University of Birmingham

Multi-ethnic genome-wide association study foratrial fibrillationRoselli, Carolina; Chaffin, Mark D ; Weng, Lu-Chen ; Aeschbacher, Stefanie; Ahlberg, Gustav; Albert, Christine M.; Almgren, Peter; Alonso, Alvaro; Anderson, Christopher D ; Aragam,Krishna G; Arking, Dan E; Barnard, John; Bartz, Traci M ; Benjamin, Emelia J; Bihlmeyer,Nathan A ; Bis, Joshua C; Bloom, Heather L ; Boerwinkle, Eric; Bottinger, Erwin P; Brody,Jennifer ADOI:10.1038/s41588-018-0133-9

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Citation for published version (Harvard):Roselli, C, Chaffin, MD, Weng, L-C, Aeschbacher, S, Ahlberg, G, Albert, CM, Almgren, P, Alonso, A, Anderson,CD, Aragam, KG, Arking, DE, Barnard, J, Bartz, TM, Benjamin, EJ, Bihlmeyer, NA, Bis, JC, Bloom, HL,Boerwinkle, E, Bottinger, EP, Brody, JA, Calkins, H, Campbell, A, Cappola, TP, Carlquist, J, Chasman, DL,Chen, LY, Chen, Y-DI, Choi, E-K, Choi, SH, Christophersen, IE, Chung, MK, Cole, JW, Conen, D, Cook, J,Crijns, HJ, Cutler, MJ, Damrauer, SM, Daniels, BR, Darbar, D, Delgado, G, Denny, JC, Dichgans, M, Dorr, M,Dudink, EA, Dudley, SC, Esa, N, Esko, T, Eskola, M, Fatkin, D, Felix, SB, Ford, I, Franco, OH, Geelhoed, B,Grewal, R, Gudnason, V, Guo, X, Gupta, N, Gustafsson, S, Gutmann, R, Hamsten, A, Harris, TB, Hayward, C,Heckbert, SR, Hernesniemi , J, Hocking, LJ, Hofman, A, Horimoto, ARVR, Huang, J, Huang, PL, Huffman, J,Ingelsson, E, Gucuk Ipek, E, Ito, K, Jimenez-Conde, J, Johnson, R, Wouter Jukema, J, Kaab, S, Kähönen, M,Kamatani, Y, Kane, JP, Kastrati, A, Kathiresan, S, Katschnig-Winter, P, Kavousi, M, Kessler, T, Kietselaer, BL,Kirchhof, P, Kleber, ME, Knight, S, Krieger, JE, Kubo, M, Launer, LJ, Laurikka, J, Lehtimäki, T, Leineweber, K,Lemaitre, RN, Li, M, Lim, HE, Lin, HJ, Lin, H, Lind, L, Lindgren, CM, Lokki, M-L, London, B, Loos, RJF, Low, S-K, Lu, Y, Lyytikäinen, L-P, Macfarlane, PW, Magnusson, PK, Mahajan, A, Malik, R, Mansur, AJ, Marcus, GM,Margolin, L, Margulies, KB, März, W, McManus, DD, Melander, O, Mohanty, S, Montgomery, JA, Morley, MP,Morris, AP, Müller-Nurasyid, M, Natale, A, Nazarian, S, Neumann, B, Newton-Cheh, C, Niemeijer, MN, Nikus, K,Nilsson, PM, Noordam, R, Oellers, H, Olesen, MS, Orho-Melander, M, Padmanabhan, S, Pak, H-N, Pare, G,Pedersen, NL, Pera, J, Pereira, A, Porteous, D, Psaty, BM, Pulit, SL, Pullinger, CR, Rader, DJ, Refsgaard, L,Ribases, M, Ridker, PM, Rienstra, M, Risch, L, Roden, D, Rosand, J, Rosenberg, MA, Rost, N, Rotter, JI, Saba,S, Sandhu, RK, Schnabel, RB, Schramm, K, Schunkert, H, Schurman, C, Scott, SA, Seppala, I, Shaffer, C,Shah, SH, Shalaby, AA, Shim, J, Shoemaker, MB, Siland, JE, Sinisalo, J, Sinner, MF, Slowik, A, Smith, AV,Smith, BH, Smith, JG, Smith, JD, Smith, NL, Soliman, EZ, Sotoodehnia, N, Stricker, BH, Sun, A, Sun, H,Svendsen, JH, Tanaka, T, Tanriverdi, K, Taylor, KD, Teder-Laving, M, Teumer, A, Theriault, S, Trompet, S,Tucker, NR, Tveit, A, Uitterlinden, AG, Van der Harst, P, Van Gelder, IC, Van Wagoner, DR, Verweij, N,Vlachopoulou, E, Volker, U, Wang, B, Weeke, PE, Weijs, B, Weiss, R, Weiss, S, Wells, Q, Wiggins, KL, Wong,J, Woo, D, Worrall, BB, Yang, P-S, Yao, J, Yoneda, ZT, Zeller, T, Zeng, L, Lubitz, SA, Lunetta, KL & Ellinor, PT2018, 'Multi-ethnic genome-wide association study for atrial fibrillation', Nature Genetics, vol. 50, no. 9, pp.1225–1233. https://doi.org/10.1038/s41588-018-0133-9Link to publication on Research at Birmingham portal

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Multi-EthnicGenome-wideAssociationStudyforAtrialFibrillationCarolinaRoselli*,MSc,1MarkD.Chaffin*,MSc,1Lu-ChenWeng*,PhD,1,2StefanieAeschbacher,MSc,3,4GustavAhlberg,MSc,5–7ChristineM.Albert,MD,MPH,8PeterAlmgren,MSc,9AlvaroAlonso,MD,PhD,10ChristopherD.Anderson,MD,MMSc,1,11KrishnaG.Aragam,MD,1,11DanE.Arking,PhD,12JohnBarnard,PhD,13TraciM.Bartz,MS,14EmeliaJ.Benjamin,MD,ScM,15–17NathanA.Bihlmeyer,BS,18JoshuaC.Bis,PhD,19HeatherL.Bloom,MD,20EricBoerwinkle,PhD,21ErwinB.Bottinger,MD,22,23JenniferA.Brody,BA,19HughCalkins,MD,24ArchieCampbell,MA,25ThomasP.Cappola,MD,ScM,26JohnCarlquist,PhD,27,28DanielI.Chasman,PhD,1,29LinY.Chen,MD,MS,30Yii-DerIdaChen,PhD,31Eue-KeunChoi,MD,PhD,32SeungHoanChoi,PhD,1IngridE.Christophersen,MD,PhD,1,2,33MinaK.Chung,MD,13JohnW.Cole,MD,MS,34,35DavidConen,MD,MPH,3,4,36JamesCook,PhD,37HarryJ.Crijns,MD,PhD,38MichaelJ.Cutler,PO,PhD,27ScottM.Damrauer,MD,39,40BrianR.Daniels,PhD,1DawoodDarbar,MD,41GracielaDelgado,MSc,42JoshuaC.Denny,MD,43MartinDichgans,MD,44–46MarcusDörr,MD,47,48EltonA.Dudink,MD,MSc,38SamuelC.Dudley,MD,PhD,49NadaEsa,MD,50TonuEsko,PhD,1,51MarkkuEskola,MD,PhD,52DianeFatkin,MD,53–55StephanB.Felix,MD,47,48IanFord,PhD,56OscarH.Franco,MD,PhD,57BastiaanGeelhoed,PhD,58RajiGrewal,MD,59,60VilmundurGudnason,MD,PhD,61,62XiuqingGuo,PhD,31NamrataGupta,PhD,1StefanGustafsson,PhD,63RebeccaGutmann,64AndersHamsten,MD,PhD,65TamaraB.Harris,MD,MS,66CarolineHayward,PhD,67SusanR.Heckbert,MD,PhD,68,69JussiHernesniemi,MD,PhD,52,70LynneJ.Hocking,PhD,71AlbertHofman,MD,PhD,57AndreaR.V.R.Horimoto,PhD,72JieHuang,MD,MPH,73PaulL.Huang,MD,PhD,2JenniferHuffman,PhD,67ErikIngelsson,MD,PhD,63,74EsraGucukIpek,MD,24KaoruIto,MD,PhD,75JordiJimenez-Conde,76,77ReneeJohnson,PhD,MGC,53J.WouterJukema,MD,PhD,78–80StefanKääb,MD,PhD,81,82MikaKähönen,MD,PhD,83YoichiroKamatani,MD,PhD,84JohnP.Kane,MD,PhD,85AdnanKastrati,MD,82,86SekarKathiresan,MD,1,11PetraKatschnig-Winter,MD,87MaryamKavousi,MD,PhD,FESC,57ThorstenKessler,MD,86BasL.Kietselaer,MD,PhD,38PaulusKirchhof,MD,88–90MarcusE.Kleber,PhD,42StaceyKnight,PhD,MStat,27,91JoseE.Krieger,MD,PhD,72MichiakiKubo,MD,PhD,92LenoreJ.Launer,PhD,66JariLaurikka,MD,PhD,93TerhoLehtimäki,MD,PhD,70KirstenLeineweber,PhD,94RozennN.Lemaitre,PhD,MPH,19ManLi,PhD,95,96 HongEuyLim,MD,PhD,97HenryJ.Lin,MD,31HonghuangLin,PhD,15,16LarsLind,MD,PhD,98CeciliaM.Lindgren,PhD,99Marja-LiisaLokki,PhD,100BarryLondon,MD,PhD,64RuthJ.F.Loos,PhD,22,101,102Siew-KeeLow,PhD,84YingchangLu,MD,PhD,22,101Leo-PekkaLyytikäinen,MD,70PeterW.Macfarlane,PhD,DSc,103PatrikK.Magnusson,PhD,104AnubhaMahajan,PhD,99RainerMalik,PhD,44AlfredoJ.Mansur,MD,PhD,105GregoryM.Marcus,MD,MAS,106LaurenMargolin,1KennethB.Margulies,MD,26WinfriedMärz,MD,107,108DavidD.McManus,MD,MSc,FHRS,50OlleMelander,MD,PhD,109SanghamitraMohanty,MD,MS,110,111JayA.Montgomery,MD,43MichaelP.Morley,MS,26AndrewP.Morris,PhD,37MartinaMüller-Nurasyid,PhD,81,82,112AndreaNatale,MD,110,111SamanNazarian,MD,PhD,113BenjaminNeumann,MD,81ChristopherNewton-Cheh,MD,MPH,1,11MaartjeN.Niemeijer,MD,PhD,57KjellNikus,MD,PhD,52PeterNilsson,MD,PhD,114RaymondNoordam,PhD,115HeidiOellers,116MortenS.Olesen,PhD,MSc,5–7MarjuOrho-Melander,PhD,9SandoshPadmanabhan,MD,117Hui-NamPak,MD,PhD,118GuillaumeParé,MD,MSc,36,119NancyL.Pedersen,MA,PhD,104JoannaPera,MD,PhD,120AlexandrePereira,MD,PhD,121,122DavidPorteous,PhD,25BruceM.Psaty,MD,PhD,69,123SaraL.Pulit,PhD,1,124,125CliveR.Pullinger,PhD,85DanielJ.Rader,MD,126LenaRefsgaard,MD,5–7MartaRibasés,PhD,127–129PaulM.Ridker,MD,MPH,8MichielRienstra,MD,PhD,58LorenzRisch,MD,MPH,130,131DanRoden,MD,43JonathanRosand,MD,MSc,1,11MichaelA.Rosenberg,MD,11,132NataliaRost,MD,MPH,FAAN,1,133JeromeI.Rotter,MD,134SamirSaba,MD,135RoopinderK.Sandhu,MD,MPH,136RenateB.Schnabel,MD,MSc,137,138KatharinaSchramm,PhD,81,112HeribertSchunkert,MD,82,86ClaudiaSchurman,PhD,22,101StuartA.Scott,PhD,139IlkkaSeppälä,MD,70ChristianShaffer,BS,43SvatiShah,MD,MHS,140AlaaA.Shalaby,MD,135,141JaeminShim,MD,PhD,142M.BenjaminShoemaker,MD,

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MSCI,43JoyleneE.Siland,BSc,58JuhaSinisalo,MD,PhD,143MoritzF.Sinner,MD,MPH,81,82AgnieszkaSlowik,MD,PhD,120AlbertV.Smith,PhD,61,62BlairH.Smith,MD,144J.GustavSmith,MD,PhD,1,145JonathanD.Smith,PhD,13NicholasL.Smith,PhD,68,69ElsayedZ.Soliman,MD,MSc,MS,146NonaSotoodehnia,MD,MPH,147BrunoH.Stricker,MD,PhD,148,149AlbertSun,MD,140HanSun,MSPH,13JesperH.Svendsen,MD,DMSc,5,7ToshihiroTanaka,MD,PhD,150KahramanTanriverdi,PhD,50KentD.Taylor,PhD,31MarisTeder-Laving,51AlexanderTeumer,PhD,48,151SébastienThériault,MD,MSc,36,119StellaTrompet,PhD,78,115NathanR.Tucker,PhD,1,2ArnljotTveit,MD,PhD,152,153AndreG.Uitterlinden,PhD,148PimVanDerHarst,MD,PhD,58IsabelleC.VanGelder,MD,PhD,58DavidR.VanWagoner,PhD,13NiekVerweij,PhD,58EfthymiaVlachopoulou,PhD,100UweVölker,PhD,48,154BiqiWang,PhD,155PeterE.Weeke,MD,PhD,5,43BobWeijs,MD,PhD,38RaulWeiss,MD,156StefanWeiss,PhD,48,154QuinnWells,MD,43KerriL.Wiggins,MS,RD,19JorgeWong,MD,157DanielWoo,MD,MS,158BradfordB.Worrall,MD,MSc,159Pil-SungYang,MD,118JieYao,MS,31ZacharyT.Yoneda,MD,43TanjaZeller,PhD,137,138LingyaoZeng,PhD,MSc,86StevenA.Lubitz*,MD,MPH,1,2,160KathrynL.Lunetta*,PhD,15,155PatrickT.Ellinor*,MD,PhD,1,2,160*TheseauthorscontributedequallytothemanuscriptAffiliations1. PrograminMedicalandPopulationGenetics,TheBroadInstituteofMITandHarvard,Cambridge,

MA,USA.2. CardiovascularResearchCenter,MassachusettsGeneralHospital,Boston,MA,USA.3. UniversityHospitalBasel,Basel,Switzerland.4. CardiovascularResearchInstituteBasel,Basel,Switzerland.5. TheHeartCentre,DepartmentofCardiology,CopenhagenUniversityHospital,Rigshospitalet,

Copenhagen,Denmark.6. LaboratoryofExperimentalCardiology,DepartmentofBiomedicalSciences,Universityof

Copenhagen.TheDanishNationalResearchFoundationCentreforCardiacArrhythmia,Copenhagen,Denmark.

7. DepartmentofClinicalMedicine,FacultyofHealthandMedicalSciences,UniversityofCopenhagen,Copenhagen,Denmark.

8. DivisionsofPreventiveandCardiovascularMedicine,BrighamandWomen’sHospital&HarvardMedicalSchool,Boston,MA,USA.

9. DepartmentofClinicalSciences,LundUniversity,Malmo,Sweden.10. DepartmentofEpidemiology,RollinsSchoolofPublicHealth,EmoryUniversity,Atlanta,GA,USA.11. CenterforGenomicMedicine,MassachusettsGeneralHospital,Boston,MA,USA.12. McKusick-NathansInstituteofGeneticMedicine,JohnsHopkinsUniversitySchoolofMedicine,

Baltimore,MD,USA.13. DepartmentsofCardiovascularMedicine,CellularandMolecularMedicine,Molecular

Cardiology,andQuantitativeHealthSciences,ClevelandClinic,Cleveland,OH,USA.14. CardiovascularHealthResearchUnit,DepartmentsofMedicineandBiostatistics,Universityof

Washington,Seattle,WA,USA.15. NHLBIandBostonUniversity’sFraminghamHeartStudy,Framingham,MA,USA.16. DepartmentofMedicine,BostonUniversitySchoolofMedicine,Boston,MA,USA.17. DepartmentofEpidemiology,BostonUniversitySchoolofPublicHealth,Boston,MA,USA.18. PredoctoralTrainingPrograminHumanGenetics,McKusick-NathansInstituteofGenetic

Medicine,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,MD,USA.

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19. CardiovascularHealthResearchUnit,DepartmentofMedicine,UniversityofWashington,Seattle,WA,USA.

20. DivisionofCardiology,EmoryUniversityandAtlantaVAMedicalCenter,Atlanta,GA,USA.21. HumanGenomeSequencingCenter,BaylorCollegeofMedicine,Houston,TX,USA.22. TheCharlesBronfmanInstituteforPersonalizedMedicine,IcahnSchoolofMedicineatMount

Sinai,NewYork,NY,USA.23. DepartmentofPharmacologyandSystemsTherapeutics,IcahnSchoolofMedicineatMount

Sinai,NewYork,NY,USA.24. JohnsHopkinsUniversity,Baltimore,MD,USA.25. GenerationScotland,CentreforGenomicandExperimentalMedicine,InstituteofGeneticsand

MolecularMedicine,UniversityofEdinburgh,Edinburgh,UK.26. PennCardiovascularInstituteandDepartmentofMedicine,PerelmanSchoolofMedicine,

UniversityofPennsylvania,Philadelphia,PA,USA.27. IntermountainHeartInstitute,IntermountainMedicalCenter,Murray,UT,USA.28. DivisionofCardiovascularMedicine,UniversityofUtah,SaltLakeCity,UT,USA.29. DivisionsofPreventiveMedicineandGenetics,BrighamandWomen’sHospital&Harvard

MedicalSchool,Boston,MA,USA.30. CardiovascularDivision,DepartmentofMedicine,UniversityofMinnesotaMedicalSchool,

Minneapolis,MN,USA.31. InstituteforTranslationalGenomicsandPopulationSciences,DepartmentofPediatrics,

LABioMedatHarbor-UCLAMedicalCenter,Torrance,CA,USA.32. SeoulNationalUniversityHospital,Seoul,Korea.33. DepartmentofMedicalResearch,BærumHospital,VestreVikenHospitalTrust,Rud,Norway.34. BaltimoreVeteransAffairsMedicalCenter,DepartmentofNeurology,Baltimore,MD,USA.35. UniversityofMarylandSchoolofMedicine,DepartmentofNeurology,Baltimore,MD,USA.36. PopulationHealthResearchInstitute,McMasterUniversity,Hamilton,Canada.37. DepartmentofBiostatistics,UniversityofLiverpool,Liverpool,UK.38. MaastrichtUniversityMedicalCenter+andCardiovascularResearchInstituteMaastricht,

DepartmentofCardiology,Maastricht,TheNetherlands.39. DepartmentofSurgery,PerelmanSchoolofMedicine,UniversityofPennsylvania,Philadelphia,

PA,USA.40. DepartmentofSurgery,CorporalMichaelCrescenzVAMedicalCenter,Philadelphia,PA,USA.41. UniversityofIllinoisChicago,Chicago,IL,USA.42. VthDepartmentofMedicine,MedicalFacultyMannheim,HeidelbergUniversity,Heidelberg,

Germany.43. DepartmentofMedicine,VanderbiltUniversityMedicalCenter,Nashville,TN,USA.44. InstituteforStrokeandDementiaResearch(ISD),UniversityHospital,LMUMunich,Munich,

Germany.45. MunichClusterforSystemsNeurology(SyNergy),Munich,Germany.46. GermanCenterforNeurodegenerativeDiseases(DZNE),Munich,Germany.47. DepartmentofInternalMedicineB,UniversityMedicineGreifswald,Greifswald,Germany.48. DZHK(GermanCentreforCardiovascularResearch),partnersite:Greifswald,Greifswald,

Germany.49. CardiovascularDivisionandLilleheiHeartInstitute,UniversityofMinnesota,Minneapolis,MN,

USA.50. UniversityofMassachusettsMedicalSchoolWorcester,Worcester,MA,USA.51. EstonianGenomeCenter,UniversityofTartu,Tartu,Estonia.52. DepartmentofCardiology,HeartCenter,TampereUniversityHospitaland,FinnishCardiovascular

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ResearchCenter-Tampere,FacultyofMedicineandLifeSciences,UniversityofTampere,Tampere,Finland.

53. VictorChangCardiacResearchInstitute,Darlinghurst,NSW,Australia.54. StVincent’sHospital,Darlinghurst,NSW,Australia.55. FacultyofMedicine,UniversityofNewSouthWales,Kensington,NSW,Australia.56. RobertsonCenterforBiostatistics,UniversityofGlasgow,Glasgow,UK.57. DepartmentofEpidemiology,ErasmusUniversityMedicalCenterRotterdam,Rotterdam,The

Netherlands.58. UniversityofGroningen,UniversityMedicalCenterGroningen,DepartmentofCardiology,

Groningen,TheNetherlands.59. Dept.ofNeuroscience,SaintFrancisMedicalCenter,Trenton,NJ,USA.60. SchoolofHealthandMedicalSciences,SetonHallUniversity,SouthOrange,NJ,USA.61. IcelandicHeartAssociation,Kopavogur,Iceland.62. FacultyofMedicine,UniversityofIceland,Reykavik,Iceland.63. DepartmentofMedicalSciences,MolecularEpidemiologyandScienceforLifeLaboratory,

UppsalaUniversity,Uppsala,Sweden.64. DivisionofCardiovascularMedicineandAbboudCardiovascularResearchCenter,Universityof

Iowa,IowaCity,IA,USA.65. CardiovascularGeneticsandGenomicsGroup,AtherosclerosisResearchUnit,Departmentof

MedicineSolna,KarolinskaInstitutet,Stockholm,Sweden.66. LaboratoryofEpidemiology,Demography,andBiometry,NationalInstituteonAging,Bethesda,

MD,USA.67. MRCHumanGeneticsUnit,InstituteofGeneticsandMolecularMedicine,Universityof

Edinburgh,Edinburgh,UK.68. CardiovascularHealthResearchUnitandDepartmentofEpidemiology,UniversityofWashington,

Seattle,WA,USA.69. KaiserPermanenteWashingtonHealthResearchInstitute,Seattle,WA,USA.70. DepartmentofClinicalChemistry,FimlabLaboratoriesandUniversityofTampereSchoolof

Medicine,Tampere,Finland.71. MusculoskeletalResearchProgramme,DivisionofAppliedMedicine,UniversityofAberdeen,

Aberdeen,UK.72. LaboratoryofGeneticsandMolecularCardiology,HeartInstitute,UniversityofSaoPaulo,Sao

Paulo,Brazil.73. BostonVAResearchInstitute,Inc.,Boston,MA,USA.74. DepartmentofMedicine,DivisionofCardiovascularMedicine,StanfordUniversitySchoolof

Medicine,Stanford,CA,USA.75. LaboratoryforCardiovascularDiseases,RIKENCenterforIntegrativeMedicalSciences,

Yokohama,Japan.76. DepartmentofNeurology,NeurovascularResearchGroupIMIM-HospitaldelMar(Institut

HospitaldelMard’InvestigacionsMédiques),Barcelona,Spain.77. UniversitatAutònomadeBarcelona,MedicineDepartment,Barcelona,Spain.78. DepartmentofCardiology,LeidenUniversityMedicalCenter,Leiden,TheNetherlands.79. DurrerCenterforCardiogeneticResearch,Amsterdam,TheNetherlands.80. InteruniversityCardiologyInstituteoftheNetherlands,Utrecht,TheNetherlands.81. DepartmentofMedicineI,UniversityHospitalMunich,Ludwig-Maximilians-University,Munich,

Germany.82. DZHK(GermanCentreforCardiovascularResearch),partnersite:MunichHeartAlliance,Munich,

Germany.

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83. DepartmentofClinicalPhysiology,TampereUniversityHospital,andFinnishCardiovascularResearchCenter-Tampere,FacultyofMedicineandLifeSciences,UniversityofTampere,Tampere,Finland.

84. LaboratoryforStatisticalAnalysis,RIKENCenterforIntegrativeMedicalSciences,Yokohama,Japan.

85. CardiovascularResearchInstitute,UniversityofCalifornia,SanFrancisco,CA,USA.86. DeutschesHerzzentrumMünchen,KlinikfürHerz-undKreislauferkrankungen,Technische

UniversitätMünchen,Munich,Germany.87. DepartmentofNeurology,MedicalUniversityofGraz,Graz,Austria.88. InstituteofCardiovascularSciences,UniversityofBirmingham,Birmingham,UnitedKingdom.89. SandwellandWestBirminghamHospitalsNHSTrustandUniversityHospitalsBirminghamNHS

FoundationTrust,Birmingham,UnitedKingdom.90. AFNET,Münster,Germany.91. DepartmentofMedicine,UniversityofUtah,SaltLakeCity,UT,USA.92. RIKENCenterforIntegrativeMedicalSciences,Yokohama,Japan.93. DepartmentofCardio-ThoracicSurgery,HeartCenter,TampereUniversityHospital,andFinnish

CardiovascularResearchCenter-Tampere,FacultyofMedicineandLifeSciences,UniversityofTampere,Tampere,Finland.

94. Dept.DiseaseGenomics,BayerAG,Wuppertal,Germany.95. DepartmentofEpidemiology,JohnsHopkinsUniversity,Baltimore,MD,USA.96. DivisionofNephrology&Hypertension,InternalMedicine,SchoolofMedicine,Universityof

Utah,SaltLakeCity,UT,USA.97. KoreaUniversityGuroHospital,Seoul,Korea.98. DepartmentofMedicalSciences,CardiovascularEpidemiology,UppsalaUniversity,Uppsala,

Sweden.99. WellcomeTrustCentreforHumanGenetics,UniversityofOxford,Oxford,UK.100. TransplantationLaboratory,Medicum,UniversityofHelsinki,Helsinki,Finland.101. TheGeneticsofObesityandRelatedMetabolicTraitsProgram,IcahnSchoolofMedicineat

MountSinai,NewYork,NY,USA.102. TheMindichChildHealthandDevelopmentInstitute,IcahnSchoolofMedicineatMountSinai,

NewYork,NY,USA.103. InstituteofHealthandWellbeing,CollegeofMedical,VeterinaryandLifeSciences,Universityof

Glasgow,Glasgow,UK.104. DepartmentofMedicalEpidemiologyandBiostatistics,KarolinskaInstitutet,Stockholm,Sweden.105. HeartInstitute,UniversityofSaoPaulo,SaoPaulo,Brazil.106. DivisionofCardiology,UniversityofCalifornia,SanFrancisco,CA,USA.107. ClinicalInstituteofMedicalandChemicalLaboratoryDiagnostics,MedicalUniversityofGraz,

Graz,Austria.108. SynlabAcademy,SynlabServicesGmbH,Mannheim,Germany.109. DepartmentofInternalMedicine,ClinicalSciences,LundUniversity,Malmo,Sweden.110. TexasCardiacArrhythmiaInstitute,St.David’sMedicalCenter,Austin,TX,USA.111. DellMedicalSchool,Austin,TX,USA.112. InstituteofGeneticEpidemiology,HelmholtzZentrumMünchen-GermanResearchCenterfor

EnvironmentalHealth,Neuherberg,Germany.113. UniversityofPennsylvania,Philadelphia,PA,USA.114. DepartmentofClinicalSciences,LundUniversityandSkåneUniversityHospital,Malmo,Sweden.115. SectionofGerontologyandGeriatrics,Departmentofinternalmedicine,LeidenUniversity

MedicalCenter,Leiden,TheNetherlands.

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116. AtrialFibrillationNETwork,Muenster,Germany.117. InstituteofCardiovascularandMedicalSciences,BHFGlasgowCardiovascularResearchCentre,

UniversityofGlasgow,Glasgow,UK.118. YonseiUniversityHealthSystem,Seoul,Korea.119. DepartmentofPathologyandMolecularMedicine,McMasterUniversity,Hamilton,Canada.120. DepartmentofNeurology,FacultyofMedicine,JagiellonianUniversityMedicalCollege,Krakow,

Poland.121. LaboratoryofGeneticsandMolecularBiology,HeartInstitute,UniversityofSaoPaulo,SaoPaulo,

Brazil.122. DepartmentofGenetics,HarvardMedicalSchool,Boston,MA,USA.123. CardiovascularHealthResearchUnit,DepartmentsofMedicine,Epidemiology,andHealth

Services,UniversityofWashington,Seattle,WA,USA.124. DepartmentofGenetics,CenterforMolecularMedicine,UniversityMedicalCentreUtrecht,

UtrechtUniversity,Utrecht,TheNetherlands.125. LiKaShingCenterforHealthInformationandDiscovery,BigDataInstitute,OxfordUniversity,

Oxford,UK.126. DivisionofCardiovascularMedicine,DepartmentofMedicine,PerelmanSchoolofMedicineat

theUniversityofPennsylvania,Philadelphia,PA,USA.127. PsychiatricGeneticsUnit,GroupofPsychiatry,MentalHealthandAddiction,Valld’Hebron

ResearchInstitute(VHIR),UniversitatAutònomadeBarcelona,Barcelona,Catalonia,Spain.128. DepartmentofPsychiatry,HospitalUniversitariValld’Hebron,Barcelona,Catalonia,Spain.129. BiomedicalNetworkResearchCentreonMentalHealth(CIBERSAM),InstitutodeSaludCarlosIII,

Madrid,Spain.130. UniversityInstituteofClinicalChemistry,UniversityofBern,Switzerland.131. LabormedizinischesZentrumDr.Risch,Schaan,Liechtenstein.132. UniversityofColoradoSchoolofMedicine,Aurora,CO,USA.133. J.PhilipKistlerStrokeResearchCenter,MassachusettsGeneralHospital,Boston,MA,USA.134. InstituteforTranslationalGenomicsandPopulationSciences,DepartmentsofPediatricsand

Medicine,LABioMedatHarbor-UCLAMedicalCenter,Torrance,CA,USA.135. DivisionofCardiology,UniversityofPittsburgh,PA,USA.136. DivisionofCardiology,UniversityofAlberta,Edmonton,Canada.137. DepartmentofGeneralandInterventionalCardiology,UniversityHeartCentreHamburg,

Hamburg,Germany.138. DZHK(GermanCentreforCardiovascularResearch),partnersite:Hamburg/Kiel/Lübeck,

Hamburg,Germany.139. DepartmentofGeneticsandGenomicSciences,IcahnSchoolofMedicineatMountSinai,New

York,NY,USA.140. DivisionofCardiology,DepartmentofMedicine,DukeUniversitySchoolofMedicine,Durham,

NC,USA.141. CardiologyDivision,PittsburghVAHealthcareSystem,Pittsburgh,PA,USA.142. KoreaUniversityAnamHospital,Seoul,Korea.143. HeartandLungCenterHUS,HelsinkiUniversityCentralHospital,Helsinki,Finland.144. DivisionofPopulationHealthSciences,UniversityofDundee,Scotland,UK.145. DepartmentofCardiology,ClinicalSciences,LundUniversityandSkåneUniversityHospital,Lund,

Sweden.146. EpidemiologicalCardiologyResearchCenter(EPICARE),WakeForestSchoolofMedicine,Winston

Salem,NC,USA.147. CardiovascularHealthResearchUnit,DepartmentsofMedicineandEpidemiology,Universityof

Page7of41

Washington,Seattle,WA,USA.148. DepartmentofEpidemiologyandInternalMedicine,ErasmusUniversityMedicalCenter

Rotterdam,Rotterdam,TheNetherlands.149. InspectorateofHealthCare,Utrecht,TheNetherlands.150. DepartmentofHumanGeneticsandDiseaseDiversity,TokyoMedicalandDentalUniversity

GraduateSchoolofMedicalandDentalSciences,Tokyo,Japan.151. InstituteforCommunityMedicine,UniversityMedicineGreifswald,Greifswald,Germany.152. DepartmentofMedicalResearch,BærumHospital,VestreVikenHospitalTrust,Gjettum,

Norway.153. InstituteofClinicalMedicine,UniversityofOslo,Oslo,Norway.154. InterfacultyInstituteforGeneticsandFunctionalGenomics,UniversityMedicineandErnst-

Moritz-Arndt-UniversityGreifswald,Greifswald,Germany.155. DepartmentofBiostatistics,BostonUniversitySchoolofPublicHealth,Boston,MA,USA.156. DivisionofCardiovascularMedicine,TheOhioStateUniversity,Columbus,OH,USA.157. DivisionofCardiology,HamiltonHealthSciences,McMasterUniversity,Hamilton,Ontario,

Canada.158. UniversityofCincinnatiCollegeofMedicine,Cincinnati,OH,USA.159. UniversityofVirginiaHealthSystem,DepartmentsofNeurologyandPublicHealthScience,

Charlottesville,VA,USA.160. CardiacArrhythmiaService,MassachusettsGeneralHospital,Boston,MA,USA.Wordcount:Abstract167,maintext1,600,references822,figurelegends367,onlinemethods2,887,onlinemethodsreferences966.Shorttitle:GWASforAtrialFibrillationCorrespondingauthor:PatrickT.Ellinor,MD,PhD,PrograminMedicalandPopulationGenetics,TheBroadInstituteofMITandHarvardCardiovascularResearchCenter,MassachusettsGeneralHospital;Boston,MA02129T:617-724-8729E:ellinor@mgh.harvard.edu

Journalsubjectcodes:

Disclosures:Dr.EllinoristhePIonagrantfromBayerAGtotheBroadInstitutefocusedonthegeneticsandtherapeuticsofatrialfibrillation.Dr.PsatyservesontheDSMBofaclinicaltrialfundedbyZollLifeCorandontheSteeringCommitteeoftheYaleOpenDataAccessProjectfundedbyJohnson&

Page8of41

Johnson.Dr.KirchhofreceivesresearchsupportfromEuropeanUnion,BritishHeartFoundation,LeducqFoundation,MedicalResearchCouncil(UK),andGermanCentreforCardiovascularResearch,fromseveraldruganddevicecompaniesactiveinatrialfibrillation,andhasreceivedhonorariafromseveralsuchcompanies.Dr.KirchhofisalsolistedasinventorontwopatentsheldbyUniversityofBirmingham(AtrialFibrillationTherapyWO2015140571,MarkersforAtrialFibrillationWO2016012783).KirstenLeineweberisanemployeeofBayerAG.ThegenotypingofparticipantsintheBroadAFStudyandtheexpressionanalysisofleftatrialtissuesamplesweresupportedbyagrantfromBayerAGtotheBroadInstitute.Theremainingauthorshavenodisclosures.

Page9of41

Atrialfibrillation(AF)affectsover33millionindividualsworldwide,1isacommoncauseofstroke,2

andhasacomplexheritability.3Weconductedthelargestmeta-analysisofgenome-wideassociation

studiesforAFtodate,consistingofoverhalfamillionindividualsincluding65,446withAF.We

performedcombinedandancestry-specificmeta-analysesaswellasconditionalandjointanalyses.In

total,weidentified97locisignificantlyassociatedwithAFincluding67ofwhichwerenovelina

combined-ancestryanalysis,and3inaEuropeanspecificanalysis.WesoughttoidentifyAF-associated

genesattheGWASlocibyperformingRNA-sequencingandexpressionquantitativetraitloci(eQTL)

analysesin101leftatrialsamples,themostrelevanttissueforAF.Wealsoperformedtranscriptome-

wideanalysesthatidentified57AF-associatedgenes,42ofwhichoverlapwithGWASloci.The

identifiedlociimplicategenesenrichedwithincardiacdevelopmental,electrophysiological,and

contractileorstructuralpathways.Theseresultsextendourunderstandingofthebiologicalpathways

underlyingAFandmayfacilitatethedevelopmentoftherapeuticsforAF.

Atrialfibrillation(AF)isthemostcommonheartrhythmdisorder,andisaleadingcauseofheartfailure

andstroke.2Priorgenome-wideassociationstudies(GWAS)haveidentifiedatleast30lociassociated

withAF.4–9Weconductedalarge-scaleanalysiswithoverhalfamillionparticipants,including65,446

withAF,frommorethan50studies.OurAFsamplewascomposedof84.2%European,12.5%Japanese,

2%AfricanAmerican,and1.3%BrazilianandHispanicpopulations(SupplementaryTableS1).Weused

theHaplotypeReferenceConsortium(HRC)referencepaneltoimputevariantsfromSNParraydatafor

75%ofthesamples(Figure1).Intheremainder,weincludedHRCoverlappingvariantsfrom1000

Genomesimputeddata,orfromacombinedreferencepanel.Weanalyzed8,328,530commonvariants

(minorallelefrequency(MAF)>5%),2,884,670lowfrequencyvariants(1%>MAF≥5%),and936,779rare

variants(MAF≤1%).

Page10of41

Thecombined-ancestrymeta-analysisrevealed94AF-associatedloci,67ofwhichwerenovelat

genome-widesignificance(P-value(P)<1x10-8).Thisconservativethresholdaccountsfortesting

independentvariantswithMAF≥0.1%usingaBonferronicorrection,whileuseofamorecommonly

utilizedthresholdof5x10-8resultedintheidentificationofanadditional10loci(SupplementaryTable

S2).Themajorityofsentinelvariants(N=92)werecommon(MAF>5%),withrelativerisksrangingfrom

1.04to1.55.Twolow-frequencysentinelvariantswereidentifiedwithinthegenesC1orf185andUBE4B

(Figure2,Table1,SupplementaryTableS3,SupplementaryFigureS1).

Wethenconductedagenesetenrichmentanalysiswiththeresultsfromthecombined-ancestry

meta-analysisusingMAGENTA.Weidentified55enrichedgenesetsorpathwaysthatlargelyfallinto

cardiacdevelopmental,electrophysiological,andcardiomyocytecontractileorstructuralfunctional

groups(SupplementaryTableS4).Intotal,48ofthe67novellocicontainoneormoregeneswithin

500kbofthesentinelvariantthatwerepartofanenrichedgenesetorpathway(SupplementaryFigure

S2).

Next,weperformedancestry-specificmeta-analyses.AmongindividualsofEuropeanancestry,we

identified3additionallociassociatedwithAF,eachofwhichhadasub-thresholdassociation(P<1x10-6)

inthecombined-ancestrymeta-analysis.TheselociwerelocatedclosetoorwithinthegenesCDK6,

EPHA3,andGOSR2(SupplementaryTableS5,SupplementaryFigureS3-4).Theregionmostsignificantly

associatedwithAFinEuropeans,Japanese,andAfricanAmericans(SupplementaryFigureS5-6)wason

chromosome4q25,upstreamofthegenePITX2(SupplementaryFigureS7).Wedidnotobserve

significantheterogeneityofeffectestimatesacrossancestriesformostassociations,suggestingthattop

geneticsusceptibilitysignalsforAFhavearelativelyconstanteffectacrossancestries(Table1,

SupplementaryTableS3,SupplementaryFigureS8).Theproportionofheritabilityexplainedbytheloci

Page11of41

fromtheEuropeanancestryanalysiswas42%,comparedtopreviouslyreported25%10(Supplementary

TableS6).

InconditionalandjointanalysesoftheEuropeanancestryresults,wefound11lociwithmultiple,

independentAF-associatedsignals.Atalocuscenteredonaclusterofsodiumchannelgenes,we

identified3regionsthatindependentlyassociatewithAFwithinSCN10A,SCN5Aandathirdsignal

betweenbothgenes.AtthepreviouslydescribedTBX5locus,8wedetectedanovelindependentsignal

closetoTBX3.Pairwiselinkagedisequilibrium(LD)estimatesbetweenindependentvariantsatbothloci

wereextremelylow(r20.6)wasamissensevariant.Amissensevariant

(rs11057401)inCCDC92waspredictedtobedamagingby4of5insilicopredictionalgorithms

(SupplementaryTableS8);andwaspreviouslyassociatedwithcoronaryarterydisease.11SincemostAF-

associatedvariantsresideinnon-codingregionswesoughttodetermineifthesentinelvariantsortheir

proxies(r2>0.6)fellwithinregulatoryregionsinhearttissuesbasedonchromatinstatesfromthe

RoadmapEpigenomicsConsortium.At64outof67novelloci,variantswerelocatedwithinregulatory

elements(SupplementaryTableS9).Comparedto1000Genomescontrolloci,AF-associatedlociwere

significantlyenrichedwithinregulatoryelements(SupplementaryFigureS9).

Wethensoughttolinkriskvariantstocandidategenesbyassessingtheireffectongeneexpression

levels.First,sinceAFoftenarisesfromthepulmonaryveinsandleftatrium(LA),weperformedRNA

sequencing,genotyping,andeQTLanalysesin101humanleftatrialsampleswithoutstructuralheart

diseasefromtheMyocardialAppliedGenomicsNetworkrepository.Second,weidentifiedeQTLsfrom

rightatrial(RA)andleftventricular(LV)cardiactissuefromtheGenotypeTissueExpression(GTEx)

Page12of41

project.Finally,weperformedatranscriptome-wideanalysisusingtheMetaXcan12method,whichinfers

theassociationbetweengeneticallypredictedgeneexpressionanddiseaserisk.

WeobservedeQTLstooneormoregenesat17novelloci.Ofthe10eQTLsdetectedinLAtissue8

werealsodetectedinRAorLV,withconsistentdirectionality.Forexample,weobservedthatrs4484922

wasaneQTLforCASQ2inLAtissueonly.AlthoughwedetectedmoreAFlociwitheQTLsintheRAorLV

data,formanyofthese(n=8)theresultspointedtomultiplegenesperlocus(SupplementaryTableS10-

12).LAeQTLstudiesmayfacilitatetheprioritizationofcandidategenes,butarecurrentlylimitedby

samplesize.

Forthetranscriptome-wideanalysesweusedGTExhumanatrialandventricularexpressiondataas

areference.Weidentified57genessignificantlyassociatedwithAF.Ofthese,42geneswerelocatedat

AFloci,whereastheremaining15were>500kbfromanAFsentinelvariant(SupplementaryTableS13,

Figure3).TheprobablecandidategenesateachlocusaresummarizedinSupplementaryTableS12.For

example,atthelocuswithleadvariantrs4484922weobservedresultsfromalldownstreamanalyses

pointingtowardsthenearestgeneCASQ2,atrs12908437towardsthegeneIGFR1,andatrs113819537

towardsthegeneSSPN.However,formanylocitheevaluationofcandidategenesremainschallenging.

WethensoughttoassessthepleiotropiceffectsofidentifiedAFriskvariants.First,wequeriedthe

NHGRI-EBIGWASCatalogtodetectassociationstootherphenotypes(SupplementaryTableS14).

Second,usingtheUKBiobank,13weperformedaphenome-wideassociationstudy(pheWAS)for12AF

riskfactors(SupplementaryTableS15).AsillustratedinFigure4,distinctclustersofvariantswere

associatedwithAFaswellasheight,BMI,andhypertension.Thepleiotropiceffectsatrs880315(CASZ1)

Page13of41

tobloodpressure14andhyptertension14,alsoobservedintheUKBiobank(hypertension,P=2.56x10-34),

mightimplyasharedmolecularpathwaybetweenhypertensionandAF.

Insum,weidentifiedatotalof97distinctAFlocifrom65,446AFcasesandmorethan522,000

referents.Inrecentpre-publicationresults,Nielsenetal.,reported111locifrom60,620AFcasesand

morethan970,000referents,15includingmorethan18,000AFcasesfromourpriorreport.8We

thereforeperformedapreliminarymeta-analysisforthetoplociinnon-overlappingparticipantsfrom

thesetwolargeeffortswitharesultingtotalofover93,000AFcasesandmorethan1millionreferents.

Inaggregate,weidentifiedatleast134distinctAF-associatedloci(SupplementaryTableS16).

FourmajorthemesemergefromtheidentifiedAFloci.First,twoAFlocicontaingenesthatare

primarytargetsforcurrentantiarrhythmicmedicationsusedtotreatAF.TheSCN5Ageneencodesa

sodiumchannelintheheart,andthetargetofsodium-channel-blockerssuchasflecainideand

propafenone.Similarly,KCNH2encodesthealphasubunitofthepotassiumchannelcomplex,thetarget

ofpotassium-channel-inhibitingmedicationssuchasamiodarone,sotalol,anddofetilide.SCN5Aand

KCNH2havepreviouslybeenimplicatedinAFthroughGWAS,8candidategeneanalysis16andfamily-

basedstudies.17,18

Second,transcriptionalregulationappearstobeakeyfeatureofAFetiology.TBX3andtheadjacent

geneTBX5havebeenshowntoregulatethedevelopmentofthecardiacconductionsystem.19Similarly,

theNKX2-5geneisanearlycueforcardiacdevelopmentandhasbeenassociatedwithcongenitalheart

disease20andheartrate21(SupplementaryTableS14).Further,reducedfunctionofthetranscription

factorPITX2hasbeenassociatedwithAF,shorteningoftheleftatrialactionpotential,andwith

Page14of41

modulationofsodiumchannelblockertherapyintheadultleftatrium.22–24Atranscriptionalco-

regulatorynetworkgovernedbyTBX5andPITX2hasbeenshowntobecriticalforatrialdevelopment.25

Third,thetranscriptome-wideanalysesrevealedanumberofcompellingfindings.Decreased

expressionofPRRX1associatedwithAF,aresultconsistentwithfindingswherereductionofPRRX1in

zebrafishandstemcell-derivedcardiomyocyteswasassociatedwithactionpotentialshortening.26

Further,increasedexpressionofTBX5andKCNJ5associatedwithAF,afindingconsistentwithgain-of-

functionmutationsinTBX5reportedinafamilywithHolt-Oramsyndromeandahighpenetranceof

AF.27Similarly,KCNJ5encodesapotassiumchannelthatunderliesacomponentoftheIKAchcurrent,a

channelthatisupregulatedinAF.Thus,priorstudiessupportboththeroleofPRRX1,TBX5,andKCNJ5in

AFandtheobserveddirectionality.

Fourth,manyofthenovellociimplicategenesthatunderlieMendelianformsofarrhythmia

syndromes.MutationsinCASQ2leadtocatecholaminergicpolymorphicventriculartachycardia.28,29

PathogenicvariantsinPKP2impaircardiomyocytecommunicationandstructuralintegrity,andarea

commoncauseofarrhythmogenicrightventricularcardiomyopathy.30,31MutationsinGJA5,KCNH2,

SCN5A,KCNJ2,MYH7,NKX2-5,havebeenmappedinavarietyofinheritedarrhythmia,cardiomyopathy,

orconductionsystemdiseases.32Ourobservationshighlightthepleiotropyofvariationingenes

specifyingcardiacconduction,morphology,andfunction,andunderscorethecomplex,polygenicnature

ofAF.

Inconclusion,weconductedthelargestAFmeta-analysistodateandreportamorethanthree-fold

increaseinthenumberoflociassociatedwiththiscommonarrhythmia.Ourresultslaythegroundwork

forfunctionalevaluationsofgenesimplicatedbyAFriskloci.Ourfindingsalsobroadenour

Page15of41

understandingofbiologicalpathwaysinvolvedinAFandmayfacilitatethedevelopmentoftherapeutics

forAF.

Page16of41

References

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Study.Circulation129,837–47(2014).

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fibrillation.JAMA304,2263–9(2010).

4. Benjamin,E.J.etal.VariantsinZFHX3areassociatedwithatrialfibrillationinindividualsof

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genesforatrialfibrillation.Circulation130,1225–35(2014).

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8. Christophersen,I.E.etal.Large-scaleanalysesofcommonandrarevariantsidentify12newloci

associatedwithatrialfibrillation.Nat.Genet.49,946–952(2017).

9. Low,S.-K.etal.Identificationofsixnewgeneticlociassociatedwithatrialfibrillationinthe

Japanesepopulation.Nat.Genet.49,953–958(2017).

10. Weng,L.-C.etal.HeritabilityofAtrialFibrillation.Circ.Cardiovasc.Genet.10,e001838(2017).

11. Klarin,D.etal.GeneticanalysisinUKBiobanklinksinsulinresistanceandtransendothelial

migrationpathwaystocoronaryarterydisease.Nat.Genet.49,1392–1397(2017).

12. Barbeira,A.etal.IntegratingtissuespecificmechanismsintoGWASsummaryresults.bioRxiv

(2017).at

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13. Sudlow,C.etal.UKBiobank:AnOpenAccessResourceforIdentifyingtheCausesofaWide

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hypertension.Hum.Mol.Genet.24,865–74(2015).

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fibrillation.bioRxiv242149(2018).doi:10.1101/242149

16. Sinner,M.F.etal.Thenon-synonymouscodingIKr-channelvariantKCNH2-K897Tisassociated

withatrialfibrillation:resultsfromasystematiccandidategene-basedanalysisofKCNH2(HERG).

Eur.HeartJ.29,907–914(2008).

17. Olson,T.M.etal.Sodiumchannelmutationsandsusceptibilitytoheartfailureandatrial

fibrillation.JAMA293,447–54(2005).

18. McNair,W.P.etal.SCN5AMutationAssociatedWithDilatedCardiomyopathy,Conduction

Disorder,andArrhythmia.Circulation110,2163–2167(2004).

19. vanWeerd,J.H.etal.AlargepermissiveregulatorydomainexclusivelycontrolsTbx3expression

inthecardiacconductionsystem.Circ.Res.115,432–41(2014).

20. Schott,J.J.etal.CongenitalheartdiseasecausedbymutationsinthetranscriptionfactorNKX2-

5.Science281,108–11(1998).

21. denHoed,M.etal.Identificationofheartrate-associatedlociandtheireffectsoncardiac

conductionandrhythmdisorders.Nat.Genet.45,621–31(2013).

22. Kirchhof,P.etal.PITX2cIsExpressedintheAdultLeftAtrium,andReducingPitx2cExpression

PromotesAtrialFibrillationInducibilityandComplexChangesinGeneExpression.Circ.

Cardiovasc.Genet.4,123–133(2011).

23. Wang,J.etal.Pitx2preventssusceptibilitytoatrialarrhythmiasbyinhibitingleft-sided

pacemakerspecification.Proc.Natl.Acad.Sci.U.S.A.107,9753–8(2010).

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24. Syeda,F.etal.PITX2ModulatesAtrialMembranePotentialandtheAntiarrhythmic

EffectsofSodium-ChannelBlockers.J.Am.Coll.Cardiol.68,1881–1894(2016).

25. Nadadur,R.D.etal.Pitx2modulatesaTbx5-dependentgeneregulatorynetworktomaintain

atrialrhythm.Sci.Transl.Med.8,354ra115(2016).

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familiesfromIsrael.Am.J.Hum.Genet.69,1378–84(2001).

29. Lahat,H.etal.Autosomalrecessivecatecholamine-orexercise-inducedpolymorphicventricular

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30. Corrado,D.,Link,M.S.&Calkins,H.ArrhythmogenicRightVentricularCardiomyopathy.N.Engl.

J.Med.376,61–72(2017).

31. Gerull,B.etal.Mutationsinthedesmosomalproteinplakophilin-2arecommonin

arrhythmogenicrightventricularcardiomyopathy.Nat.Genet.36,1162–1164(2004).

32. HRS/EHRAExpertConsensusStatementontheStateofGeneticTestingfortheChannelopathies

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1308–1339(2011).

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Figure1.Studyandanalysisflowchart

Top,overviewoftheparticipatingstudies,numberofAFcasesandreferents,andthepercentof

samplesimputedwitheachreferencepanel.Middle,summaryoftheprimaryanalysesandthenewly

discoveredlociforAF.Bottom,overviewofthesecondaryanalysestoevaluateAFriskvariantsandloci.

23,685 AF cases 148,192 referents

35% HRC

65% 1000G(+GoNL)

17,517 AF cases 10,987 referents

100% HRC

16,064 AF cases 334,953 referents

100% HRC

8,180 AF cases 28,612 referents

100% 1000G

AFGen Consortium Broad AF Study Biobank Japan UK Biobank

Impact of risk variants on gene expression

Functional impact of risk variants

Association of risk variants to other traits GSEA

eQTL Left atrial tissue GTEx cardiac tissue

Predicted gene expression MetaXcan

Coding variation Variant Effect Predictor

Regulatory regions

HaploReg

Published GWAS GWAS catalog

AF risk factors

PheWAS in UK Biobank

Gene Set Enrichtment Analysis

MAGENTA

70 novel loci in meta-analyses of GWAS

Combined ancestry analysis 67 novel

European ancestry analysis 3 additional novel

Page20of41

Figure2.Manhattanplotofcombined-ancestrymeta-analysis

Theplotshows67novel(red)and27known(blue)geneticlociassociatedwithAFatasignificancelevel

ofP<1x10-8(dashedline),forthecombined-ancestrymeta-analysis.They-axishasabreakbetween–

log10(P)of30and510toemphasizethenovelloci.

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Figure3.VolcanoplotofMetaXcanresultsfromhumanhearttissues.

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−3 −2 −1 0 1 2 3

010

2030

40Heart Left Ventricle

Effect

−log 1

0(p)

●

●

●

●

●●

●

●

●

●

●

●

●

●●

●

●

●●

●●●●●●

●●

●●

●

● ●●● ● ●

●

●

●●

●

●

●

●

●

●●●

● ●

● ●

CEP68

TBX5

DEK

KDM1B TPMT

KCNJ5

GMCL1

PCM1

C11orf45

PXN

MKRN2

C3orf83 GNB4

NUCKS1

ERCC6L2 PGAP3

PRRX1

SYNE2

FAM13B

ARL3 TES

PCYOX1 WIPF1

IGF1R FBN2

CCDC92 REEP2

MTSS1 SLC27A6

MAPT ZNF664 BEST3

DNAH10OS MPPED2 UBE2D3

METTL11B

a Left ventricle b Right atrial appendage

Effect size for association of predicted gene expression and AF risk Effect size for association of predicted gene expression and AF risk

Page22of41

TheplotsshowtheresultsfromMetaXcanbasedonleftventricle(a,N=190)andrightatrialappendage(b,N=159)tissuefromGTEx.Each

plottedpointrepresentstheassociationresultsfromMetaXcanforanindividualgene.Thex-axisshowstheeffectsizeforMetaXcanassociations

ofpredictedgeneexpressionandAFriskforeachtestedgene.They-axisshowsthe–log10(P)fortheMetaXcanassociationspergene.Genes

withpositiveeffect(red)showedanassociationofincreasedpredictedgeneexpressionwithAFrisk.Geneswithnegativeeffect(blue)showed

anassociationofdecreasedpredictedgeneexpressionwithAFrisk.ThehighlightedgenesaresignificantafterBonferronicorrectionforall

testedgenesandtissueswithaP<5.36x10-6.Theresultforonegeneforrightatrialappendage(b)isnotshown(SNX4,Effect=6.94,P=0.2).

Page23of41

Figure4.Cross-traitassociationsofAFriskvariantswithAFriskfactorsintheUKBiobank.

TheheatmapshowsassociationsofnovelandknownsentinelvariantsatAFrisklocifromthecombined-

ancestrymeta-analysis.Shownarevariantsandphenotypeswithsignificantassociationsaftermultiple

testing,correctingfor12phenotypesviaBonferroniwithP<4.17x10-3.Listednexttothephenotypeson

they-axisarethenumberofcasesforbinarytraitsortotalsamplesizeforquantitativetraits.

Hierarchicalclusteringwasperformedonavariantlevelusingthecompletelinkagemethodbasedon

Euclidiandistance.ThecoloringrepresentstheZ-scoreorientedtowardsAFrisk,redindicatesincreased

valueoftraitorincreasedriskfordiseaseinthesamedirectionofAFrisk,andblueindicatesincreased

valueoftraitorincreasedriskfordiseaseintheoppositedirectionofAFrisk.Abbreviations,BMI,body-

massindex,CAD,coronaryarterydisease,PVD,pulmonaryvasculardisease.

Page24of41

Table1.Novellociincombined-ancestrymeta-analysis

Rsid Chr hg19 Risk/RefAlleleRAF[%] RR 95%CI P NearestGene(s) Func

impQual I

2HET PHET

rs187585530 1 10167425 A/G 0.53 1.55 1.36-1.77 1.18x10-10 UBE4B missense 0.81 0 1.000rs880315 1 10796866 C/T 37 1.04 1.03-1.06 5.04x10-09 CASZ1 intronic 0.97 40.7 0.150rs146518726 1 51535039 A/G 3 1.18 1.12-1.24 2.05x10-10 C1orf185 intronic 0.96 0 1.000rs4484922 1 116310818 G/C 68 1.07 1.05-1.08 4.57x10-16 CASQ2 intronic 0.98 0 0.689rs79187193 1 147255831 G/A 95 1.12 1.08-1.16 8.07x10-10 GJA5 upstream 0.97 39.8 0.190rs4951261 1 205717823 C/A 38 1.05 1.03-1.06 1.17x10-09 NUCKS1 intronic 0.99 0 0.788rs6546620 2 26159940 C/T 75 1.07 1.05-1.09 2.96x10-14 KIF3C intronic 0.95 33 0.201rs6742276 2 61768745 A/G 61 1.05 1.03-1.06 2.42x10-11 XPO1 upstream 0.99 0 0.731rs72926475 2 86594487 G/A 87 1.07 1.05-1.10 3.49x10-10 REEP1,KDM3A intergenic 0.97 38.7 0.180rs56181519 2 175555714 C/T 74 1.08 1.06-1.10 1.52x10-19 WIPF1,CHRNA1 intergenic 0.94 0 0.519rs295114 2 201195602 C/T 60 1.07 1.05-1.09 1.76x10-20 SPATS2L intronic 1.00 21.9 0.275rs2306272 3 66434643 C/T 32 1.05 1.04-1.07 4.54x10-11 LRIG1 missense 0.99 30.6 0.218rs17490701 3 111587879 G/A 86 1.07 1.05-1.10 5.43x10-11 PHLDB2 intronic 0.97 46.8 0.111rs4855075 3 179170494 T/C 14 1.06 1.04-1.08 4.00x10-09 GNB4 upstream 0.95 10.1 0.348rs3822259 4 10118745 T/G 68 1.05 1.03-1.06 1.93x10-09 WDR1 upstream 0.96 0 0.922rs3960788 4 103915618 C/T 42 1.05 1.04-1.07 2.09x10-12 SLC9B1 intronic 0.98 35.7 0.183rs55754224 4 114428714 T/C 25 1.05 1.03-1.07 9.25x10-09 CAMK2D intronic 0.99 0 0.511rs10213171 4 148937537 G/C 8 1.11 1.08-1.14 6.09x10-14 ARHGAP10 intronic 0.96 0 0.584rs174048 5 142650404 C/T 16 1.07 1.05-1.09 1.05x10-11 ARHGAP26,NR3C1 intergenic 0.99 0 0.852rs6882776 5 172664163 G/A 67 1.06 1.05-1.08 3.18x10-14 NKX2-5 upstream 0.95 0 0.858rs73366713 6 16415751 G/A 86 1.11 1.09-1.14 5.80x10-21 ATXN1 intronic 0.94 0 0.879rs34969716 6 18210109 A/G 31 1.09 1.07-1.11 2.91x10-25 KDM1B intronic 0.80 19.5 0.290rs3176326 6 36647289 G/A 80 1.06 1.04-1.08 7.95x10-11 CDKN1A intronic 0.95 0 0.450rs117984853 6 149399100 T/G 9 1.12 1.09-1.15 8.38x10-17 UST downstream 0.83 56.5 0.100rs55734480 7 14372009 A/G 27 1.05 1.03-1.07 7.34x10-10 DGKB intronic 0.94 0 0.441rs6462078 7 28413187 A/C 75 1.06 1.04-1.08 1.35x10-11 CREB5 intronic 0.98 22.2 0.278rs74910854 7 74110705 G/A 7 1.10 1.07-1.13 3.36x10-09 GTF2I intronic 0.74 24.4 0.265

Page25of41

rs62483627 7 106856002 A/G 24 1.05 1.03-1.07 5.17x10-09 COG5 intronic 0.98 15.1 0.318rs7789146 7 150661409 G/A 80 1.06 1.04-1.08 6.51x10-10 KCNH2 intronic 0.96 66 0.0193rs7846485 8 21803735 C/A 87 1.09 1.07-1.12 3.71x10-15 XPO7 intronic 0.99 0 0.676rs62521286 8 124551975 G/A 7 1.13 1.10-1.16 1.24x10-16 FBXO32 intronic 0.96 0 0.678rs35006907 8 125859817 A/C 33 1.05 1.03-1.06 2.76x10-09 MTSS1,LINC00964 regulatoryreg. 0.97 0 0.542rs6993266 8 141762659 A/G 54 1.05 1.03-1.06 9.73x10-10 PTK2 intronic 0.99 5.7 0.374rs4977397 9 20235004 A/G 57 1.04 1.03-1.06 8.60x10-09 SLC24A2,MLLT3 intergenic 0.95 38.3 0.166rs4743034 9 109632353 A/G 23 1.05 1.03-1.07 3.98x10-09 ZNF462 intronic 1.00 0 0.963rs10760361 9 127178266 G/T 65 1.04 1.03-1.06 7.03x10-09 PSMB7 upstream 0.97 0 0.680rs7919685 10 65315800 G/T 53 1.06 1.04-1.07 5.00x10-16 REEP3 intronic 1.00 49.2 0.0965rs11001667 10 77935345 G/A 22 1.06 1.05-1.08 1.06x10-11 C10orf11 intronic 0.98 26.8 0.243rs1044258 10 103605714 T/C 66 1.05 1.03-1.06 1.07x10-09 C10orf76 3'UTR 0.98 14 0.325rs1822273 11 20010513 G/A 27 1.07 1.05-1.09 8.99x10-17 NAV2 intronic 0.98 0 0.764rs949078 11 121629007 C/T 27 1.05 1.04-1.07 4.77x10-11 SORL1,MIR100HG intergenic 0.97 0 0.600rs113819537 12 26348429 C/G 74 1.05 1.03-1.07 2.23x10-09 SSPN upstream 0.98 0 0.597rs12809354 12 32978437 C/T 15 1.08 1.06-1.11 5.48x10-16 PKP2 intronic 0.97 31.5 0.211rs7978685 12 57103154 T/C 28 1.06 1.04-1.07 5.99x10-12 NACA downstream 0.98 2.4 0.393rs35349325 12 70097464 T/C 54 1.05 1.04-1.07 9.04x10-13 BEST3 upstream 0.96 0 0.863rs11180703 12 76223817 G/A 56 1.05 1.03-1.06 3.58x10-10 KRR1,PHLDA1 intergenic 0.97 0 0.482rs12810346 12 115091017 T/C 15 1.07 1.05-1.09 2.34x10-09 TBX5-AS1,TBX3 intergenic 0.84 0 0.428rs12298484 12 124418674 C/T 67 1.05 1.03-1.06 2.05x10-09 DNAH10 intronic 1.00 0 0.973rs9580438 13 23373406 C/T 32 1.06 1.04-1.07 1.01x10-13 LINC00540,BASP1P1 intergenic 0.98 0 0.485rs28631169 14 23888183 T/C 20 1.07 1.05-1.09 3.80x10-14 MYH7 intronic 0.97 14.5 0.319rs2145587 14 32981484 A/G 28 1.08 1.06-1.10 2.32x10-21 AKAP6 intronic 0.94 0 0.888rs73241997 14 35173775 T/C 16 1.07 1.05-1.10 1.10x10-13 SNX6,CFL2 intergenic 0.98 62.2 0.0318rs10873299 14 77426711 A/G 38 1.05 1.03-1.07 9.62x10-11 LRRC74,IRF2BPL intergenic 0.96 4.4 0.381rs62011291 15 63800013 G/A 23 1.05 1.04-1.07 6.14x10-09 USP3 intronic 0.96 0 0.727rs12591736 15 70454139 G/A 82 1.06 1.04-1.08 2.47x10-09 TLE3,UACA intergenic 0.92 0 0.966rs12908004 15 80676925 G/A 16 1.08 1.06-1.10 1.95x10-14 LINC00927,ARNT2 intronic 0.96 57.4 0.0520rs12908437 15 99287375 T/C 39 1.05 1.03-1.06 1.25x10-10 IGF1R intronic 0.98 0 0.818rs2286466 16 2014283 G/A 81 1.07 1.05-1.09 3.53x10-14 RPS2 synonymous 0.92 0 0.882

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rs8073937 17 7435040 G/A 37 1.05 1.04-1.07 1.02x10-11 POLR2A,TNFSF12 intergenic 0.96 12.3 0.335rs72811294 17 12618680 G/C 89 1.07 1.05-1.09 6.87x10-09 MYOCD intronic 0.95 32.3 0.206rs242557 17 44019712 G/A 61 1.04 1.03-1.06 4.35x10-09 MAPT intronic 0.94 62.1 0.0319rs7219869 17 68337185 G/C 44 1.05 1.03-1.06 1.49x10-10 KCNJ2,CASC17 intergenic 0.99 16.1 0.312rs9953366 18 46474192 C/T 66 1.05 1.04-1.07 9.03x10-11 SMAD7 intronic 0.93 0 0.565rs2145274 20 6572014 A/C 91 1.11 1.08-1.14 6.97x10-13 CASC20,BMP2 regulatoryreg. 0.96 19 0.295rs7269123 20 61157939 C/T 58 1.05 1.03-1.06 5.59x10-09 C20orf166 intronic 0.85 68.7 0.0123rs2834618 21 36119111 T/G 90 1.12 1.09-1.14 2.93x10-18 LOC100506385 intronic 0.93 21.6 0.277rs465276 22 18600583 G/A 61 1.05 1.04-1.07 1.84x10-11 TUBA8 intronic 0.90 0 0.654Abbreviations,Chr,chromosome,CI,confidenceinterval,Func,functionalconsequence(mostsevereconsequencebyvarianteffectpredictor),HET,

heterogeneity,I2,I-square,impQual,averageimputationquality,P,P-value,RAF,riskallelefrequency,reg,region,RR,relativerisk.

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Methods

Samples

Participantsfrommorethan50studieswereincludedinthisanalysis.Participantswerecollectedfrom

bothcase-controlstudiesforatrialfibrillation(AF)andpopulationbasedstudies.Themajorityofstudies

werepartoftheAtrialFibrillationGenetics(AFGen)consortiumandtheBroadAFStudy(BroadAF).

AdditionalsummarylevelresultsfromtheUKBiobank(UKBB)andtheBiobankJapan(BBJ)were

included(Figure1).Casesincludeparticipantswithparoxysmalorpermanentatrialfibrillation,oratrial

flutter,andreferentswerefreeofthesediagnoses.Adjudicationofatrialfibrillationforeachstudyis

describedintheSupplementaryNotes.AscertainmentofAFintheUKBiobankincludessampleswith

oneormoreofthefollowingcodes1)Non-cancerillnesscode,self-reported(1471,1483),2)Operation

code(1524),3)Diagnoses–main/secondaryICD10(I48,I48.0-4,I48.9),4)Underlying

(primary/secondary)causeofdeath:ICD10(I48,I48.0-4,I48.9)5)Diagnoses–main/secondaryICD9

(4273),6)Operativeprocedures–main/secondaryOPCS(K57.1,K62.1-4).1–3Baselinecharacteristicsfor

eachstudyarereportedinSupplementaryTableS17.Weanalyzed:55,114casesand482,295referents

ofEuropeanancestry,1,307casesand7,660referentsofAfricanAmericanancestry,8,180casesand

28,612referentsofJapaneseancestry,568casesand1,096referentsfromBraziland277casesand

3,081referentsofHispanicethnicity.SamplesfromtheUKBiobank,theBroadAFStudy,andthe

followingstudiesfromtheAFGenconsortium:SiGN,EGCUT,PHBandtheVanderbiltAtrialFibrillation

Registry,werepreviouslynotincludedinprimaryAFGWASdiscoveryanalyses.Thereisminimalsample

overlapfromthestudiesMGHAF,BBJandAFLMUbetweenthisandpreviousanalyses.Ethicsapproval

forparticipationwasobtainedindividuallybyeachstudy.

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GenotypingandGenotypeCalling

SampleswithintheBroadAFStudyweregenotypedattheBroadInstituteusingtheInfinium

PsychArray-24v1.2BeadChip.Theyweregenotypedin19batches,groupedbyoriginofthesamples

andwithabalancedcasecontrolmixoneacharray.Commonvariants(≥1%MAF)werecalledwith

GenomeStudiov1.6.2.2andBirdseedv1.33,4whilerarevariants(95%samplecallrate,

Hardy-Weinberg-Equilibrium(HWE)P>1x10-6andvariantcall-rate>97%.Forcommonvariants,a

consensusmergewasperformedbetweenthecall-setsfromGenomeStudioandBirdseed.Foreach

genotypeonlyconcordantcallsbetweenthetwoalgorithmswerekept.Thecommonvariantsfromthe

consensuscallwerethencombinedwiththerarevariantscallsfromthezCallalgorithm.Samplesfrom

allbatcheswerejoinedpriortoperformingpre-imputationQCsteps.Detailedproceduresfor

genotypingandgenotypecallingfortheSiGNstudy,6theUKBiobank,7,8andtheBiobankJapan9are

describedelsewhere.Detailsongenotypingandcallingforallparticipatingstudiesarelistedin

SupplementaryTableS18.

Imputation

Pre-imputationQCfilteringofsamplesandvariantswasconductedbasedonrecommendedguidelines

asdescribedinSupplementaryTableS19.QCstepswereperformedbyeachstudyandaredescribedin

SupplementaryTableS18.MoststudieswithEuropeanancestrysamplesperformedimputationwith

theHRCreferencev1.110panelontheMichiganImputationServer.11StudieswithoutavailableHRC

imputationwereincludedbasedonimputationtothe1000GenomesPhase1integratedv3panel

(March2012).12ParticipantsoftheSiGNstudywereimputedtoacombinedreferencepanelconsisting

of1000Genomesphase1plusGenomeoftheNetherlands.13StudiesfromBrazilwereimputedwiththe

HRCreferencev1.1panel.StudiesofJapaneseancestryorHispanicethnicitywereimputedtothe1000G

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Phase1integratedv3panel(March2012).StudiesofAfricanAmericanancestrywereimputedtothe

HRCreferencev1.1panelorthe1000GPhase1integratedv3panel(March2012).Studieswereadvised

tousetheHRCpreparationandcheckingtool(http://www.well.ox.ac.uk/~wrayner/tools/)priorto

imputation.PrephasingandimputationmethodsforeachstudyaredescribedinSupplementaryTable

S18.

Primarystatisticalanalyses

Genome-wideassociationtestingonautosomalchromosomeswasperformedusinganadditivegenetic

effectmodelbasedongenotypeprobabilities.Eachancestrygroupwasanalyzedseparatelyforeach

study.FortheBroadAFStudy,theprimarystatisticalanalysiswasperformedjointlyonunrelated

individuals,excludingoneofeachpairforrelatedsampleswithPI_HAT>0.2ascalculatedinPLINK

v1.90.14,15Sampleswithsexmismatchesandsamplecallrate0.0442),preferentiallykeepingsampleswithAF

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casestatus.Primaryanalysesforallotherstudieswereperformedatthestudysitesandthesummary

leveldataoftheresultswereprovided.Prevalentcaseswereanalyzedinalogisticregressionmodeland

mostincidentcaseswereanalyzedinaCoxproportionalhazardsmodel.Studieswithbothprevalentand

incidentcasesanalyzedtheseeitherseparatelyusingalogisticregressionmodelorCoxproportional

hazardsmodelrespectively,orjointlyinalogisticregressionmodel(SupplementaryTableS18).

Summarylevelresultswerefiltered,keepingvariantswithimputationquality>0.3andMAF*

imputationquality*Nevents≥10.Post-imputationQCstepswerealsoperformed,whichincludeda

checkofallelefrequencies,inspectionofManhattan-plots,QQ-plots,PZ-plots,andthedistributionof

effectestimatesandstandarderrors,calculationofgenomicinflation(λGC),andconsistentdirectionality

forknownAFriskvariants.19

Meta-analyses

Summarylevelresultsweremeta-analyzedjointlywithMETALusingafixedeffectmodelwithinverse-

varianceweightedapproach,correctingforgenomiccontrol.20Separatemeta-analyseswereconducted

foreachancestry.TheresultsfortheJapanese9andHispanic1specificanalyseshavepreviouslybeen

reportedandwerenotincludedasseparateresults.Variantswereincludediftheywerepresentinat

leasttwostudiesandshowedanaverageMAF≥0.1%.Tocorrectformultipletesting,agenome-wide

significancethresholdofP<1x10-8wasappliedforeachanalysis.Thisthresholdisbasedonanaive

BonferronicorrectionforindependentvariantswithMAF≥0.1%,usinganLDthresholdofr2

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statistic22acrossancestryspecificmeta-analyses.Weaccountformultipletestingacross94variants

usingaBonferronicorrection,resultinginasignificancethresholdofP<5.32x10-4fortheheterogeneity

test.

BroadAFLDreferenceandproxies

Alinkagedisequilibrium(LD)referencefilewascreatedincluding26,796Europeanancestryindividuals

fromth