.vanIperen235,236,RamachandranS.Vasan48,237,238,GermaineC.Verwoert104,Jarmo19

Virtamo26,VeroniqueVitart128,BenjaminF.Voight45,239,PeterVollenweider240,AlineWagner241,LouiseV.20

Wain228,NicholasJ.Wareham12,HughWatkins3,103,AlanB.Weder242,Harm-JanWestra243,Rainford21

Wilks244,TomWilsgaard245,246,JamesF.Wilson111,128,TienY.Wong81,82,83,Tsun-PoYang14,247,JieYao30,22

LoicYengo174,175,176,WeihuaZhang77,78,JingHuaZhao12,XiaofengZhu248,PascalBovet249,56,RichardS.23

Cooper55,KarenL.Mohlke54,DanishSaleheen250,206,Jong-YoungLee52,PaulElliott77,251,HincoJ.24

Gierman49,252,CristenJ.Willer8,253,254,LudeFranke255,GKeesHovingh256,KentD.Taylor30,George25

Dedoussis181,PeterSever199,AndrewWong159,LarsLind61,ThemistoclesL.Assimes38,IngerNjølstad245,246,26

PeterEH.Schwarz74,ClaudiaLangenberg12,HaroldSnieder36,MarkJ.Caulfield9,42,OlleMelander33,27

MarkkuLaakso162,JuhaSaltevo257,RainerRauramaa127,164,JaakkoTuomilehto26,258,259,260,Erik28

Ingelsson102,3,TerhoLehtimäki31,32,KristianHveem136,WalterPalmas261,WinfriedMärz262,263,Meena29

Kumari28,VeikkoSalomaa26,Yii-DerI.Chen30,JeromeI.Rotter30,PhilippeFroguel174,175,176,23,Marjo-Riitta30

Jarvelin219,131,264,251,EdwardG.Lakatta226,KariKuulasmaa26,PaulW.Franks19,207,18,AndersHamsten16,17,31

H.-ErichWichmann86,179,265,ColinN.A.Palmer13,KariStefansson11,124,PaulMRidker4,5,RuthJ.F.32

4

Loos12,266,267,AravindaChakravarti1,PanosDeloukas14,268,AndrewP.Morris269,3#,ChristopherNewton-1

Cheh148,149,45,100#,PatriciaB.Munroe9,42#2*Theseauthorscontributedequallytothiswork.3#Theseauthorsjointlysupervisedthiswork.4Correspondingauthors:ChristopherNewton-Cheh(cnewtoncheh@mgh.harvard.edu)andPatriciaB.5Munroe(p.b.munroe@qmul.ac.uk).6 7

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AUTHORAFFILIATIONS11.CenterforComplexDiseaseGenomics,McKusick-NathansInstituteofGeneticMedicine,Johns2HopkinsUniversitySchoolofMedicine,Baltimore,MD21205,USA32.Cardiology,DepartmentofMedicine,GenevaUniversityHospital,RueGabrielle-Perret-Gentil4,12114Geneva14,Switzerland53.WellcomeTrustCentreforHumanGenetics,UniversityofOxford,Oxford,OX37BN,UK64.DivisionofPreventiveMedicine,BrighamandWomen'sHospital,900CommonwealthAve.East,7Boston,MA02215,USA85.HarvardMedicalSchool,Boston,MA02115,USA96.DepartmentofBiostatistics,UniversityofMichigan,AnnArbor,MI48109,USA107.CenterforStatisticalGenetics,UniversityofMichigan,AnnArbor,MI48109,USA118.DepartmentofComputationalMedicineandBioinformatics,UniversityofMichigan,AnnArbor,MI1248109,USA139.ClinicalPharmacology,WilliamHarveyResearchInstitute,QueenMaryUniversityofLondon,London,14EC1M6BQ,UK1510.GlaxoSmithKline,GunnelsWoodRoad,StevenageSG12NY,UK1611.deCODEGenetics/Amgen,Inc.,Reykjavik,Iceland1712.MRCEpidemiologyUnit,UniversityofCambridgeSchoolofClinicalMedicine,InstituteofMetabolic18Science,CambridgeBiomedicalCampus,Cambridge,CB20QQ,UK1913.MedicalResearchInstitute,UniversityofDundee,NinewellsHospitalandMedicalSchool,Dundee,20DD19SY,UK2114.WilliamHarveyResearchInstitute,BartsandTheLondonSchoolofMedicineandDentistry,Queen22MaryUniversityofLondon,London,UK2315.InstituteofGeneticEpidemiology,HelmholtzZentrumMünchen,Neuherberg85764,Germany2416.CardiovascularResearchUnit,CenterforMolecularMedicineL8:03,DepartmentofMedicine,25KarolinskaInstitutet,17176Stockholm,Sweden2617.CenterforMolecularMedicine,KarolinskaUniversityHospitalSolna,Stockholm,Sweden2718.DepartmentofPublicHealthandClinicalMedicine,UmeåUniversity,Sweden2819.DepartmentofClinicalSciences,GeneticandMolecularEpidemiologyUnit,SkåneUniversity29HospitalMalmö,SE-20502Malmö,Sweden3020.DepartmentofOdontology,UmeåUniversity,Sweden3121.CentreofExcellenceforPublicHealth,QueensUniversityBelfast,GrosvenorRoad,BelfastBT126JP,32UK3322.LaboratoryofGenetics,IntramuralResearchProgram,NationalInstituteonAging,National34InstitutesofHealth,Baltimore,Maryland21224,USA3523.DepartmentofGenomicsofCommonDisease,SchoolofPublicHealth,ImperialCollegeLondon,36HammersmithHospital,London,UK3724.INSERMUMR970,ParisCardiovascularResearchCenterPARCC,56rueLeblanc,75015Paris,France3825.UniversityParis-Descartes,SorbonneParisCité,12ruedel’Ecoledemedicine,F-75006Paris,France3926.NationalInstituteforHealthandWelfare,FI-00271Helsinki,Finland4027.InstituteforMolecularMedicineFinlandFIMM,UniversityofHelsinki,00290Helsinki,Finland4128.GeneticEpidemiologyGroup,Dept.EpidemiologyandPublicHealth,UCL,London,WC1E6BT,UK4229.VthDepartmentofMedicine,MedicalFacultyMannheim,HeidelbergUniversity,Theodor-Kutzer-43Ufer1-3,68167Mannheim,Germany4430.InstituteforTranslationalGenomicsandPopulationSciences,LosAngelesBiomedicalResearch45InstituteatHarbor-UCLAMedicalCenter,1124W.CarsonStreet,Torrance,CA90502,USA4631.DepartmentofClinicalChemistry,FimlabLaboratories,Tampere33520,Finland47

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32.DepartmentofClinicalChemistry,UniversityofTampereSchoolofMedicine,Tampere33014,1Finland233.UniversityofLund,DeptInternalMedicine,Malmo,SE20502,Sweden334.UniversityofVerona,DeptofInternalMedicine,Verona,Italy37134435.UppsalaUniversity,UppsalaClinicalResearchCenter,SE-75185Uppsala,Sweden536.DepartmentofEpidemiology,UniversityofGroningen,UniversityMedicalCenterGroningen,6Hanzeplein1,9713GZGroningen,TheNetherlands737.DeptofMedicalEpidemiologyandBiostatistics,KarolinskaInstitutet,Box281,SE-171778Stockholm,Sweden938.DepartmentofMedicine,StanfordUniversitySchoolofMedicine,Stanford,CA94305,USA1039.SecondDepartmentofCardiology,AttikonHospital,SchoolofMedicine,UniversityofAthens,11Athens,Greece1240.Children'sHospitalOaklandResearchInstitute,Oakland,CA94609,USA1341.DepartmentofCardiovascularGenetics,InstituteofCardiovascularSciences,UniversityCollege14London,LondonWC1E6JF,UK1542.NIHRBartsCardiovascularBiomedicalResearchUnit,QueenMaryUniversityofLondon,London,16EC1M6BQ,UK1743.DivisionofEndocrinology,BostonChildren’sHospital,Boston,MA02115,USA1844.CenterforBasicandTranslationalObesityResearch,BostonChildren’sHospital,Boston,MA02115,19USA2045.PrograminMedicalandPopulationGenetics,BroadInstitute,7CambridgeCenter,Cambridge,MA2102142,USA2246.NovoNordiskFoundationCentreforBasicMetabolicResearch,SectionofMetabolic,Genetics,23FacultyofHealthandMedicalSciences,UniversityofCopenhagen,Copenhagen,2100,Denmark2447.DepartmentofEpidemiologyResearch,StatensSerumInstitut,2300,Copenhagen,Denmark2548.NationalHeart,LungandBloodInstitute'sFraminghamHeartStudy,Framingham,MA01702,USA2649.Dept.Dev.Bio.AndGenetics,StanfordUniversityMedicalCenter,Stanford,CA94305,USA2750.DepartmentofPsychiatry,VUUniversityMedicalCenter,Amsterdam,TheNetherlands2851.NationalHeart,LungandBloodInstitute,CardiovascularEpidemiologyandHumanGenomics29Branch,Bethesda,MD20814,USA3052.CenterforGenomeScience,NationalInstituteofHealth,OsongHealthTechnologyAdministration31Complex,Chungcheongbuk-do,RepublicofKorea3253.DivisionofTranslationalMedicineandHumanGenetics,DepartmentofMedicine,Universityof33Pennyslvania,USA3454.DepartmentofGenetics,UniversityofNorthCarolina,ChapelHill,NC27599,USA3555.DepartmentofPreventiveMedicineandEpidemiology,LoyolaUniversityChicagoStritchSchoolof36Medicine,Maywood,IL,60153,USA3756.InstituteofSocialandPreventiveMedicine(IUMSP),CentreHospitalierUniversitaireVaudoisand38UniversityofLausanne,RoutedelaCorniche10,1010Lausanne,Switzerland3957.AlistofmembersandaffiliationsappearsintheSupplementaryNote4058.HudsonAlphaInstituteforBiotechnology,Huntsville,AL35086,USA4159.DepartmentofNutrition,UniversityofNorthCarolina,ChapelHill,NC27599,USA4260.GeneticEpidemiologyUnit,DepartmentofEpidemiology,ErasmusMC,Rotterdam,3015CN,The43Netherlands4461.UppsalaUniversity,DepartmentofMedicalSciences,SE-75185Uppsala,Sweden4562.DipartimentodiScienzeFarmacologicheeBiomolecolari,UniversitàdiMilano,Milan,Italy4663.CentroCardiologicoMonzino,IRCCS,Milan,Italy47

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64.INSERMCentreforResearchinEpidemiologyandPopulationHealth,U1018,Villejuif,France1UniversityParis-Sud,URMS1018,Villejuif,France265.GeriatricUnit,AziendaSanitariaFirenze(ASF),Florence,Italy366.WellcomeTrustSangerInstitute,WellcomeTrustGenomeCampus,CB101SA,Hinxton,UK467.UniversityofCambridgeMetabolicResearchLaboratories,Level4,InstituteofMetabolicScience5Box289AddenbrookesHospitalCambridgeCB2OQQ,UK668.NIHRCambridgeBiomedicalResearchCentre,Level4,InstituteofMetabolicScienceBox2897AddenbrookesHospitalCambridgeCB2OQQ,UK869.SchoolofLifeScience,UniversityofLincoln,JosephBanksLaboratories,LincolnLN67DL,UK970.CardiovascularHealthResearchUnit,DepartmentofMedicine,UniversityofWashington,Seattle,10WA98101,USA1171.HumanGeneticsCenter,SchoolofPublicHealth,UniversityofTexasHealthScienceCenterat12Houston,1200PresslerSt.,Suite453E,Houston,TX77030,USA1372.MedicalGenomicsandMetabolicGeneticsBranch,NationalHumanGenomeResearchInstitute,14NIH,Bethesda,MD20892,USA1573.DepartmentofBiologicalPsychology,VUUniversity,Amsterdam,TheNetherlands1674.DeptofMedicineIII,UniversityofDresden,MedicalFacultyCarlGustavCarus,Fetscherstrasse74,1701307Dresden,Germany1875.TheBartsHeartCentre,WilliamHarveyResearchInstitute,QueenMaryUniversityofLondon,19LondonEC1M6BQ,UK2076.Nephrology,CentreHospitalierUniversitaireVaudoisandUniversityofLausanne,Bugnon17,100521Lausanne,Switzerland2277.DepartmentofEpidemiologyandBiostatistics,SchoolofPublicHealth,ImperialCollegeLondon,23NorfolkPlace,LondonW21PG,UK2478.DepartmentofCardiology,EalingHospitalNHSTrust,UxbridgeRoad,Southall,MiddlesexUB13EU,25UK2679.ImperialCollegeHealthcareNHSTrust,London,UK2780.NationalInstituteofCancerResearch,NationalHealthResearchInstitutes.35KeyanRd.,Zhunan28Town,MiaoliCounty350,Taiwan2981.SingaporeEyeResearchInstitute,SingaporeNationalEyeCentre,Singapore168751,Singapore3082.Duke-NUSGraduateMedicalSchoolSingapore,Singapore169857,Singapore3183.DepartmentofOphthalmology,NationalUniversityofSingaporeandNationalUniversityHealth32System,Singapore1192283384.DivisionofBiostatisticsandBioinformatics,InstituteofPopulationHealthSciences,NationalHealth34ResearchInstitutes.35KeyanRd.,ZhunanTown,MiaoliCounty350,Taiwan3585.UniversityofDundee,NinewellsHospitalandMedicalSchool,Dundee,DD19SY,UK3686.InstituteofEpidemiologyI,HelmholtzZentrumMünchen,Neuherberg85764,Germany3787.InstituteofEpidemiologyII,HelmholtzZentrumMünchen,Neuherberg85764,Germany3888.UMR744Inserm-Lille2-InstitutPasteurLille,France3989.DepartmentofPublicHealthandPrimaryCare,UniversityofCambridge,CambridgeCB18RN,UK4090.NIHRBloodandTransplantResearchUnitinDonorHealthandGenomics,DepartmentofPublic41HealthandPrimaryCare,UniversityofCambridge,CambridgeCB18RN,UK4291.DivisionofCardiovascularEpidemiology,InstituteofEnvironmentalMedicine,KarolinskaInstitutet,43Stockholm,Sweden4492.BHFGlasgowCardiovascularResearchCentre,InstituteofCardiovascularandMedicalSciences,45UniversityofGlasgow,126UniversityPlace,Glasgow,G128QT,UK4693.CardiovascularEpidemiologyandGenetics.IMIM(InstitutHospitaldelMard'Investigacions47Mèdiques),Barcelona,Spain48

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94.DepartmentofImmunology,GeneticsandPathology,UniversityofUppsala,Box815,Biomerical1center,75108Uppsala,Sweden295.ScienceforLifeLaboratory,UniversityofUppsala,Box815,Biomericalcenter,75108Uppsala,3Sweden496.InstitutfürIntegrativeundExperimentelleGenomik,UniversiätzuLübeck,RatzeburgerAllee160,523538Lübeck,Germany697.DeutschesZentrumfürHerz-Kreislauf-Forschung(DZHK),partnersiteHamburg,Kiel,Lübeck,7UniversitätzuLübeck,Lübeck,Germany898.EstonianGenomeCenter,UniversityofTartu,Tartu,51010,Estonia999.DivisionsofEndocrinology/Children'sHospital,Boston,MA02115,USA10100.BroadInstituteofHarvardandMIT,Cambridge,MA02139USA11101.DepartmentofHygieneandEpidemiology,UniversityofIoanninaMedicalSchool,Ioannina,45110,12Greece13102.DepartmentofMedicalSciences,MolecularEpidemiologyandScienceforLifeLaboratory,Uppsala14University,Uppsala,Sweden15103.DivisionofCardiovascularMedicine,RadcliffeDepartmentofMedicine,UniversityofOxford,16Oxford,OX39DU,UK17104.DepartmentofEpidemiology,ErasmusMC,UniversityMedicalCenterRotterdam,P.O.Box2040,183000CARotterdam,TheNetherlands19105.ToulouseUniversitySchoolofMedicine,RangueilUniversityHospital,INSERMUMR1027,20Toulouse,France21106.TranslationalGerontologyBranch,NationalInstituteonAging,BaltimoreMD,USA22107.InstituteofMolecularMedicine,UniversityofTexasHealthScienceCenteratHouston,TX,USA23108.TropicalMetabolismResearchUnit,TropicalMedicineResearchInstitute,UniversityoftheWest24Indies,Mona,Kingston7,Jamaica25109.DepartmentofEpidemiology,UniversityofNorthCarolina,ChapelHill,NC27599,USA26110.CardiothoracicSurgeryUnit,DepartmentofMolecularMedicineandSurgery,KarolinskaInstitutet,2717176Stockholm,Sweden28111.InstituteforPopulationHealthSciencesandInformatics,UniversityofEdinburgh,TeviotPlace,29Edinburgh,EH89AG,Scotland30112.SynpromicsLtd,9Bioquarter,LittleFranceRoad,Edinburgh,EH164UX,Scotland31113.UniversityofMichiganMedicalSchool,7220MSRBIII,AnnArborMI48109,USA32114.EPIMEDResearchCentre-EpidemiologyandPreventiveMedicine,DepartmentofClinicaland33ExperimentalMedicine,UniversityofInsubria,Varese,Italy34115.DepartmentofEpidemiologyandPrevention,IRCCSIstitutoNeurologicoMediterraneo35NEUROMED,86077Pozzilli,Italy36116.DepartmentofCardiovascularSciences,UniversityofLeicester,GlenfieldHospital,LeicesterLE3379QP,UK38117.NationalInstituteforHealthResearchLeicesterCardiovascularBiomedicalResearchUnit,39GlenfieldHospital,LeicesterLE39QP,UK40118.DivisionofEndocrinology,DiabetesandMetabolism,Cedars-SinaiMedicalCenter,LosAngeles,CA4190048,USA42119.DepartmentofGeneticEpidemiology,InstituteofEpidemiologyandPreventiveMedicine,43UniversityofRegensburg,Franz-Josef-Strauss-Allee11,93053Regensburg,Germany44120.DepartmentofNephrology,UniversityHospitalRegensburg,Franz-Josef-Strauss-Allee11,9305345Regensburg,Germany46121.DepartmentofMedicineIII,DivisionPathobiochemistry,TechnischeUniversitätDresden,Dresden,47Germany48

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122.OxfordCentreforDiabetes,EndocrinologyandMetabolism,UniversityofOxford,Oxford,UK1123.IcelandicHeartAssociation,Kopavogur,Iceland2124.FacultyofMedicine,UniversityofIceland,Reykjavik,Iceland3125.InstituteofClinicalMedicine/ObstetricsandGynaecology,UniversityofOulu,Oulu,Finland4126.MedicalResearchCenter,OuluUniversityHospital,Oulu,Finland5127.KuopioResearchInstituteofExerciseMedicine,Kuopio,Finland6128.InstituteofGeneticsandMolecularMedicine,WesternGeneralHospital,Edinburgh,EH42XU7Scotland,UK8129.UREN,INSERMU557,INRAU1125,CNAM,SMBH,SorbonneParisCité,UniversitéParis13,9Bobigny,France10130.InstituteofBiomedicine,UniversityofOulu,MedicalResearchCenterOuluandOuluUniversity11Hospital,Finland12131.BiocenterOulu,P.O.Box5000,Aapistie5A,FI-90014UniversityofOulu,Finland13132.DepartmentofGastroenterologyandMetabolism,PoznanUniversityofMedicalSciences,Poznan,14Poland15133.CenterforBiomedicine,EuropeanAcademyBozen/Bolzano(EURAC),Bolzano,39100,Italy-16affiliatedinstituteoftheUniversityofLübeck,Germany17134.DepartmentofGenetics,HarvardMedicalSchool,Boston,02115,USA18135.DepartmentofEpidemiology,HarvardT.H.ChanSchoolofPublicHealth,Boston,MA,USA19136.HUNTResearchCentre,DepartmentofPublicHealthandGeneralPractice,NorwegianUniversity20ofScienceandTechnology,7600Levanger,Norway21137.St.OlavHospital,TrondheimUniversityHospital,Trondheim,Norway22138.CardiovascularGeneticsDivision,UniversityofUtahSchoolofMedicine,SaltLakeCity,Utah,USA23139.DepartmentofGeneticMedicine,WeillCornellMedicalCollegeQatar,Doha,Qatar24140.DepartmentofRadiology,ErasmusMC,TheNetherlands25141.DepartmentofNeurology,ErasmusMC,UniversityMedicalCenterRotterdam,P.O.Box2040,300026CARotterdam,TheNetherlands27142.ResearchUnitofMolecularEpidemiology,HelmholtzZentrumMünchen,Neuherberg85764,28Germany29143.HannoverUnifiedBiobank,HannoverMedicalSchool,Hannover30625,Germany30144.HannoverMedicalSchool,InstituteforHumanGenetics,Carl-Neuberg-Strasse1,30625Hanover,31Germany32145.KaiserPermanente,DivisionofResearch,Oakland,CA94612,USA33146.DepartmentofMedicine,UniversityofWashington,Seattle,Washington98101,USA34147.DepartmentofClinicalPhysiology,TampereUniversityHospital,Tampere33521,Finland35148.CenterforHumanGeneticResearch,MassachusettsGeneralHospital,Boston,MA02114,USA36149.CardiovascularResearchCenter,MassachusettsGeneralHospital,Boston,MA02114,USA37150.DepartmentofMedicine,HarvardMedicalSchool,Boston,MA,USA38151.CardiologyDivision,DepartmentofMedicine,MassachusettsGeneralHospital39152.DivisionofTransplantation,DepartmentofSurgery,UniversityofPennsylvania,PA19104USA40153.DepartmentofPediatrics,UniversityofPennsylvania,Philadelphia,PA,USA41154.DepartmentofPublicHealthandPrimaryCare,InstituteofPublicHealth,UniversityofCambridge,42CambridgeCB22SR,UK43155.InstituteforTranslationalGenomicsandPopulationSciences,DepartmentofPediatrics,LABioMed44atHarbor-UCLAMedicalCenter,1124W.CarsonStreet,Torrance,CA90502,USA45156.1stCardiologyDepartment,OnassisCardiacSurgeryCenter356,SygrouAve,Athens,Greece46157.NationalHeartandLungInstitute,ImperialCollegeLondon,HammersmithHospitalCampus,47DucaneRoad,LondonW120NN,UK48

10

158.DepartmentofMedicine,Children'sHospitalOaklandResearchInstitute,Oakland,CA94609,USA1159.MRCUnitforLifelongHealthandAgeingatUCL,London,WC1B5JU,UK2160.DepartmentofMedicalGenetics,UniversityofLausanne,Lausanne,Switzerland3161.SwissInstituteofBioinformatics,Lausanne,Switzerland4162.DepartmentofMedicine,UniversityofEasternFinlandandKuopioUniversityHospital,702105Kuopio,Finland6163.InstituteofBiomedicine/Physiology,UniversityofEasternFinland,KuopioCampus,Finland7164.DepartmentofClinicalPhysiologyandNuclearMedicine,KuopioUniversityHospital,Kuopio,8Finland9165.OfficeofPopulationStudiesFoundationInc.,Talamban,CebuCity,6000,Philippines10166.DepartmentofAnthropology,Sociology,andHistory,UniversityofSanCarlos,Talamban,Cebu11City,6000,Philippines12167.DivisionofEndocrineandMetabolism,DepartmentofInternalMedicine,ChichungVeterans13GeneralHospital,Taichung40705,Taiwan14168.SchoolofMedicine,NationalYang-MingUniversity,Taipei,Taiwan15169.DepartmentofMedicalResearch,TaichungVeteransGeneralHospital,Taichung407,Taiwan16170.PopulationSciencesBranch,NationalHeartLung,andBloodInstitute,NationalInstitutesof17Health,Bethesda,MD,USA18171.CardiovascularCenter,TaichungVeteransGeneralHospital,Taichung,40705,Taiwan19172.InstituteofClinicalMedicine,NationalYangMingUniversitySchoolofMedicine,Taipei112,20Taiwan21173.SectionofComputationalBiomedicine,DepartmentofMedicine,BostonUniversitySchoolof22Medicine,Boston,02446MA,USA23174.EuropeanGenomicInstituteforDiabetes(EGID),FR3508Lille,France24175.CentreNationaldelaRechercheScientifique(CNRS)UMR8199,LillePasteurInstitute,1ruedu25ProfCalmette,59019LilleCedex,France26176.Lille2University,Lille,France27177.CenterforEvidence-basedHealthcare,UniversityofDresden,MedicalFacultyCarlGustavCarus,28Fetscherstrasse74,01307Dresden,Germany29178.DepartmentofMedicineI,UniversityHospitalGrosshadern,Ludwig-MaximiliansUniversity,30Munich,Germany31179.InstituteofMedicalInformatics,BiometryandEpidemiology,ChairofEpidemiology,Ludwig-32Maximilians-Universität,München81377,Germany33180.NeurologyUnit,UniversityofCambridge,R3,Box83,CambridgeBiomedicalCampus,Cambridge,34Cb20QQ,UK35181.DepartmentofDietetics-Nutrition,HarokopioUniversity,70El.VenizelouStr,Athens,Greece36182.INSERMU1142LIMICS,UMR_S1142SorbonneUniversités,UPMCUniversitéParis06,Université37Paris13,Paris,France38183.DepartmentofTwinResearchandGeneticEpidemiology,King'sCollegeLondon,London,UK39184.DepartmentofLifeandReproductionSciences,UniversityofVerona,StradaleGrazie8,3713440Verona,Italy41185.DepartmentofMedicine,KuopioUniversityHospital,Kuopio,Finland42186.UnitofGeneralPractice,OuluUniversityHospital,Oulu,Finland43187.DepartmentofMedicine,ProgramforPersonalizedandGenomicMedicine,Universityof44Maryland,SchoolofMedicine,Baltimore,Maryland21201,USA45188.DepartmentofEpidemiology,HumanGeneticsandEnvironmentalSciences,SchoolofPublic46Health,UniversityofTexasHealthScienceCenteratHouston,1200PresslerSt.,Suite453E,Houston,TX4777030,USA48

11

189.IstitutodiRicercaGeneticaeBiomedica(IRGB),ConsiglioNazionaledelleRicerche,c/oCittadella1UniversitariadiMonseratto,Monserrato,Cagliari09042,Italy2190.DepartmentofCardiology,SchoolofMedicine,UniversityofTampere,Tampere33014,Finland3191.SchoolofMedicine,UniversityofTampere,Tampere33014,Finland4192.NationalHeart,LungandBloodInstitute,DivisionofIntramuralResearch,Bethesda,MD,USA5193.InstituteofPsychiatry,PsychologyandNeuroscience,King'sCollegeLondon,LondonSE58AF,UK6194.DivisionsofEndocrinology,Children'sHospitalBoston,Massachusetts02115,USA7195.GeneticsandPrograminGenomics,Children'sHospitalBoston,Massachusetts02115,USA8196.DepartmentofPsychiatry,EMGOInstitute,NeuroscienceCampus,VUUniversityMedicalCentre,9VanderBoechorststraat7,1081BTAmsterdam,TheNetherlands10197.DepartmentofPsychiatry,UniversityofGroningen,UniversityMedicalCenterGroningen,11Hanzeplein1,9713GZGroningen,TheNetherlands12198.DepartmentofPsychiatry,LeidenUniversityMedicalCentre,P.O.Box9600,2300RCLeiden,The13Netherlands14199.InternationalCentreforCirculatoryHealth,ImperialCollegeLondon,W21PG,UK15200.DepartmentofNeurology,GeneralCentralHospital,Bolzano,39100,Italy16201.DepartmentofNeurology,UniversityofLübeck,Lübeck,Germany17202.DepartmentofEpidemiology,UniversityofWashington,Seattle,WA,USA18203.DepartmentofHealthServices,UniversityofWashington,Seattle,WA19204.GroupHealthResearchInstitute,GroupHealthCooperative,Seattle,WA20205.DivisionofBiostatistics,WashingtonUniversitySchoolofMedicine,SaintLouis,MO,63110,USA21206.CenterforNon-CommunicableDiseases,Karachi,Pakistan22207.DepartmentofNutrition,HarvardSchoolofPublicHealth,Boston,MA,USA23208.InstituteofPhysiology,UniversityMedicineGreifswald,Greifswald,Germany24209.DepartmentofBiostatistics,UniversityofWashington,Seattle,WA,USA25210.UniversityofOttawaHeartInstitute,CardiovascularResearchMethodsCentreOntario,Canada26211.RuddyCanadianCardiovascularGeneticsCentre,Ontario,Canada27212.NationalHeart,Lung,andBloodInstitute,6701RockledgeAve.,Bethesda,MD20892,USA28213.LeicesterNIHRBiomedicalResearchUnitinCardiovascularDisease,GlenfieldHospital,Leicester29LE39QP,UK30214.SouthKareliaCentralHospital,Lappeenranta,Finland31215.DeutschesHerzzentrumMünchen,Germany32216.TechnischeUniversitätMünchen,Germany33217.DeutschesZentrumfürHerz-Kreislauf-Forschung(DZHK),München,Germany34218.MunichHeartAlliance,Germany35219.CenterForLife-courseHealthResearch,P.O.Box5000,FI-90014UniversityofOulu,Finland36220.CollegeofMedicine,NationalDefenseMedicalCenter,Taipei,Taiwan37221.SawSweeHockSchoolofPublicHealth,NationalUniversityofSingaporeandNationalUniversity38HealthSystem,Singapore11759739222.UniversityofEasternFinlandandKuopioUniversityHospital,70210Kuopio,Finland40223.ConwayInstituteofBiomolecularandBiomedicalResearch,UniversityCollegeDublin,Dublin4,41Ireland42224.DepartmentofHaematology,UniversityofCambridge,Cambridge,UK43225.DepartmentofMedicine,NationalUniversityofSingaporeandNationalUniversityHealthSystem,44Singapore119228,Singapore45226.LaboratoryofCardiovascularScience,IntramuralResearchProgram,NationalInstituteonAging,46NationalInstitutesofHealth,Baltimore,Maryland,21224,USA47227.InstituteforCommunityMedicine,UniversityMedicineGreifswald,Greifswald,Germany48

12

228.DepartmentofHealthSciences,UniversityofLeicester,UniversityRd,LeicesterLE17RH,UK1229.Departmentofinternalmedicine,ErasmusMC,Rotterdam,3000CA,TheNetherlands2230.DepartmentofPublicHealthandClinicalNutrition,UniversityofEasternFinland,Finland3231.ResearchUnit,KuopioUniversityHospital,Kuopio,Finland4232.ResearchInstituteforPrimordialPreventionofNon-communicableDisease,IsfahanUniversityof5MedicalSciences,Isfahan,Iran6233.JohnsHopkinsMedicalInstitutions,1830EastMonumentSt.,Baltimore,MD21287,USA7234.CentreofMedicalSystemsBiology(CMSB1-2),NGIErasmusMedicalCenter,Rotterdam,The8Netherlands9235.DepartmentofClinicalEpidemiology,BiostatisticsandBioinformatics,AcademicMedicalCenter,10Amsterdam,TheNetherlands11236.DurrerCenterforCardiogeneticResearch,ICIN-NetherlandsHeartInstitute,Utrecht,The12Netherlands13237.SectionofPreventivemedicine,DepartmentofMedicine,BostonUniversitySchoolofMedicine,14Boston,02446MA,USA15238.Cardiology,DepartmentofMedicine,BostonUniversitySchoolofMedicine,Boston,02446MA,16USA17239.DepartmentofPharmacology,UniversityofPennsylvaniaPerelmanSchoolofMedicine,18Philadelphia,Pennsylvania,USA19240.DepartmentofInternalmedicine,UniversityHospitalLausanne,Lausanne,Switzerland20241.DepartmentofEpidemiologyandPublicHealth,EA3430,UniversityofStrasbourg,Strasbourg,21France22242.DivisionofCardiovascularMedicine,DepartmentofInternalMedicine,UniversityofMichigan23MedicalSchool,AnnArbor,MI,USA24243.UniversityMedicalCenterGroningen,UniversityofGroningen,Groningen,9700RB,The25Netherlands26244.EpidemiologyResearchUnit,TropicalMedicineResearchInstitute,UniversityoftheWestIndies,27Mona,Kingston7,Jamaica28245.DepartmentofCommunityMedicine,FacultyofHealthSciences,UniversityofTroms¯,Troms¯,29Norway30246.DepartmentofClinicalMedicine,FacultyofHealthSciences,UniversityofTroms¯,Troms¯,Norway31247.MRCCancerUnit,UniversityofCambridge,Cambridge,UK32248.DepartmentofEpidemiologyandBiostatistics,SchoolofMedicine,CaseWesternReserve33University,Cleveland,OH,44106,USA34249.MinistryofHealth,Victoria,RepublicofSeychelles35250.DepartmentofBiostatisticsandEpidemiology,UniversityofPennsylvania,USA36251.MRC-PHECentreforEnvironmentandHealth,SchoolofPublicHealth,ImperialCollegeLondon,37NorfolkPlace,LondonW21PG,UK38252.EnterpriseInformatics,IlluminaInc.,SantaClaraCA,95050,USA39253.DepartmentofInternalMedicine,DivisionofCardiovascularMedicine,UniversityofMichigan,Ann40Arbor,MI48109,USA41254.DepartmentofHumanGenetics,UniversityofMichigan,AnnArbor,Michigan,USA42255.DepartmentofGenetics,UniversityofGroningen,UniversityMedicalCentreGroningen,43Groningen,9711,TheNetherlands44256.DeptVascularMedicine,AcademicMedicalCenter,Amsterdam,TheNetherlands45257.DepartmentofMedicine,CentralFinlandHealthCareDistrict,Jyväskylä,Finland46258.DasmanDiabetesInstitute,Dasman,15462Kuwait47259.SaudiDiabetesResearchGroup,KingAbdulazizUniversity,21589Jeddah,SaudiArabia48

13

260.CentreforVascularPrevention,Danube-UniversityKrems,3500Krems,Austria1261.DepartmentofMedicine,ColumbiaUniversity,622West168thSt.,NewYork,NY10032,USA2262.SynlabAcademy,SynlabServicesGmbH,P5,7,68161Mannheim,Germany3263.ClinicalInstituteofMedicalandChemicalLaboratoryDiagnostics,MedicalUniversityofGraz,80364Graz,Austria5264.UnitofPrimaryCare,OuluUniversityHospital,Kajaanintie50,P.O.Box20,FI-90220Oulu,900296OYS,Finland7265.Grosshadern,Klinikum,München81377,Germany8266.TheCharlesBronfmanInstituteforPersonalizedMedicine,TheIcahnSchoolofMedicineatMount9Sinai,NewYork,NY10029,USA10267.MindichChildhealthDevelopmentInstitute,TheIcahnSchoolofMedicineatMountSinai,New11York,NY10029,USA12268.PrincessAl-JawharaAl-BrahimCentreofExcellenceinResearchofHereditaryDisorders(PACER-13HD),KingAbdulazizUniversity,Jeddah21589,SaudiArabia14269.DepartmentofBiostatistics,UniversityofLiverpool,LiverpoolL693GA,UK15

16

14

ABSTRACT1Todissectthegeneticarchitectureofbloodpressureandassesseffectsontarget-organdamage,2

weanalyzed128,272SNPsfromtargetedandgenome-widearraysin201,529individualsofEuropean3

ancestryandgenotypesfromanadditional140,886individualswereusedforvalidation.Weidentified4

66bloodpressureloci,ofwhich17werenoveland15harboredmultipledistinctassociationsignals.5

The66indexSNPswereenrichedforcis-regulatoryelements,particularlyinvascularendothelialcells,6

consistentwithaprimaryroleinbloodpressurecontrolthroughmodulationofvasculartoneacross7

multipletissues.The66indexSNPscombinedinariskscoreshowedcomparableeffectsin64,4218

individualsofnon-Europeandescent.The66-SNPbloodpressureriskscorewassignificantlyassociated9

withtarget-organdamageinmultipletissues,withminoreffectsinthekidney.Ourfindingsexpand10

currentknowledgeofbloodpressurepathwaysandhighlighttissuesbeyondtheclassicrenalsystemin11

bloodpressureregulation. 12

15

INTRODUCTION1

Thereareconsiderablephysiological,clinicalandgeneticdatathatpointtothekidneyasthe2

majorregulatorofbloodpressure(BP)andtorenaldamageasaconsequenceoflong-termBPelevation.3

However,alternativehypotheses,suchasincreasingsystemicvascularresistance,arealsoserious4

contenderstoexplaintheriseofBPwithincreasingage,butwithlimitedgeneticsupport.Thegenetic5

basisofelevatedbloodpressureorhypertension(HTN)involvesmanylocithathavebeenidentified6

usinglarge-scaleanalysesofcandidategenes1,2,linkagestudies,andgenome-wideassociationstudies7

(GWAS)3-12.ThegenesunderlyingBPregulationcanhelpresolvemanyoftheopenquestionsregarding8

BP(patho-)physiology.While~40-50%ofBPvariabilityisheritable13,14,thegeneticvariationidentified9

todateexplainsonly~2%1-12.10

TheCardio-MetaboChipisacustomgenotypingmicroarraydesignedtofacilitatecost-effective11

follow-upofnominalassociationsformetabolicandcardiovasculartraits,includingBP.Thisarray12

comprises196,725variants,including~5,000SNPswithnominal(P<0.016)evidenceofBPassociationin13

ourpreviousGWASmeta-analysis5.Furthermore,thearrayincludesseveraldensescaffoldsforfine14

mappingofselectedlocispanning,onaverage,genomicregionsof350kilobases5,16,ofwhich24include15

genome-widesignificantBPassociationinthecurrentstudy5,16.16

RESULTS17

NovelgeneticlociassociatedwithsystolicanddiastolicBP18

Weperformedmeta-analysesofassociationsummarystatisticsfromatotalof201,52919

individualsofEuropean(EUR)ancestryfrom74studies:(i)109,096individualsfrom46studies20

genotypedonCardio-MetaboChip;and(ii)92,433individualsfrom28studieswithimputedgenotype21

datafromgenome-widegenotypingatvariantsincludedontheCardio-MetaboChip.Twenty-fourofthe22

28studieswithgenome-widegenotypingdatahadcontributedtopreviousanalyses(Supplementary23

Tables1-3)5,7.24

BPwasmeasuredusingstandardizedprotocolsinallstudies5,17(SupplementaryTable1,Online25

methods).AssociationstatisticsforsystolicanddiastolicBP(SBPandDBP)inmodelsadjustingforage,26

age2,sex,andbodymassindex(BMI),wereobtainedforeachstudyseparately,withstudy-specific27

genomiccontrolappliedtocorrectforpossiblepopulationstructure.Fixed-effectsmeta-analysis28

proceededin4stages,separatelyforthefollowingSNPassociations:Stage1,usingresultsbasedon4629

studiesusingCardio-MetaboChipgenotypesof109,096participants;Stage2,usingadditionalresults30

basedonimputedgenotypesfromgenome-widegenotypingarraysin4previouslyunpublishedstudies;31

16

Stage3usingimputedgenotypesfromgenome-widegenotypingarraysin24previouslypublished1

studies5;andStage4,thejointmeta-analysisofStages1-3includingatotalof201,529independent2

individuals(SupplementaryFigure1,SupplementaryTables2-3,SupplementaryNote).Toaccountfor3

populationstructurebetweenstudiesinStages1-3ofourmeta-analysis,genomiccontrolcorrectionwas4

appliedtometa-analysisresultsfromeachofthesestagesinanapproachaggregatingsummary5

statisticsfromGWASandCardio-MetaboChipstudies18,19.6

Afterstage4,67lociattainedgenome-widesignificance(P<5x10-8),18ofwhichwerenot7

previouslyreportedintheliterature(SupplementaryTable4).Quantile-quantileplotsofthestage48

meta-analysisshowedanexcessofsmallPvalues,withanelevatedgenomiccontrollambdaestimate9

thatwaspersistent,albeitattenuated,afterexcludingall66loci(SupplementaryFigure2).This10

observationiscompatiblewitheitherresidualuncorrectedpopulationstratificationorthepresenceofa11

largenumberofvariantsthataretrulyassociatedwithBPbutfailtoachievegenome-widesignificance12

inthecurrentmeta-analysis.TheCardio-MetaboChiparray’sinclusionofSNPsfromapriorBPGWAS513

doesnotappeartobethesoleexplanation,aswedidnotobserveasignificantdecreaseoftheexcessof14

smallPvaluesafterexclusionofallSNPsthatwereincludedontheCardio-MetaboChipbasedon15

nominalBPassociation(SupplementaryFigures3and4).Sincethequantile-quantileplotscontinuedto16

showdeviationfromthenullexpectation,wesoughtadditionalvalidationfor18variantsattaining17

genome-widesignificance,butwithoutpriorsupportintheliterature,inupto140,886individualsof18

EuropeanancestryfromUKBiobank20.FortheseSNPs,weperformedastage5meta-analysiscombining19

theassociationsummarystatisticsfromstage4andUKBiobank,inatotalofupto342,415individuals20

(SupplementaryTable5).21

Uponstage5meta-analysis,17of18variantsretainedgenome-widesignificancefortheprimary22

trait(SBPorDBPresultwiththelowerPvalue).Theonevariantthatwasnotgenome-widesignificant23

hadaborderlinePvalueof4.49x10-8atstage4.Thesefindingsareconsistentwithappropriate24

calibrationoftheassociationteststatisticsatstage4suchthatobservingonefailureamong1825

validationtestsisconsistentwiththeuseofathreshold(P<5x10-8)designedtohavea1in20chance26

ofaresultasormoreextremesolelyduetochance.Intotal,66lociattainedgenome-widesignificance:27

13lociforSBPonly,12lociforDBPonly,and41lociforbothtraits.Ofthese,17BPlociwerenovel,28

while49werepreviouslyreportedatgenome-widesignificance(Table1andFigure1).29

ComparedwithpreviouslyreportedBPvariants5,7,21,theaverageabsoluteeffectsizeofthe30

newlydiscoveredvariantsissmaller,withcomparableminorallelefrequency(MAF),presumablyowing31

totheincreasedpowerofalargersamplesize(Table2).Asexpectedfromthehighcorrelationbetween32

17

SBPandDBPeffects,theobserveddirectionsofeffectsforthetwotraitsweregenerallyconcordant1

(SupplementaryFigure5),andtheabsoluteeffectsizeswereinverselycorrelatedwithMAF(Table12

andSupplementaryFigure6).The66BPSNPsexplained3.46%and3.36%ofSBPandDBPvariance,3

respectively,amodestincreasefrom2.95%and2.78%forSBPandDBP,respectively,forthe494

previouslyreportedSNPs(SupplementaryNote).Thelowpercentvarianceexplainedisconsistentwith5

estimatesthatlargenumbersofcommonvariantswithweakeffectsatalargenumberoflociinfluence6

BP5.7

Signalrefinementatthe66BPloci8

Toidentifydistinctsignalsofassociationatthe66BPlociandthevariantsmostlikelytobe9

causalforeach,westartedwithanapproximateconditionalanalysisusingamodelselectionprocedure10

implementedintheGCTA-COJOpackage22,23aswellasadetailedliteraturereviewofallpublishedBP11

associationstudies.GCTA-COJOanalysiswasperformedusingtheassociationsummarystatisticsforSBP12

andDBPfromtheStage4EURancestrymeta-analyses,withthelinkagedisequilibrium(LD)between13

variantsestimatedonthebasisofCardio-MetaboChipgenotypedatafrom7,006individualsofEUR14

ancestryfromtheGoDARTScohort24.MorethanonedistinctBPassociationsignalwasidentifiedat1315

lociatP<5x10-8(SupplementaryTable6,SupplementaryFigures7,andSupplementaryNote).Atsix16

loci,thedistinctsignalswereidentifiedforbothSBPandDBPanalyzedseparately;thesetrait-specific17

associationswererepresentedbythesameorhighlycorrelated(r2>0.8)SNPsat5ofthe6loci18

(SupplementaryTables7and8).WerepeatedGCTA-COJOanalysesusingthesamesummary19

associationresults,butwithadifferentreferencesampleforLDestimates(WTCCC1-T2D/58BC,N=20

2,947,SupplementaryNote)andobservedminimaldifferencesarisingfromminorfluctuationsinthe21

associationPvalueinthejointregressionmodels(SupplementaryTables7and8).LD-based22

comparisonsofpublishedassociationsignalsatestablishedBPloci,andthecurrentstudy’sfindings23

suggestedthatat10loci,thesignalsidentifiedbythesingle-SNPandtheGCTA-COJOanalyseswere24

distinctfromthosereportedintheliterature(SupplementaryTable9).25

Wethenperformedmultivariableregressionmodelinginasinglelargecohort(Women’s26

GenomeHealthStudy,WGHS,N=23,047)withsimultaneousadjustmentforboth1)allcombinationsof27

putativeindexSNPsforeachdistinctsignalfromtheGCTA-COJOconditionalanalyses,and2)allindex28

SNPsforallpotentialdistinctsignalsidentifiedbyourliteraturereview(SupplementaryTable9,29

SupplementaryNote).AlthoughWGHSisverylargeasasinglestudy,powerisreducedinasingle30

samplecomparedtothatintheoverallmeta-analysis(23kvs.342kindividuals)andconsequentlythe31

18

failuretoreachsignificancedoesnotrepresentnon-replicationforindividualSNPs.TheWGHSanalysis1

supportedtwodistinctassociationsignalsateightof13lociidentifiedintheGCTA-COJOanalysis,but2

couldnotprovidesupportfortheremainingfive(SupplementaryTable10).ThejointSNPmodelingin3

WGHSadditionallysupportedtwodistinctsignalsofassociationatthreeotherloci(GUCY1A3-GUCY1B3,4

SYNPO2LandTBX5-TBX3),atwhichtheSNPidentifiedinthecurrentstudyisdistinctfromthat5

previouslyreportedintheliterature5,11.6

Wesoughttorefinethelocalizationoflikelyfunctionalvariantsatlociwithhigh-density7

coverageontheCardio-MetaboChip.WefollowedaBayesianapproachtodefine,foreachsignal,8

crediblesetsofvariantsthathave99%probabilityofcontainingortaggingthecausalvariant9

(SupplementaryNote).Toimprovetheresolutionofthemethod,theanalyseswererestrictedto2410

regionsselectedtofinemap(FM)geneticassociations,andthatincludedatleastoneSNPreaching11

genome-widesignificanceinthecurrentmeta-analyses(SupplementaryTable11).Twenty-oneofthe12

Cardio-MetaboChipFMregionswereBPlociintheoriginaldesign,withthreeofthenewlydiscovered13

BPlociinFMregionsthatwereoriginallyselectedforothernon-BPtraits.Weobservedthatthe99%14

credibleSNPsetsatfiveBPlocispanned<20kb.ThegreatestrefinementwasobservedattheSLC39A815

locusforSBPandDBP,andattheZC3HC1andPLCE1lociforDBP,wherethe99%crediblesetsincluded16

onlytheindexvariants(SupplementaryTable12).AlthoughSNPsincrediblesetswereprimarilynon-17

coding,theyincludedonesynonymousandsevennon-synonymousvariantsthatattainedhighposterior18

probabilityofdrivingsevendistinctassociationsignalsatsixBPloci(SupplementaryTable12).Of19

these,threevariantsaloneaccountformorethan95%oftheposteriorprobabilityofdrivingthe20

associationsignalobservedateachofthreeloci(SupplementaryTable12and13).Despitereduced21

statisticalpower,theanalysesrestrictedtothesampleswithCardio-MetaboChipgenotypesonly22

(N=109,096)identifiedthemajorityofSNPsidentifiedintheGWAS+Cardio-MetaboChipdata23

(SupplementaryTable12).ThefulllistofSNPsinthe99%crediblesetsarelistedinSupplementary24

Table13.25

WhatdotheBPvariantsdo?26

IndexSNPsortheirproxies(r2>0.8)alteredaminoacidsequenceat11of66BPloci(Table1).27

Thus,themajorityofBP-associationsignalsarelikelydrivenbynon-codingvariantshypothesizedto28

regulateexpressionofsomenearbygeneincis.Tocharacterizetheireffects,wefirstsoughtSNPs29

associatedwithgeneexpression(eSNPs)fromarangeofavailableexpressiondatawhichincluded30

hypertensiontargetendorgansandcellsofthecirculatorysystem(hearttissue,kidneytissue,brain31

19

tissue,aorticendothelialcells,bloodvessels)andothertissue/celltypes(CD4+macrophages,monocytes1

lymphoblastoidcelllines,skintissue,fattissue,andlivertissue).FourteenBP-associatedSNPsatthe2

MTHFR-NPPB,MDM4,ULK4,CYP1A1-ULK3,ADM,FURIN-FES,FIGN,andPSMD5lociwereeSNPsacross3

differenttissues(SupplementaryTable14).Ofthese14eSNPs,threewerealsopredictedtoalterthe4

aminoacidsequenceattheMTHFR-NPPB,MAP4andULK4loci,providingtwopotentialmechanismsto5

exploreinfunctionalstudies.Second,weusedgeneexpressionlevelsmeasuredinwholebloodintwo6

differentsampleseachincluding>5,000individualsofEURdescent.WetestedwhethertheleadBPSNP7

wasassociatedwithexpressionofanytranscriptincis(<1MbfromtheleadSNPateachlocus)atafalse8

discoveryrate(FDR)of<0.05,accountingforallpossiblecis-transcriptassociationtestsgenome-wide.9

ItislikelythatwedidnotgenotypethecausalgeneticvariantunderlyingeachBPassociationsignal;a10

nearbySNP-transcriptassociation,duetoLD,maythereforereflectanindependentgeneticeffecton11

expressionthatisunrelatedtotheBPeffect.Consequently,weassumedthattheleadBPSNPandthe12

mostsignificanteSNPforagiventranscriptshouldbehighlycorrelated(r2>0.7).Furthermore,we13

assumedthatthesignificanceofthetranscriptassociationwiththeleadBPSNPshouldbesubstantially14

reducedinaconditionalmodeladjustingforthebesteSNPforagiventranscript.EighteenSNPsat1515

lociwereassociatedwith22differenttranscripts,withatotalof23independentSNP-transcript16

associations(threeSNPswereassociatedwithtwotranscriptseach,SupplementaryTable15,17

SupplementaryNote).ThegenesexpressedinaBPSNPallele-specificmannerareclearlyhigh-priority18

candidatestomediatetheBPassociation.Inwholeblood,thesegenesincludedobviousbiological19

candidatessuchasGUCY1A3,encodingthealphasubunitofthesolubleguanylatecyclaseprotein,and20

ADM,encodingadrenomedullin,bothofwhichareknowntoinducevasodilation25,26.Therewassome21

overlapofeSNPsbetweenthewholebloodandothertissuedatasetsattheMTHFR-NPPB,MDM4,22

PSMD5,ULK4andCYP1A1-ULK3loci,illustratingadditionalpotentiallycausalgenesforfurtherstudy.23

AnalternativemethodforunderstandingtheeffectonBPofnon-codingvariantsistodetermine24

whethertheyfallwithinDNaseIhypersensitivitysites(DHSs).Weperformedtwoanalysestoinvestigate25

whetherBPSNPsortheirLDproxies(r2>0.8)wereenrichedinDHSsinacell-type-specificmanner26

(SupplementaryNote).First,weusedEpigenomicsRoadmapandENCODEDHSdatafrom123adultcell27

linesortissues27-29toestimatethefoldincreaseintheproportionofBPSNPsmappingtoDHSs28

comparedtoSNPsassociatedatgenome-widesignificancewithnon-BPphenotypesfromtheNHGRI29

GWAScatalog30.Weobservedthat7outofthe10celltypeswiththegreatestrelativeenrichmentofBP30

SNPsmappingtoDHSswerefrombloodvessels(vascularormicro-vascularendothelialcell-linesorcells)31

and11ofthe12endothelialcellswereamongthetopquartermostenrichedamongthe123celltypes32

20

(Figure2andSupplementaryTable16).Inasecondanalysisofanexpandedsetoftissuesandcelllines,1

inwhichcelltypesweregroupedintotissues(SupplementaryTable17),BP-associatedSNPenrichment2

inDHSsinbloodvesselswasagainobserved(P=1.2x10-9),aswellasinheartsamples(P=5.3x10-8;3

SupplementaryTable18).4

WenexttestedwhethertherewasenrichmentofBPSNPsinH3K4me331sites,amethylation5

markassociatedwithbothpromoterandenhancerDNA.Weobservedsignificantenrichmentinarange6

ofcelltypesincludingCD34primarycells,adultkidneycells,andmusclesatelliteculturedcells7

(SupplementaryTable19).EnrichmentofBPSNPsinpredictedstrongandweakenhancerstatesandin8

activepromoters32inarangeofcelltypeswasalsoobserved(SupplementaryTable20,Supplementary9

Figure8).10

WeusedMeta-AnalysisGene-setEnrichmentofvariaNTAssociations(MAGENTA)33toattempt11

toidentifypathwaysover-representedintheBPassociationresults.Nogenesetsmeetingexperiment-12

widesignificanceforenrichmentforBPassociationwereidentifiedbyMAGENTAaftercorrectionfor13

multipletesting,althoughsomeattainednominalsignificance(SupplementaryTable21,Supplementary14

Note).WealsoadaptedtheDEPICT34pathwayanalysistool(Data-drivenExpressionPrioritized15

IntegrationforComplexTraits)toidentifyassembledgene-setsthatareenrichedforgenesnear16

associatedvariants,andtoassesswhethergenesfromassociatedlociwerehighlyexpressedin17

particulartissuesorcelltypes.UsingtheextendedBPlocuslistbasedongenome-widesignificantloci18

fromthisanalysisandpreviouslypublishedSNPsthatmaynothavereachedgenome-widesignificance19

inthecurrentanalysis(SupplementaryTable9),weidentifiedfivesignificant(FDR≤5%)genesets:20

abnormalcardiovascularsystemphysiology,GAlpha1213signalingevents,embryonicgrowth21

retardation,prolongedQTinterval,andabnormalvitellinevasculaturemorphology.Wealsofoundthat22

suggestiveSBPandDBPassociations(P<1x10-5)wereenrichedforreconstitutedgene-setsatDBPloci23

(mainlyrelatedtodevelopmentalpathways),butnotatSBPloci(SupplementaryTable22,24

SupplementaryNote).Inafinalanalysis,weassessedCardio-MetaboChipSNPsatthefine-mappingloci25

usingformaldehyde-assistedisolationofregulatoryelements(FAIRE-gen)inlymphoblastoidcelllines35.26

OurresultsprovidedsupportfortwoSNPs,oneofwhichSNP(rs7961796attheTBX5-TBX3locus)was27

locatedinaregulatorysite.AlthoughtheotherSNP(rs3184504attheSH2B3locus)isanon-28

synonymousvariant,therewasalsoaregulatorysiteindicatedbyDNaseIandH3K4me1signaturesat29

thelocus,makingtheSNPapotentialregulatoryvariant(SupplementaryTable23)36.BothSNPswere30

includedinthelistof99%credibleSNPsateachlocus.31

21

Asian-andAfricanancestryBPSNPassociation1

Wetestedthe66leadSNPsattheestablishedandnovellociforassociationwithBPinupto2

20,875individualsofSouthAsian(SAS)ancestry(PROMISandRACEstudies),9,637individualsofEast3

Asian(EAS)ancestry(HEXA,HALST,CLHNS,DRAGON,andTUDRstudies),and33,909individualsof4

African(AFR)ancestry(COGENT-BPconsortium,Jupiter,SPT,Seychelles,GXE,andTANDEMstudies).As5

expected,theeffectallelefrequenciesareverysimilaracrossstudiesofthesameethnicity,but6

markedlydifferentacrossdifferentancestrygroups(SupplementaryFigure9).Manyassociationsof7

individualSNPsfailedtoreachP<0.05fortheBPtraitwiththelowerPvalue(SupplementaryTable24),8

whichcouldpotentiallybeduetothemuchlowerstatisticalpoweratthesamplesizesavailable,9

differentpatternsofLDateachlocusacrossancestries,variabilityinallelefrequency,ortruelackof10

associationinindividualsofagivennon-Europeanancestry.Thelowstatisticalpowerforthegreat11

majorityofSNPstestedisvisibleconsideringSNP-by-SNPpowercalculationsusingEuropeanancestry12

effectsizes(SupplementaryTable24).However,concordantdirectionsofalleliceffectsforbothSBP13

andDBPwereobservedfor45/66SNPsinSAS,36/60SNPsinEAS,and42/66SNPsinAFRsamples:the14

strongestconcordancewithSASmaynotbesurprisingbecauseSouthAsiansaremorecloselyrelatedto15

EuropeansthanareEastAsiansorAfricans.Moreover,strongcorrelationofeffectsizeswasobserved16

betweenEURsampleswithSAS,EAS,orAFRsamples(r=0.55,0.60,and0.48,respectively).A66-SNP17

SBPorDBPriskscoreweresignificantpredictorsofSBPandDBPinallsamples.A1mmHghigherSBPor18

DBPriskscoreinEURsampleswasassociatedwitha0.58/0.50mmHghigherSBP/DBPinSASsamples19

(SBPP=1.5x10-19,DBPP=3.2x10-15),0.49/0.50mmHghigherSBP/DBPinEASsamples(SBP20

P=1.9x10-10,DBPP=1.3x10-7),and0.51/0.47mmHghigherSBP/DBPinAFRsamples(SBP21

P=2.2x10-21,DBPP=6.5x10-19).Theattenuationofthegeneticriskscoreestimatesinnon-European22

ancestriesispresumablyduetoinclusionofasubsetofvariantsthatlackassociationinthenon-23

Europeanoradmixedsamples.24

Wesubsequentlyperformedatrans-ethnicmeta-analysisofthe66SNPsinall64,421samples25

acrossthethreenon-Europeanancestries.Aftercorrectingfor66tests,12/66SNPsweresignificantly26

associatedwitheitherSBPorDBP(P<7.6x10-4),withacorrelationofEURandnon-EUReffect27

estimatesof0.77forSBPand0.67forDBP;theEuropean-ancestrySBPorDBPriskscorewasassociated28

with0.53/0.48mmHghigherBPperpredictedmmHgSBP/DBPrespectively(SBPP<6.6x10-48,DBP29

P<1.3x10-38).For7ofthe12significantSNPs,noassociationhaspreviouslybeenreportedingenome-30

widestudiesofnon-Europeanancestry.Someheterogeneityofeffectswasobservedbetween31

Europeanandnon-Europeaneffectestimates(SupplementaryTable24).Takentogether,thesefindings32

22

suggestthat,inaggregate,BPlociidentifiedusingdatafromindividualsofEURancestryarealso1

predictiveofBPinnon-EURsamples,butlargernon-Europeansamplesizeswillbeneededtoestablish2

preciselywhichindividualSNPsareassociatedinagivenethnicgroup.3

Impactonhypertensivetargetorgandamage4

Long-termelevatedBPcausestargetorgandamage,especiallyintheheart,kidney,brain,large5

bloodvessels,andtheretinalvessels37.Consequently,thegeneticeffectofthe66SBPandDBPSNPson6

end-organoutcomescanbedirectlytestedusingtheriskscore,althoughsomeoutcomeslackedresults7

forasmallnumberofSNPs.Interestingly,BPriskscoressignificantlypredicted(SupplementaryNote)8

coronaryarterydiseaserisk,leftventricularmassandwallthickness,stroke,urinaryalbumin/creatinine9

ratio,carotidintima-medialthicknessandcentralretinalarterycaliber,butnotheartfailureorother10

kidneyphenotypes,afteraccountingforthenumberofoutcomesexamined(Table3).Becauseoutlier11

effectscanaffectriskscores,werepeatedtheriskscoreanalysisremovingiterativelySNPsthat12

contributedtostatisticalheterogeneity(SNP-traiteffectsrelativetoSNP-BPeffects).Heterogeneitywas13

definedbasedonamultipletestingadjustedsignificancethresholdforCochran’sQtestofhomogeneity14

ofeffects(SupplementaryNote).TheriskscoreanalysesrestrictedtothesubsetofSNPsshowingno15

heterogeneityofeffectrevealedessentiallyidenticalresults,withtheexceptionthaturinary16

albumin/creatinineratiowasnolongersignificant.Theper-SNPresultsareprovidedinSupplementary17

Table25andSupplementaryFigures10.Becauselarge-scaleGWASofnon-BPcardiovascularrisk18

factorsareavailable,weexaminedtheBPriskscoresaspredictorsofothercardiovascularriskfactors:19

LDL-cholesterol,HDL-cholesterol,triglycerides,type2diabetes,BMI,andheight.Weobservednominal20

(P<0.05)associationsoftheBPriskscoreswithriskfactors,althoughmostlyintheoppositedirectionto21

theriskfactor-CVDassociation(SupplementaryTable26).ThefailuretodemonstrateaneffectofBP22

riskscoresonheartfailuremayreflectlimitedpowerfromamodestsamplesize,butthelackof23

significanteffectsonrenalmeasuressuggeststhattheepidemiologicrelationshipofhigherBPand24

worserenalfunctionmaynotreflectdirectconsequencesofBPelevation.25

DISCUSSION26

ThestudyreportedhereisthelargesttodatetoinvestigatethegenomicsofBPinmultiple27

continentalancestries.Ourresultshighlightfourmajorfeaturesofinter-individualvariationinBP:(1)28

weidentified66(17novel)genome-widesignificantlociforSBPandDBPbytargetedgenotypinginup29

to342,415individualsofEuropeanancestrythatcumulativelyexplain~3.5%ofthetrait;(2)thevariants30

wereenrichedforcis-regulatoryelements,particularlyinvascularendothelialcells;(3)thevariantshad31

23

broadlycomparableBPeffectsinSouthAsians,EastAsianandAfricans,albeitinsmallersamplesizes;1

and,(4)a66SNPrisk-scorepredictedtargetorgandamageintheheart,cerebralvessels,carotidartery2

andtheeyewithlittleevidenceforaneffectinkidneys.Overall,therewasnoenrichmentofasingle3

geneticpathwayinourdata;rather,ourresultsareconsistentwiththeeffectsofBParisingfrom4

multipletissuesandorgans.5

GeneticandmolecularanalysesofMendeliansyndromesofhypertensionandhypotensionpoint6

largelytoarenalorigin,involvingmultipleraredeleteriousmutationsinproteinsthatregulatesalt-7

waterbalance38.ThisisstrongsupportforGuyton’shypothesisthattheregulationofsodiumexcretion8

bythekidneyanditseffectsonextracellularvolumeareaprimepathwaydeterminingintra-arterial9

pressure39.However,ourgeneticdatafromunselectedindividualsinthegeneralcommunityargues10

againstasingledominantrenaleffect.The66SNPsweidentifiedarenotchanceeffects,buthavea11

globaldistributionandimpactonBPthatareconsistentasmeasuredbytheireffectsacrossthemany12

studiesmeta-analyzed.Thattheyarepolymorphicacrossallcontinentalancestriesarguesfortheir13

originandfunctionaleffectspriortohumancontinentaldifferentiation.14

Howeverseveralofthe17novellocicontainstrongpositionalbiologicalcandidates,theseare15

describedingreaterdetailinSupplementaryTable27andtheSupplementaryNote.Thesinglemost16

commonfeatureweidentifiedwastheenrichmentofregulatoryelementsforgeneexpressionin17

vascularendothelialcells.Thebroaddistributionofthesecellsacrossbothlargeandsmallvesselsand18

acrossalltissuesandorganssuggestthatfunctionalvariationinthesecellsaffectsendothelial19

permeabilityorvascularsmoothmusclecellcontractilityviamultiplepathways.Thesehypotheseswill20

needtoberigorouslytestedinappropriatemodels,toassessthecontributionofthesepathwaystoBP21

control,andthesepathwayscouldalsobetargetsforsystemicanti-hypertensivetherapyastheyarefor22

thepulmonarycirculation42.23

Insummary,thesegeneticobservationsmaycontributetoanimprovedunderstandingofBP24

biologyandare-evaluationofthepathwaysconsideredrelevantfortherapeuticBPcontrol.25

24

SUPPLEMENTARYNOTE1

SupplementaryNoteisavailableintheonlineversionofthepaper.2

SUMMARYSTATISTICS3

Fullsummarystatistics(Pvalues)areintheonlineversionofthepaper(file“ICBPCMfinalMeta.csv.zip”).4

URLs5

http://hgdownload.cse.ucsc.edu/goldenPath/hg19/encodeDCC/wgEncodeUwDnaseforenrichment6

analyses.Accessed3/13/2013.7

http://www.genome.gov/gwastudiesforenrichmentanalyses.Accessed3/13/2013.8

http://genome.ucsc.edu/ENCODE/cellTypes.htmlforenrichmentanalyses.Accessed3/13/2013.9

ACKNOWLEDGEMENTS10

We thank all the studyparticipants of this study for their contributions.Detailed acknowledgment of11

fundingsourcesisprovidedintheSupplementaryNote.12

AUTHORCONTRIBUTIONS13

Analysisgroup14Designofsecondaryanalyses:G.B.E.,T.Ferreira,T.J.,A.P.M.,P.B.M.,C.N.-C.Computationofsecondary15analyses:G.B.E.,T.Ferreira,T.J.,A.P.M.,P.B.M.,C.N.-C.Paperwriting:A.C.,G.B.E.,T.Ferreira,T.J.,A.P.M.,16P.B.M.,C.N.-C.Studymanagement:P.B.M.,C.N.-C.17Cardio-MetaboChipornewGWAS18WGHS:Studyphenotyping:P.M.R.,D.I.C.,L.M.R.Genotypingoranalysis:P.M.R.,D.I.C.,L.M.R.,19F.GiulianiniStudyPI:P.M.R.20JUPITER:Studyphenotyping:P.M.R.,D.I.C.,L.M.R.Genotypingoranalysis:D.I.C.,L.M.R.,F.Giulianini21StudyPI:P.M.R.,D.I.C.22deCODE:Studyphenotyping:G.B.Genotypingoranalysis:G.T.StudyPI:K.S.,U.T.23GoDARTS:Studyphenotyping:C.N.A.P.,L.A.D.,A.D.M.,A.S.F.D.Genotypingoranalysis:C.N.A.P.,L.A.D.,24A.D.M.,M.I.M.,C.G.,N.W.W.R.R.StudyPI:C.N.A.P.,A.D.M.25KORAF3/F4:Studyphenotyping:A.D.,H.Schunkert,J.E.Genotypingoranalysis:A.-K.P.,M.M.-N.,N.K.,26T.I.StudyPI:H.-E.W.,A.Peters27GLACIER:Studyphenotyping:F.R.,G.H.Genotypingoranalysis:P.W.F.,D.Shungin,I.B.,S.Edkins,F.R.28StudyPI:P.W.F.29B58C:Genotypingoranalysis:S.Kanoni,K.E.S.,WellcomeTrustCaseControlConsortium,E.M.,30T.Ferreira,T.J.StudyPI:P.D.31MORGAM:Studyphenotyping:K.Kuulasmaa,F.Gianfagna,A.Wagner,J.DallongevilleGenotypingor32analysis:M.F.H.,F.GianfagnaStudyPI:J.V.,J.F.,A.E.33SardiNIA:Studyphenotyping:E.G.L.Genotypingoranalysis:E.G.L.,O.Meirelles,S.Sanna,R.N.,A.Mulas,34K.V.T.35

25

NFBC1986:Studyphenotyping:M.R.J.,S.Sebert,K.H.H.,A.L.H.Genotypingoranalysis:M.Kaakinen,1A.L.H.StudyPI:M.R.J.2DESIR:Genotypingoranalysis:N.B.-N.,L.Y.,S.L.StudyPI:P.F.,N.B.-N.,B.B.3DILGOM:Studyphenotyping:S.M.Genotypingoranalysis:K.Kristiansson,M.P.,A.S.H.StudyPI:V.S.4IMPROVE:Studyphenotyping:D.B.Genotypingoranalysis:R.J.S.,K.G.StudyPI:A.Hamsten,E.Tremoli5HyperGEN:Studyphenotyping:S.C.H.,D.C.R.Genotypingoranalysis:A.C.,V.P.,G.B.E.StudyPI:S.C.H.6FENLAND(MetaboChip):Studyphenotyping:R.J.F.L.,J.a.L.,N.J.W.,K.K.O.Genotypingoranalysis:7R.J.F.L.,J.a.L.,N.J.W.,K.K.O.StudyPI:N.J.W.8WhitehallII:Studyphenotyping:M.KumariGenotypingoranalysis:M.Kumari,S.Shah,C.L.StudyPI:9A.Hingorani,M.Kivimaki10LURIC:Genotypingoranalysis:M.E.K.,G.DelgadoStudyPI:W.M.11MESA:Studyphenotyping:W.P.Genotypingoranalysis:W.P.,X.G.,J.Y.,V.D.,K.D.T.,J.I.R.,Y.-D.C.Study12PI:W.P.13HUNT2:Studyphenotyping:K.Kvaløy,J.H.,O.L.H.Genotypingoranalysis:A.U.J.StudyPI:K.H.14FINCAVAS:Genotypingoranalysis:T.L.,L.-P.L.,K.N.,M.KähönenStudyPI:T.L.,M.Kähönen15GenNet:Studyphenotyping:R.S.C.,A.B.W.Genotypingoranalysis:A.C.,V.P.,M.X.S.,D.E.A.,G.B.E.16StudyPI:A.C.,R.S.C.,A.B.W.17SCARFSHEEP:Studyphenotyping:B.G.Genotypingoranalysis:R.J.S.StudyPI:A.Hamsten,U.d.F.18DPS:Studyphenotyping:J.L.Genotypingoranalysis:A.U.J.,P.S.C.StudyPI:J.T.,M.U.19DR'sEXTRA:Studyphenotyping:P.K.Genotypingoranalysis:A.U.J.,M.H.StudyPI:R.Rauramaa,T.A.L.20FIN-D2D2007:Genotypingoranalysis:A.U.J.,L.L.B.StudyPI:J.Saltevo,L.M.21METSIM:Studyphenotyping:H.M.S.Genotypingoranalysis:A.U.J.,A.StančákováStudyPI:M.L.,J.K.22MDC-CVA:Studyphenotyping:O.MelanderGenotypingoranalysis:O.Melander,C.F.StudyPI:23O.Melander24BRIGHT:Studyphenotyping:A.F.D.,M.J.B.,N.J.S.,J.M.C.Genotypingoranalysis:T.J.,P.B.M.StudyPI:25M.J.C.,A.F.D.,M.J.B.,N.J.S.,J.M.C.,P.B.M.26NESDA:Studyphenotyping:J.H.S.Genotypingoranalysis:H.Snieder,I.M.N.StudyPI:B.W.P.27EPIC(MetaboChip):Studyphenotyping:R.J.F.L.,J.a.L.,N.J.W.Genotypingoranalysis:J.a.L.,N.J.W.28StudyPI:N.J.W.,K.-T.K.29ELY:Studyphenotyping:C.L.,J.a.L.,N.J.W.Genotypingoranalysis:C.L.,J.a.L.,N.J.W.StudyPI:N.J.W.30DIAGEN:Studyphenotyping:J.G.,G.M.Genotypingoranalysis:A.U.J.,G.M.StudyPI:P.E.S.,S.R.B.31GOSH:Studyphenotyping:P.K.M.,N.L.P.Genotypingoranalysis:E.I.,P.K.M.,N.L.P.,T.FallStudyPI:E.I.32Tromsø:Studyphenotyping:T.W.Genotypingoranalysis:A.U.J.,A.J.S.,N.StudyPI:I.N.33ADVANCE:Studyphenotyping:T.L.A.,C.I.Genotypingoranalysis:T.L.A.,E.L.S.,T.Q.StudyPI:T.L.A.,34T.Q.,C.I.35ULSAM:Studyphenotyping:E.I.,J.SundstromGenotypingoranalysis:E.I.,N.E.,J.Sundstrom,A.-C.S.36StudyPI:J.Sundstrom37PIVUS:Studyphenotyping:L.Lind,J.SundstromGenotypingoranalysis:L.Lind,N.E.,J.Sundstrom,T.A.38StudyPI:L.Lind,J.Sundstrom39MRCNSHD:Studyphenotyping:D.K.Genotypingoranalysis:A.Wong,J.a.L.,D.K.,K.K.O.StudyPI:D.K.40ASCOT:Studyphenotyping:A.Stanton,N.P.Genotypingoranalysis:T.J.,M.J.C.,P.B.M.StudyPI:P.S.,41M.J.C.42THISEAS:Genotypingoranalysis:L.S.R.,S.Kanoni,E.M.,G.KolovouStudyPI:G.Dedoussis,P.D.43PARC:Studyphenotyping:R.M.K.Genotypingoranalysis:K.D.T.,E.Theusch,J.I.R.,X.L.,M.O.G.,Y.D.I.C.44StudyPI:R.M.K.45AMC-PAS:Genotypingoranalysis:G.K.H.,P.D.StudyPI:G.K.H.46CARDIOGENICS:Genotypingoranalysis:S.Kanoni,A.H.G.StudyPI:P.D.,A.H.G.,J.E.,N.J.S.,H.Schunkert47Secondaryanalyses48

26

Allele-specificFAIRE:Designofsecondaryanalysis:A.J.P.S.Computationofsecondaryanalysis:A.J.P.S.,1F.D.,P.H.2ASAPeQTL:Designofsecondaryanalysis:A.F.C.Computationofsecondaryanalysis:L.Folkersen,3P.Eriksson4CARDIOGENICSeQTL:Computationofsecondaryanalysis:L.Lataniotis5CMdesign:P.B.M.,C.N.-C.,T.J.,B.F.V.6Comprehensiveliteraturereview:Designofsecondaryanalysis:P.B.M.Computationofsecondary7analysis:K.W.,P.B.M.8DEPICT:Designofsecondaryanalysis:L.Franke,T.H.P.,J.N.H.Computationofsecondaryanalysis:T.H.P.9DHSandmethylationanalysisbytissue:Designofsecondaryanalysis:C.J.W.Computationofsecondary10analysis:E.M.S.11DHSandmethylationbycell-line:Designofsecondaryanalysis:D.I.C.Computationofsecondary12analysis:D.I.C.,F.Giulianini13FHSeSNP:Designofsecondaryanalysis:R.JoehanesComputationofsecondaryanalysis:R.Joehanes14ICBPSC:C.N.-C.,M.J.C.,P.B.M.,A.C.,K.M.R.,P.-O'R.,W.P.,D.L.,M.D.T.,B.M.P.,A.D.J.,P.Elliott,C.M.v.D.,15D.I.C.,A.V.S.,M.Bochud,L.V.W.,H.Snieder,G.B.E.16KidneyeQTL:Computationofsecondaryanalysis:H.J.G.,S.K.K.17MAGENTA:Designofsecondaryanalysis:D.I.C.Computationofsecondaryanalysis:D.I.C.18Miscellaneous:Computationofsecondaryanalysis:H.Warren19MuTHEReQTL:Designofsecondaryanalysis:P.D.Computationofsecondaryanalysis:L.Lataniotis,T.-20P.Y.21NESDAeQTL:Designofsecondaryanalysis:R.JansenComputationofsecondaryanalysis:R.Jansen,A.V.22NTReQTL:Designofsecondaryanalysis:R.JansenComputationofsecondaryanalysis:R.Jansen,J.-J.H.23StudyPI:D.I.B.24eQTL,EGCUT:Designofsecondaryanalysis:A.MetspaluComputationofsecondaryanalysis:T.E.,25A.Metspalu26eQTL,Groningen:Designofsecondaryanalysis:L.FrankeComputationofsecondaryanalysis:H.J.W.,27L.Franke28PubliceSNPandmethylation:Designofsecondaryanalysis:A.D.J.,J.D.E.Computationofsecondary29analysis:A.D.J.,J.D.E.30PubMedsearch:Designofsecondaryanalysis:G.B.E.Computationofsecondaryanalysis:G.B.E.,L.Lin31WGHSconditional:Designofsecondaryanalysis:D.I.C.Computationofsecondaryanalysis:D.I.C.,32F.Giulianini,L.M.R.33LookupofCardio-MetaboChipvariants34HEXA:Genotypingoranalysis:Y.J.K.,Y.K.K.,Y.-A.S.StudyPI:J.-Y.L.35RACe:Studyphenotyping:D.Saleheen,W.Zhao,A.R.,A.R.Genotypingoranalysis:W.Zhao,A.R.,A.R.36StudyPI:D.Saleheen37HALST:Studyphenotyping:C.A.H.Genotypingoranalysis:J.I.R.,Y.-D.C.,C.A.H.,R.-H.C.,I.-S.C.StudyPI:38C.A.H.39CLHNS:Studyphenotyping:N.R.L.,L.S.A.Genotypingoranalysis:Y.W.,N.R.L.,L.S.A.StudyPI:K.L.M.,40L.S.A.41GxE/SpanishTown:Studyphenotyping:B.O.T.,C.A.M.,R.W.Genotypingoranalysis:C.D.P.StudyPI:42R.S.C.,C.A.M.,R.W.,T.Forrester,J.N.H.43DRAGON:Studyphenotyping:W.-J.L.,W.H.-H.S.,K.-W.L.,I-TeLeeGenotypingoranalysis:J.I.R.,Y.-D.C.,44E.K.,D.A.,K.D.T.,X.G.StudyPI:W.H.-H.S.45SEY:Studyphenotyping:P.B.Genotypingoranalysis:M.Bochud,G.B.E.,F.M.StudyPI:P.B.,M.Bochud,46M.Burnier,F.P.47

27

TUDR:Studyphenotyping:W.H.-H.S.,I-TeLee,W.-J.L.Genotypingoranalysis:J.I.R.,Y.-D.C.,E.K.,K.D.T.,1X.G.StudyPI:W.H.-H.S.2TANDEM:Studyphenotyping:P.B.,M.BochudGenotypingoranalysis:G.B.E.,F.M.StudyPI:P.B.,3M.Bochud,M.Burnier,F.P.4Imputedgenotypes5FHS:Studyphenotyping:D.L.Genotypingoranalysis:D.L.StudyPI:D.L.6ARIC:Studyphenotyping:E.B.Genotypingoranalysis:G.B.E.,E.B.,A.C.M.,A.C.,S.K.G.StudyPI:E.B.,7A.C.8RS:Genotypingoranalysis:G.C.V.,A.G.U.StudyPI:A.Hofman,A.G.U.,O.H.F.D.9CoLaus:Studyphenotyping:P.V.Genotypingoranalysis:Z.K.StudyPI:P.V.10NFBC1966:Studyphenotyping:M.R.J.Genotypingoranalysis:P.O.R.StudyPI:M.R.J.11SHIP:Studyphenotyping:R.RettigGenotypingoranalysis:A.T.12CHS:Studyphenotyping:B.M.P.Genotypingoranalysis:K.M.R.StudyPI:B.M.P.13EPIC(GWAS):Studyphenotyping:N.J.W.,R.J.F.L.,J.a.L.Genotypingoranalysis:N.J.W.,J.H.Z.,J.a.L.14StudyPI:N.J.W.,K.-T.K.15SU.VI.MAX:Studyphenotyping:S.H.Genotypingoranalysis:S.H.,P.M.StudyPI:P.M.16Amish:Genotypingoranalysis:M.E.M.StudyPI:A.Parsa17FENLAND(GWAS):Studyphenotyping:N.J.W.,J.a.L.,R.J.F.L.,K.K.O.Genotypingoranalysis:N.J.W.,18J.a.L.,R.J.F.L.,K.K.O.StudyPI:N.J.W.19DGI:Studyphenotyping:C.N.C.Genotypingoranalysis:C.N.C.,G.KosovaStudyPI:C.N.C.20ERF(EUROSPAN):Genotypingoranalysis:N.A.StudyPI:C.M.v.D.21MIGEN:Studyphenotyping:S.Kathiresan,R.E.Genotypingoranalysis:S.Kathiresan,R.E.Designof22secondaryanalysis:S.Kathiresan,R.E.23MICROS:Studyphenotyping:P.P.P.Genotypingoranalysis:A.A.H.StudyPI:A.A.H.,P.P.P.24FUSION:Genotypingoranalysis:A.U.J.StudyPI:M.Boehnke,F.S.C.,K.L.M.,J.Saramies25TwinsUK:Genotypingoranalysis:C.M.StudyPI:T.D.S.26PROCARDIS:Genotypingoranalysis:M.Farrall,A.G.StudyPI:M.Farrall27BLSA:Studyphenotyping:L.FerrucciGenotypingoranalysis:T.T.StudyPI:L.Ferrucci28ORCADES:Studyphenotyping:J.F.W.StudyPI:J.F.W.29Croatia-Vis:Genotypingoranalysis:V.V.,C.H.StudyPI:V.V.,C.H.30NSPHS:Genotypingoranalysis:S.EnrothStudyPI:U.G.31InCHIANTI:Genotypingoranalysis:T.T.StudyPI:S.Bandinelli32AGESReykjavik:Studyphenotyping:V.G.Genotypingoranalysis:A.V.S.StudyPI:V.G.33Lookup34CARDIoGRAMplusC4D:Genotypingoranalysis:P.D.StudyPI:J.Danesh,H.Schunkert,T.L.A.,J.E.,35S.Kathiresan,R.Roberts,N.J.S.,P.D.36CHARGEcIMT:Genotypingoranalysis:C.O'D.,J.C.B.37CHARGEEYE:Genotypingoranalysis:T.Y.W.,X.S.,R.A.J.StudyPI:T.Y.W.38CHARGE-HFconsortium:Studyphenotyping:R.S.V.,J.F.F.Genotypingoranalysis:H.L.,J.F.F.StudyPI:39R.S.V.40CKDGen:Genotypingoranalysis:M.G.,V.M.41COGENT:Studyphenotyping:N.F.,J.R.Genotypingoranalysis:N.F.,X.Z.,B.J.K.,B.O.T.,J.R.42EchoGenconsortium:Studyphenotyping:R.S.V.,J.F.F.Genotypingoranalysis:H.L.,J.F.F.StudyPI:43R.S.V.44KidneyGenConsortium:Studyphenotyping:J.C.C.,J.S.K.,P.ElliottGenotypingoranalysis:W.Zhang,45J.C.C.,J.S.K.StudyPI:J.C.C.,J.S.K.46MetaStroke:Genotypingoranalysis:S.Bevan,H.S.M.47NeuroCHARGE:Genotypingoranalysis:M.Fornage,M.A.I.StudyPI:M.A.I.48

28

PROMIS:Studyphenotyping:D.Saleheen,W.Zhao,J.DaneshGenotypingoranalysis:W.ZhaoStudyPI:1D.Saleheen2SEED:Studyphenotyping:T.Y.W.,C.-Y.C.Genotypingoranalysis:E.-S.T,C.-Y.C.,C.-Y.C.StudyPI:C.-Y.C.,3T.Y.W.4UKBiobank:BPgroupleaders:MarkCaulfield,P.ElliottGenotypingoranalysis:M.R.B.,H.Warren,5ClaudiaCabrera,EvangelosEvangelou,HeGao.6

COMPETINGFINANCIALINTERESTS7

Theauthorsdeclarecompetingfinancialinterests(seecorrespondingsectionintheSupplementary8Note).9 10

29

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FIGURELEGENDS1

Figure1.ManhattanplotsforSBPandDBPfromthestage4Cardio-MetaboChip-widemeta-analysis.2

Pvalues(expressedas-log10P)areplottedbyphysicalgenomicpositionlabeledbychromosome.SNPsin3

newloci(3.5MBwindowaroundtheindexSNP),identifiedinthisstudy,arelabeledindarkred(SBP)or4

darkblue(DBP);SNPsinpreviouslyknownlociarelabeledinorange(SBP)orlightblue(DBP).Thelocus5

namesareindicated.Thegreycrossesindicategenomicpositionsatwhichthey-axiswastruncated6

(SNPswithP<10-15).7

Figure2.EnrichmentofDNAsehypersensitivesitesamongBPlociindifferentcell-types.Enrichment8

analysesofSBPorDBPassociatedlociaccordingtodiscoveryPvalueusingnarrowpeaks(panelA)or9

broadpeaks(panelB).SNPswereselectedaccordingtodifferentPvaluecutoffs(x-axis)andafold10

enrichmentofoverlapwithDNAsehypersensitivesitescomparedtounrelatedGWASSNPswas11

calculated(y-axis)(seeSupplementaryNote).The12endothelialcell-linesareindicatedincolorandfor12

eachendothelialcell-typetherankusingthe10-14Pvaluecutoffisindicated.ECdenotesendothelial13

cells.14

TABLELEGENDS15

Table1.SBPandDBPassociationat66loci.16

Meta-analysis results of up to342,415 individualsof Europeanancestry for SBPandDBP: Established17

andnew lociaregroupedseparately. Nearestgenesareshownas locus labelsbut thisshouldnotbe18

interpretedassupportthatthecausalgeneisthenearestgene.TheleadSNPwiththelowestPvalue19

foreitherBPtraitisshownastheleadSNPandbothSBPandDBPresultsarepresentedevenifbothare20

notgenome-widesignificant.TheSNPeffectsareshownaccordingtotheeffectinmmHgpercopyof21

thecodedallele (that is theallelecoded0,1,2)underanadditivegeneticmodel.“*” inthe leadSNP22

column indicates a non-synonymous coding SNP (either the SNP itself or another SNP in r2 >0.8). #23

Establishedlocihavesmallertotalsamplesizesrelativetonovelloci(seeSupplementaryNote).24

Table2.OverviewofnovelandknownBPvariantproperties.25

Keycharacteristicsof thenovelandestablishedBP loci are shown.MAFandeffect sizeestimatesare26

derivedfromtheCardio-MetaboChipdata.Varianceexplainedestimatesareestimatedfromonelarge27

study (SupplementaryNote). Novel loci are classified as previously unknown to be linked to BP by a28

systematicPubMedreviewofallgenesina200kbwindow(SupplementaryNote).29

30

32

Table3.Predictionofhypertensivetargetorgandamagebyamulti-BPSNPscore.1

Shown are the estimated effects of a BP risk score comprised of up to 66 SNPs (see column “Total2

#SNPs”) on risk of dichotomous outcome (as odds ratios) or increment in continuous measures per3

predictedmmHgoftheSBPorDBPscore.Theeffectsizesareexpressedasincrementalchangeinthe4

phenotypeforquantitativetraitsandnaturallogarithmoftheoddsratioforbinarytraits,per1mmHg5

predicted increase in SBP or DBP. P values are bolded if they meet an analysis-wide significance6

threshold(<0.05/18=0.0028).ResultsforallSNPs(“all”)andforprunedresults(“p”)areshown.The7

prunedresultswereobtainedbyiterativeremovalofSNPsfromtheriskscorestartingwiththeSNPwith8

lowestheterogeneityPvalue.IterationstoremoveSNPswerecontinueduntiltheheterogeneityP value9

was<0.0028 (seeSupplementaryNote). ThenumberofSNPs removedwhencalculating thepruned10

results is indicatedby “# SNPs rem.”. The results per individual SNP canbe found inSupplementary11

Table15.CAD:coronaryarterydisease,LV:leftventricle,CKD:chronickidneydisease,eGFR:estimated12

glomerular filtration rate, cr: creatinine, cIMT: carotid intima:media thickness. Var. type denotes the13

variabletypeandcont.forcontinuous,ordic.fordichotomous.Eth.=Ethnicity,Consort.=Consortium,14

EUR=Europeanancestry,EAS=EastAsianancestry.15

16

33

Table1.NewandknownBPloci.1Locusno. Locusname LeadSNP Chr Position

(hg19)CA/NC

Codedallelefreq

Traits SBP DBP

Effect SE Pvalue TotalN Effect SE Pvalue TotalN#

NEW1 HIVEP3 rs7515635 1 42,408,070 T/C 0.468 SBP 0.307 0.0444 4.81E-12 340,969 0.1365 0.0263 2.05E-07 340,934NEW2 PNPT1 rs1975487 2 55,809,054 A/G 0.464 DBP -0.2107 0.045 2.81E-06 337,522 -0.1602 0.0266 1.75E-09 337,517NEW3 FGD5 rs11128722 3 14,958,126 A/G 0.563 SBP&DBP -0.3103 0.0469 3.61E-11 310,430 -0.1732 0.0279 5.16E-10 310,429NEW4 ADAMTS9 rs918466 3 64,710,253 A/G 0.406 DBP -0.0865 0.0459 5.94E-02 336,671 -0.1819 0.027 1.73E-11 336,653NEW5 TBC1D1-FLJ13197 rs2291435 4 38,387,395 T/C 0.524 SBP&DBP -0.3441 0.0449 1.90E-14 331,382 -0.156 0.0266 4.26E-09 331,389NEW6 TRIM36 rs10077885 5 114,390,121 A/C 0.501 SBP&DBP -0.284 0.0444 1.64E-10 338,328 -0.1735 0.0263 3.99E-11 338,323NEW7 CSNK1G3 rs6891344 5 123,136,656 A/G 0.819 DBP 0.2811 0.058 1.24E-06 338,688 0.2311 0.0343 1.58E-11 338,678NEW8 CHST12-LFNG rs2969070 7 2,512,545 A/G 0.639 SBP&DBP -0.2975 0.0464 1.44E-10 335,991 -0.1821 0.0274 2.92E-11 335,972NEW9 ZC3HC1 rs11556924

*

7 129,663,496 T/C 0.384 SBP&DBP -0.2705 0.0468 7.64E-09 325,929 -0.2141 0.0276 8.15E-15 325,963NEW10 PSMD5 rs10760117 9 123,586,737 T/G 0.415 SBP 0.283 0.0457 6.10E-10 333,377 0.0999 0.0269 2.08E-04 333,377NEW11 DBH rs6271* 9 136,522,274 T/C 0.072 SBP&DBP -0.5911 0.0899 4.89E-11 306,394 -0.4646 0.0532 2.42E-18 306,463NEW12 RAPSN,PSMC3,SLC39A13 rs7103648 11 47,461,783 A/G 0.614 SBP&DBP -0.3349 0.0462 4.43E-13 335,614 -0.2409 0.0272 9.03E-19 335,592

NEW13 LRRC10B rs751984 11 61,278,246 T/C 0.879 SBP&DBP 0.4074 0.0691 3.80E-09 334,583 0.3755 0.0409 4.20E-20 334,586NEW14 SETBP1 rs12958173 18 42,141,977 A/C 0.306 SBP&DBP 0.3614 0.0489 1.43E-13 331,007 0.1789 0.0289 5.87E-10 331,010NEW15 INSR rs4247374 19 7,252,756 T/C 0.143 SBP&DBP -0.5933 0.0673 1.23E-18 302,458 -0.3852 0.0396 2.08E-22 302,459NEW16 ELAVL3 rs17638167 19 11,584,818 T/C 0.047 DBP -0.4784 0.1066 7.13E-06 333,137 -0.3479 0.0632 3.71E-08 333,107NEW17 CRYAA-SIK1 rs12627651 21 44,760,603 A/G 0.288 SBP&DBP 0.3905 0.0513 2.69E-14 310,738 0.2037 0.0301 1.36E-11 310,722EST1 CASZ1 rs880315 1 10,796,866 T/C 0.641 SBP&DBP -0.475 0.062 2.09E-14 184,226 -0.257 0.038 1.34E-11 184,212EST2 MTHFR-NPPB rs17037390

*

1 11,860,843 A/G 0.155 SBP&DBP -0.908 0.081 5.95E-29 195,493 -0.499 0.05 1.20E-23 195,481EST3 ST7L-CAPZA1-MOV10 rs1620668 1 113,023,980 A/G 0.822 SBP&DBP -0.535 0.076 1.45E-12 197,966 -0.285 0.047 9.00E-10 197,948EST4 MDM4 rs4245739 1 204,518,842 A/C 0.737 DBP 0.326 0.068 1.37E-06 191,594 0.243 0.041 4.63E-09 191,578EST5 AGT rs2493134* 1 230,849,359 T/C 0.579 SBP&DBP -0.413 0.058 9.65E-13 199,505 -0.275 0.036 9.53E-15 199,502EST6 KCNK3 rs2586886 2 26,932,031 T/C 0.599 SBP&DBP -0.404 0.059 5.94E-12 197,269 -0.254 0.036 1.92E-12 197,272EST7 NCAPH rs772178 2 96,963,684 A/G 0.64 DBP -0.072 0.061 2.39E-01 192,513 -0.208 0.038 3.58E-08 192,501EST8 FIGN-GRB14 rs1371182 2 165,099,215 T/C 0.443 SBP&DBP -0.444 0.058 1.89E-14 196,262 -0.252 0.036 1.50E-12 196,240EST9 HRH1-ATG7 rs2594992 3 11,360,997 A/C 0.607 SBP -0.334 0.06 2.31E-08 189,895 -0.136 0.037 2.20E-04 189,854EST10 SLC4A7 rs711737 3 27,543,655 A/C 0.604 SBP 0.334 0.058 9.93E-09 200,282 0.17 0.036 2.24E-06 200,260EST11 ULK4 rs2272007* 3 41,996,136 T/C 0.18 DBP -0.11 0.077 1.52E-01 193,915 0.328 0.047 3.94E-12 193,900EST12 MAP4 rs6442101* 3 48,130,893 T/C 0.692 SBP&DBP 0.396 0.062 1.62E-10 200,543 0.303 0.038 1.60E-15 200,534EST13 MECOM rs6779380 3 169,111,915 T/C 0.539 SBP&DBP -0.439 0.06 1.85E-13 186,535 -0.239 0.037 6.87E-11 186,521EST14 FGF5 rs1458038 4 81,164,723 T/C 0.3 SBP&DBP 0.659 0.065 5.36E-24 188,136 0.392 0.04 7.36E-23 188,088EST15 ARHGAP24 rs17010957 4 86,719,165 T/C 0.857 SBP -0.498 0.082 1.51E-09 196,325 -0.173 0.051 6.63E-04 196,292EST16 SLC39A8 rs13107325

*

4 103,188,709 T/C 0.07 SBP&DBP -0.837 0.127 4.69E-11 175,292 -0.602 0.078 1.63E-14 175,372EST17 GUCY1A3-GUCY1B3 rs4691707 4 156,441,314 A/G 0.652 SBP -0.349 0.06 7.10E-09 198,246 -0.163 0.037 1.08E-05 198,226EST18 NPR3-C5orf23 rs12656497 5 32,831,939 T/C 0.403 SBP&DBP -0.487 0.06 3.85E-16 194,831 -0.228 0.037 4.73E-10 194,829EST19 EBF1 rs11953630 5 157,845,402 T/C 0.366 SBP&DBP -0.38 0.065 3.91E-09 167,698 -0.23 0.04 8.07E-09 167,708EST20 HFE rs1799945* 6 26,091,179 C/G 0.857 SBP&DBP -0.598 0.086 3.28E-12 185,306 -0.43 0.053 3.10E-16 185,273EST21 BAT2-BAT5 rs2187668 6 32,605,884 T/C 0.126 DBP -0.291 0.092 1.60E-03 189,806 -0.372 0.057 4.31E-11 189,810EST22 ZNF318-ABCC10 rs6919440 6 43,352,898 A/G 0.57 SBP -0.337 0.058 4.92E-09 200,733 -0.125 0.035 4.25E-04 200,730EST23 RSPO3 rs1361831 6 127,181,089 T/C 0.541 SBP&DBP -0.482 0.058 7.38E-17 197,027 -0.271 0.036 2.34E-14 197,012EST24 PLEKHG1 rs17080093 6 150,997,440 T/C 0.075 DBP -0.564 0.111 3.83E-07 194,728 -0.411 0.068 1.71E-09 194,734EST25 HOTTIP-EVX rs3735533 7 27,245,893 T/C 0.081 SBP&DBP -0.798 0.106 6.48E-14 197,881 -0.445 0.065 1.09E-11 197,880EST26 PIK3CG rs12705390 7 106,410,777 A/G 0.227 SBP 0.619 0.069 2.69E-19 198,297 0.059 0.042 1.63E-01 198,290EST27 BLK-GATA4 rs2898290 8 11,433,909 T/C 0.491 SBP 0.377 0.058 8.85E-11 197,759 0.167 0.036 3.17E-06 197,726EST28 CACNB2 rs12243859 10 18,740,632 T/C 0.326 SBP&DBP -0.402 0.061 6.13E-11 199,136 -0.335 0.038 8.11E-19 199,124EST29 C10orf107 rs7076398 10 63,533,663 A/T 0.188 SBP&DBP -0.563 0.076 1.72E-13 187,013 -0.409 0.047 2.55E-18 187,024EST30 SYNPO2L rs12247028 10 75,410,052 A/G 0.611 SBP -0.364 0.063 8.16E-09 180,194 -0.159 0.039 3.89E-05 180,094EST31 PLCE1 rs932764* 10 95,895,940 A/G 0.554 SBP&DBP -0.495 0.059 6.88E-17 195,577 -0.224 0.036 6.28E-10 195,547EST32 CYP17A1-NT5C2 rs943037 10 104,835,919 T/C 0.087 SBP&DBP -1.133 0.105 2.35E-27 193,818 -0.482 0.064 4.48E-14 193,799EST33 ADRB1 rs740746 10 115,792,787 A/G 0.73 SBP&DBP 0.486 0.067 4.59E-13 184,835 0.32 0.041 8.63E-15 184,868EST34 LSP1-TNNT3 rs592373 11 1,890,990 A/G 0.64 SBP&DBP 0.484 0.063 2.02E-14 177,149 0.282 0.039 3.61E-13 177,134EST35 ADM rs1450271 11 10,356,115 T/C 0.468 SBP&DBP 0.413 0.059 3.40E-12 191,246 0.199 0.036 4.11E-08 191,221EST36 PLEKHA7 rs1156725 11 16,307,700 T/C 0.804 SBP&DBP -0.447 0.072 5.65E-10 200,889 -0.292 0.044 3.67E-11 200,899EST37 SIPA1 rs3741378* 11 65,408,937 T/C 0.137 SBP -0.486 0.084 8.04E-09 194,563 -0.183 0.052 4.17E-04 194,551EST38 FLJ32810-TMEM133 rs633185 11 100,593,538 C/G 0.715 SBP&DBP 0.522 0.067 6.97E-15 183,845 0.288 0.041 2.38E-12 183,825EST39 PDE3A rs3752728 12 20,192,972 A/G 0.737 DBP 0.331 0.066 4.32E-07 200,440 0.319 0.04 2.35E-15 200,408EST40 ATP2B1 rs11105354 12 90,026,523 A/G 0.84 SBP&DBP 0.909 0.081 3.88E-29 195,206 0.459 0.05 2.61E-20 195,195EST41 SH2B3 rs3184504* 12 111,884,608 T/C 0.475 SBP&DBP 0.498 0.062 9.97E-16 177,067 0.362 0.038 1.28E-21 177,122EST42 TBX5-TBX3 rs2891546 12 115,552,499 A/G 0.11 DBP -0.529 0.1 1.36E-07 172,012 -0.38 0.061 4.71E-10 171,980EST43 CYP1A1-ULK3 rs936226 15 75,069,282 T/C 0.722 SBP&DBP -0.549 0.067 3.06E-16 187,238 -0.363 0.041 1.03E-18 187,221EST44 FURIN-FES rs2521501 15 91,437,388 A/T 0.684 SBP&DBP -0.639 0.069 3.35E-20 164,272 -0.358 0.042 1.85E-17 164,255EST45 PLCD3 rs7213273 17 43,155,914 A/G 0.658 SBP -0.413 0.066 4.71E-10 164,795 -0.185 0.041 7.23E-06 164,788EST46 GOSR2 rs17608766 17 45,013,271 T/C 0.854 SBP -0.658 0.083 2.27E-15 188,895 -0.218 0.051 1.95E-05 188,928EST47 ZNF652 rs12940887 17 47,402,807 T/C 0.38 DBP 0.321 0.06 7.06E-08 192,546 0.261 0.037 1.07E-12 192,524EST48 JAG1 rs1327235 20 10,969,030 A/G 0.542 SBP&DBP -0.395 0.059 2.23E-11 192,680 -0.308 0.036 1.78E-17 192,659EST49 GNAS-EDN3 rs6026748 20 57,745,815 A/G 0.125 SBP&DBP 0.867 0.089 3.15E-22 192,338 0.552 0.055 4.86E-24 192,327

34

Table2.OverviewofnovelandknownBPvariantproperties. 1 2

17newloci 49establishedloci 66lociMinorallelefrequency(mean,range)

32.1%[5%-50%] 28.9%[7%-49%] 29.8%[5%-50%]

EffectsizeSBP[mmHg](range,mean)

0.09-0.59,0.34 0.07-1.13,0.5 0.07-1.13,0.46

EffectsizeDBP[mmHg](range,mean)

0.1-0.46,0.23 0.06-0.60,0.3 0.06-0.6,0.28

VarianceexplainedSBP 0.52% 2.95% 3.46%VarianceexplainedDBP 0.58% 2.78% 3.36%

35

Table3.BPriskscoreeffectsondiseaseoutcomes. 1 2

Phenotype Var.type(cont./dic.)

Eth. Consort. TotalNorno.ca/co

Total#SNPs

SBP_score DBP_score

effect(all)

Pvalue(all)

het.Pvalue(all)

Pvalue(p)

#SNPsrem.

effect(all)

Pvalue(all)

het.Pvalue(all)

Pvalue(p)

#SNPsrem.

HEART CAD dich. EUR

SASCARDIoGRAMplusC4D

63,746/130,681

61 1.042 1.72E-44 1.75E-25 4.08E-32 10 1.069 1.19E-42 6.63E-27 2.2E-38 10

heartfailure dich. EUR CHARGE 2,526/18,400

66 1.021 2.77E-02 1.63E-01 2.77E-02 0 1.035 2.31E-02 1.70E-01 2.31E-02 0

LVmass cont. EUR CHARGE 11,273 66 0.480 6.43E-04 3.58E-01 6.43E-04 0 0.754 1.23E-03 3.21E-01 1.23E-03 0

LVwallthickness cont. EUR CHARGE 11,311 66 0.004 4.45E-06 5.83E-02 4.45E-06 0 0.007 3.19E-06 6.40E-02 3.19E-06 0

KIDNEY

CKD dich. EUR CHARGE 6,271/68,083

65 1.010 1.37E-01 1.77E-03 2.65E-01 1 1.008 4.49E-01 1.25E-03 7.69E-01 1

eGFR(basedoncr) cont. EUR CHARGE 74,354 65 0.000 7.07E-01 3.12E-05 3.22E-01 2 0.000 9.41E-01 3.02E-05 9.65E-01 2

eGFR(basedoncystatin)

cont. EUR CHARGE 74,354 65 0.001 9.05E-02 9.28E-06 4.11E-01 1 0.001 3.30E-01 5.64E-06 6.9E-01 1

creatinine cont. EUR KidneyGEN

23,812 66 0.000 9.42E-01 6.31E-03 9.42E-01 0 0.000 4.11E-01 7.16E-03 4.11E-01 0

microalbuminuria dich. EUR CHARGE 2,499/29,081

65 0.011 2.10E-01 4.79E-02 2.1E-01 0 0.023 1.02E-01 5.66E-02 1.02E-02 0

urinaryalbumin/crratio

cont. EUR CHARGE 31,580 65 0.009 2.52E-03 3.02E-04 0.53E-03 1 0.015 2.40E-03 3.08E-04 8.31E-03 1

STROKE

stroke,allsubtypes dich. EUR CHARGE 1,544/18,058

66 0.056 6.11E-06 8.26E-02 6.11E-06 0 0.085 3.79E-05 4.98E-02 3.79E-05 0

stroke,ischemicsubtype

dich. EUR CHARGE 1,164/18,438

66 0.067 3.33E-06 1.75E-01 3.33E-06 0 0.096 5.63E-05 8.82E-02 5.63E-05 0

stroke,ischemicsubtype

dich. EUR MetaStroke

11,012/40,824

66 0.036 1.69E-10 4.72E-02 1.69E-10 0 0.056 1.29E-09 2.51E-02 1.29E-09 0

VASCULATURE

cIMT cont. EUR CHARGE 27,610 66 0.004 4.80E-15 5.06E-08 7.32E-10 4 0.005 4.15E-11 3.84E-10 6.2E-07 5

EYE

mildretinop. dich. EUR CHARGE 1,122/18,289

66 1.021 1.37E-01 6.01E-03 1.37E-01 0 1.046 5.78E-02 7.81E-03 5.78E-02 0

centralretinalarterycaliber

cont. EUR CHARGE 18,576 66 0.343 3.29E-14 2.56E-06 2.06E-13 2 0.570 3.61E-14 2.44E-06 7.05E-13 3

mildretinop. dich. EAS SEED 289/5,419

66 1.033 2.55E-01 2.42E-01 2.55E-01 0 1.087 8.55E-02 2.87E-01 8.55E-02 0

centralretinalarterycaliber

cont. EAS SEED 6,976 63 0.320 1.39E-04 9.07E-01 1.39E-04 0 0.533 2.19E-04 8.91E-01 2.19E-04 0

36

ONLINEMETHODS 1

Cohortscontributingtosystolic(SBP)anddiastolicbloodpressure(DBP)analyses 2StudiescontributingtoBPassociationdiscoveryincludingcommunity-andpopulation-based 3

collectionsaswellasstudiesofnon-BPtraits,analyzedascaseandcontrolsamplesseparately.Details 4oneachofthestudiesincludingstudydesignandBPmeasurementareprovidedinSupplementary 5Table1,genotypinginformationinSupplementaryTable2,andparticipantcharacteristicsin 6SupplementaryTable3.Allparticipantsprovidedwritteninformedconsentandthestudieswere 7approvedbylocalResearchEthicsCommitteesand/orInstitutionalReviewBoards. 8

Europeanancestrymeta-analysis 9BPwasmeasuredusingstandardizedprotocolsinallstudiesregardlessofwhethertheprimary 10

focuswasBPoranothertrait.Weinitiallyanalyzedaffectedandunaffectedindividualsfromsamples 11selectedascases(e.g.type2diabetes)orcontrols,separately.However,becausesensitivityanalyses 12didnotrevealanysignificantdifferenceinBPeffectsizeestimatesbetweencaseandcontrolsamples 13(datanotshown),weanalyzedallsamplescombined.Whenavailable,theaverageoftwoBP 14measurementswasusedforassociationanalyses(SupplementaryTable1).Ifanindividualwastakinga 15BP-loweringtreatment,theunderlyingsystolicBP(SBP)anddiastolicBP(DBP)wereestimatedbyadding 1615mmHgand10mmHg,respectively,tothemeasuredvalues,asdoneinprioranalyses. 17

Ameta-analysisof340,934individualsofEuropeandescentwasundertakeninfourstageswith 18subsequentvalidationinanindependentcohort.Becausestage1Cardio-MetaboChipsamplesincluded 19manySNPsselectedonthebasisofassociationwithBPinearlierGWAS,weperformedgenomiccontrol 20usingasetofputativenullSNPsbasedonP>0.10inearlierGWASofSBPandDBPorboth.Stage2 21sampleswithgenome-widegenotypingusedtheentiregenome-widesetofSNPsforgenomiccontrol 22giventhelackofascertainment.ThestudydesignissummarizedinSupplementaryFigure1,andfurther 23detailsareprovidedinSupplementaryTables2-5andtheSupplementaryNote. 24

SystematicPubMedsearch+/-100kbofeachnewlydiscoveredindexSNP 25Allgeneswithanyoverlapwitha200kbregioncenteredaroundeachofthe17newlydiscovered 26

leadSNPswereidentifiedusingtheUCSCGenomeBrowser.Asearchtermwasconstructedforeach 27geneincludingtheshortandlonggenenameandtheterms“bloodpressure”and“hypertension”(e.g. 28forNPPAonchr1:“NPPAORnatriureticpeptideAAND(bloodpressureORhypertension)”)andthe 29searchresultsofeachsearchtermfromPubMedwereindividuallyreviewed. 30

Traitvarianceexplained 31Thetraitvarianceexplainedby66leadSNPsatnovelandknownlociwasevaluatedinonestudy 32

thatcontributedtothediscoveryeffort:theAtherosclerosisRiskinCommunities(ARIC)study.We 33constructedalinearregressionmodelwithall66orthesubsetof49knownSNPsasasetofpredictors 34oftheBPresidualafteradjustmentforcovariatesoftheadjustedtreatment-correctedBPphenotype 35(SBPorDBP).Ther2fromtheregressionmodelwasusedastheestimateoftraitvarianceexplained. 36

EuropeanancestryGCTA-COJOanalysis 37ToidentifymultipledistinctassociationsignalsatanygivenBPlocus,weundertookapproximate 38

conditionalanalysesusingamodelselectionprocedureimplementedintheGCTA-COJOsoftware 39package44,45.ToevaluatetherobustnessoftheGCTA-COJOresultstothechoiceofreferencedataset, 40modelselectionwasperformedusingtheLDbetweenvariantsinseparateanalysesfromtwodatasetsof 41Europeandescent,bothwithindividualsfromtheUKwithCardio-MetaboChipgenotypedata:GoDARTS 42with7,006individualsandWTCCC1-T2D/58BCwith2,947individuals.AssumingthattheLDbetween 43

37

SNPsmorethan10Mbawayorondifferentchromosomesiszero,weundertooktheGCTA-COJOstep- 1wisemodelselectiontoselectSNPsthatwereconditionally-independentlyassociatedwithSBPandDBP, 2inturn,atagenome-widesignificance,givenbyP<5×10-8(SupplementaryTables6-8)usingthestage4 3combinedEuropeanGWAS+Cardio-MetaboChipmeta-analysis. 4

ConditionalanalysesintheWomen’sGenomeHealthStudy(WGHS) 5Multivariable regression modeling was performed for each possible combination of putative 6

independentSNPsfroma)modelselectionimplementedinGCTA-COJOandb)acomprehensivemanual 7reviewof the literature (SupplementaryTable9). AnySNPwithP <5x10-8 inaprevious reportedBP 8GWASwas considered. A totalof46SNPswereexamined (SupplementaryTable10). Genome-wide 9genotypingdataimputedto1000GenomesintheWGHS(N=23,047)wereused.Regressionmodeling 10wasperformedintheRstatisticallanguage(SupplementaryTable10). 11

FinemappinganddeterminationofcrediblesetsofcausalSNPs 12TheGCTA-COJOandWGHSconditionalanalysesidentifiedmultipledistinctsignalsofassociationat 13

multipleloci(SupplementaryTables6and10).Ofthe24lociconsideredinfine-mappinganalyses,16 14hadnoevidencefortheexistenceofmultipledistinctassociationsignals,soitisreasonabletoassume 15thatthereisasinglecausalSNPandthereforethecrediblesetsofvariantscouldbeconstructedusing 16theassociationsummarystatisticsfromtheunconditionalmeta-analyses.However,intheremaining 17eightloci,whereevidenceofsecondarysignalswasobservedfromGCTA-COJO,weperformed 18approximateconditionalanalysesacrosstheregionbyconditioningoneachindexSNP(Supplementary 19Table11).ByadjustingfortheotherindexSNPsatthelocus,wecanthereforeassumeasinglevariantis 20drivingeach“conditionally-independent”associationsignal,andwecanconstructthe99%credibleset 21ofvariantsonthebasisoftheapproximateconditionalanalysisfromGCTA-COJO(Supplementary 22Tables12-13).Atfiveoftheeightlociwithmultipledistinctsignalsofassociation,oneindexSNP 23mappedoutsideofthefine-mappingregion,soacrediblesetcouldnotbeconstructed. 24

eQTLanalysis:WholeBlood 25NESDA/NTR:WholebloodeQTLanalyseswereperformedinsamplesfromtheNetherlands 26

StudyofDepressionandAnxiety(NESDA)46andtheNetherlandsTwinRegistry(NTR)47studies.RNA 27expressionanalysiswasperformedinthestatisticalsoftwareR.Theresidualsresultingfromthelinear 28regressionanalysisoftheprobesetintensityvaluesontothecovariatessex,age,bodymassindex 29(kg/m2),smokingstatuscodedasacategoricalcovariate,severaltechnicalcovariates,andthree 30principalcomponentswereused.TheeQTLeffectsweredetectedusingalinearmixedmodelapproach, 31includingforeachprobesettheexpressionlevel(normalized,residualizedandwithoutthefirst50 32expressionPCs)asdependentvariable;theSNPgenotypevaluesasfixedeffects;andfamilyidentifier 33andzygosity(inthecaseoftwins)asrandomeffectstoaccountforfamilyandtwinrelations48. 34

TheeQTLeffectsweredefinedasciswhenprobeset–SNPpairswereatdistance<1Mbase 35pairs.AtaFDRof0.01appliedgenome-wide,notjustforcandidateSNPs,thePvaluethresholdwas 361x10-4forthecis-eQTLanalysis.Foreachprobesetthatdisplayedastatisticallysignificantassociation 37withatleastoneSNPlocatedwithinitscisregion,weidentifiedthemostsignificantlyassociatedSNP 38anddenotedthisasthetopcis-eQTLSNP.SeeSupplementaryNotefordetails. 39

eQTLanalysis:SelectedpublishedeQTLdatasets 40LeadBPSNPandproxies(r2>0.8)weresearchedagainstacollecteddatabaseofexpressionSNP 41

(eSNP)results.ThereportedeSNPresultsmetcriteriaforstatisticalthresholdsforassociationwithgene 42transcriptlevelsasdescribedintheoriginalpapers.Thenon-bloodcelltissueeQTLssearchedincluded 43

38

aorticendothelialcells49,leftventricleoftheheart50,cd14+monocytes51andthebrain52.Theresults 1arepresentedinSupplementaryTables14-15. 2

Enrichmentanalyses:Analysisofcell-specificDNasehypersensitivitysites(DHSs)usinganORmethod 3TheoverlapofCardio-MetaboChipSNPswithDHSswasexaminedusingpubliclyavailabledata 4

fromtheEpigenomicsRoadmapProjectandENCODE,choosingdifferentcutoffsofCardio-MetaboChipP 5values.TheDHSmappingswereavailablefor123mostlyadultcellsandtissues53(downloadedfrom 6TheDHSmappingswerespecifiedasboth“narrow”and“broad”peaks,referringtoreductionofthe 7experimentaldatatopeakcallsat0.1%and1.0%FDRthresholds,respectively.Thus,the“narrow” 8peaksarelargelynestedwithinthe“broad”peaks.ExperimentalreplicatesoftheDHSmappings 9(typicallyduplicates)werealsoavailableforthemajorityofcellsandtissues. 10 SNPsfromtheCardio-MetaboChipgenome-widescanwerefirstclumpedinPLINKinwindowsof 11100kbandmaximumr2=0.1amongLDrelationshipsfromthe1000GenomesEuropeandata.Then,the 12resultingindexSNPsateachPvaluethresholdweretaggedwithr2=0.8inwindowsof100kb,again 13usingLDrelationshipsinthe1000Genomes,restrictedtoSNPswithMAF>1%andalsopresentinthe 14HapMap2CEUpopulation.AreferencesetofSNPswasconstructedusingthesameclumpingand 15taggingproceduresappliedtoGWAScatalogSNPs(availableathttp://www.genome.gov/gwastudies/, 16accessed3/13/2013)54withdiscoveryP<5x10-8inEuropeanpopulations.Asmallnumberofreference 17SNPsortheirproxiesoverlappingtheBPSNPsortheirproxieswereexcluded.AfterLDpruningand 18exclusions,therewereatotalof1,196referenceSNPs.ForeachcelltypeandPvaluethreshold,the 19enrichmentofSBPorDBPSNPs(ortheirLDproxies)mappingtoDHSswasexpressedasanoddsratio 20(OR)relativetotheGWAScatalogreferenceSNPs(ortheirLDproxies),usinglogisticmixedeffect 21modelstreatingthereplicatepeakdeterminationsasrandomeffects(glmerpackageinR).The 22significanceoftheenrichmentORswasderivedfromthesignificanceofbetacoefficientsforthemain 23effectsinthemixedmodels(Figure2,SupplementaryTable16). 24

Enrichmentanalyses:Analysisoftissue-specificenrichmentofBPvariantsandH3K4me3sites 25Ananalysistotestforsignificantcell-specificenrichmentintheoverlapofBPSNPs(ortheir 26

proxies)withH3K4me3siteswasperformedasdescribedinTrynkaetal,201355.Themeasureof 27overlapisa“score”thatisconstructedbydividingtheheightofanH3K4me3ChIPsignalinaparticular 28cellbythedistancebetweenthenearesttestSNP.Thesignificanceofthescores(i.e.Pvalue)forall 29SNPswasdeterminedbyapermutationapproachthatcomparestheobservedscorestoscoresofSNPs 30withsimilarpropertiestothetestSNPs,essentiallyintermsofLDandproximitytogenes 31(SupplementaryNote).Thenumberofpermutationsdeterminedthenumberofsignificantdigitsinthe 32Pvaluesandweconducted10,000iterations.ResultsareshowninSupplementaryTable19. 33

Enrichmentanalyses:Analysisoftissue-specificDHSsandchromatinstatesusingGREGOR 34TheDNase-seqENCODEdataforallavailablecelltypesweredownloadedintheprocessed 35“narrowPeak”format.Thelocalmaximaofthetagdensityinbroad,variable-sized“hotspot”regionsof 36chromatinaccessibilitywerethresholdedatFDR1%withpeakssettoafixedwidthof150bp.Individual 37celltypeswerefurthergroupedinto41broadtissuecategoriesbytakingtheunionofDHSsforall 38relatedcelltypesandreplicates.ForeachGWASlocus,asetofmatchedcontrolSNPswasselected 39basedonthreecriteria:1)numberofvariantsinLD(r2>0.7;±8variants),2)MAF(±1%),and3)distance 40tonearestgene(±11,655bp).Tocalculatethedistancetothenearestgene,thedistancetothe5’ 41flankinggene(startandendposition)andtothe3’flankinggenewascalculatedandtheminimumof 42these4valueswasused.IftheSNPfellwithinthetranscribedregionofagene,thedistancewas0.The 43probabilitythatasetofGWASlocioverlapwitharegulatoryfeaturemoreoftenthanweexpectby 44chancewasestimated. 45

39

Enrichmentanalyses:FAIREanalysisofBPvariantsinfine-mappingregionsinlymphoblastoidcelllines 1FAIREanalysiswasperformedonasampleof20lymphoblastoidcelllinesofEuropeanorigin.All 2

samplesweregenotypedusingtheCardio-MetaboChipgenotypingarray,andBPSNPsandLDproxies(r2 3>0.8)atthefinemappingloci(N=24,seeSupplementaryTable23)wereassessedtoidentify 4heterozygousimbalancebetweennon-treatedandFAIRE-treatedchromatin.Apairedt-testwasusedto 5comparetheBallelefrequency(BAF)arisingfromformaldehyde-fixedchromatinshearedbysonication 6andDNApurifiedtotheBAFwhenthesamechromatinsampleunderwentFAIREtoenrichforopen 7chromatin.Threehundredandfifty-sevenCardio-MetaboChipBPSNPsweredirectlygenotypedacross 8thefinemappingregions.TheBonferroni-correctedthresholdofsignificanceisP<0.0001(0.05/357). 9TheresultsforSNPswithP<0.05arereportedin(SupplementaryTable23).FAIREresultswerenot 10availableforsomeSNPswithmissingdataduetogenotypefailureornothaving>3heterozygous 11individualsforstatisticalanalysis.ThereforetherearenoresultsforthreelowerfrequencyBPloci 12(SLC39A8,CYP17A1-NT5C2andGNAS-EDN3)andforthesecondsignalatthefollowingloci:MTHFR- 13NPPB(rs2272803),MECOM(rs2242338)andHFErs1800562). 14

Pathwayanalyses:MAGENTA 15MAGENTAtestsforenrichmentofgenesetsfromaprecompiledlibraryderivedfromGO,KEGG, 16

PATHTER,REACTOME,INGENUITY,andBIOCARTAwasperformedasdescribedbySegréetal,201056. 17Enrichmentofsignificantgene-widePvaluesingenesetsisassessedby1)usingLDanddistancecriteria 18todefinethespanofeachgene,2)selectingthesmallestPvalueamongSNPsmappingtothegene 19span,and3)adjustingthisPvalueusingaregressionmethodthataccountsforthenumberofSNPs,the 20LD,etc.Inthesecondstep,MAGENTAexaminesthedistributionoftheseadjustedPvaluesanddefines 21thresholdsforthe75%ileandthe95%ile.Inthethirdstep,MAGENTAcalculatesanenrichmentforeach 22genesetbycomparingthenumberofgenesinthegenesetwithPvaluelessthaneitherthe75thor 2395th%iletothenumberofgenesinthegenesetwithPvaluegreaterthaneitherthe75thor95th%ile, 24andthencomparingthisquotienttothesamequotientamonggenesnotinthegeneset.Thisgene-set 25quotientisassignedaPvaluebasedonreferencetoahypergeometricdistribution.Theresultsbased 26onouranalysesareindicatedinSupplementaryTable21. 27

Pathwayanalyses:DEPICT 28WeappliedtheDEPICT57analysisseparatelyongenome-widesignificantlocifromtheoverallblood 29

pressure(BP)Cardio-MetaboChipanalysisincludingpublishedbloodpressureloci(seeSupplementary 30Table22).SNPsattheHFEandBAT2-BAT5loci(rs1799945,rs1800562,rs2187668,rs805303, 31rs9268977)couldnotbemapped.Asasecondaryanalysis,weadditionallyincludedassociatedloci(P< 321x10-5)fromtheCardio-MetaboChipstage4combinedmeta-analysesofSBPandtheDBP.DEPICT 33assignedgenestoassociatedregionsiftheyoverlappedorresidedwithinassociatedLDblockswithr2> 340.5toagivenassociatedSNP. 35

Literaturereviewforgenesatthenewlydiscoveredloci 36RecognizingthatthemostsignificantlyassociatedSNPatalocusmaynotbelocatedinthecausal 37

geneandthatthefunctionalconsequencesofaSNPoftenextendsbeyond100kb,weconducteda 38literaturereviewofgenesinextendedregionsaroundnewlydiscoveredBPindexSNPs.Thegenesfor 39thisextensivereviewwereidentifiedbyDEPICT(SupplementaryTable22). 40

Non-Europeanmeta-analysis 41Toassesstheassociationofthe66significantlocifromtheEuropeanancestrymeta-analysisinnon- 42

Europeanethnicities,weobtainedlookupresultsforthe66indexSNPsforparticipantsofSouth-Asian 43ancestry(8datasets,totalN=20,875),East-Asianancestry(5datasets,totalN=9,637),andAfrican-and 44

40

African-Americanancestry(6datasets,totalN=33,909).Theassociationanalyseswereallconducted 1withthesamecovariates(age,age2,sex,BMI)andtreatmentcorrection(+15/10mmHginthepresence 2ofanyhypertensivemedication)astheassociationanalysesforthediscoveryeffortinEuropeans.Tests 3forheterogeneityacrosseffectestimatesinEuropean,SouthAsian,EastAsianandAfricanderived 4sampleswereperformedusingGWAMA58. 5

Geneticriskscoreandcardiovascularoutcomes 6ThegtxpackagefortheRstatisticalprogramminglanguagewasusedtoestimatetheeffectofthe 7

SNP-riskscoreontheresponsevariableinaregressionmodel59. 89

41

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