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
License:None: All rights reserved
Document VersionPeer reviewed version
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
Publisher Rights Statement:Final Version of Record available at: https://doi.org/10.1038/s41588-018-0133-9
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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:[email protected]
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
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16. Sinner,M.F.etal.Thenon-synonymouscodingIKr-channelvariantKCNH2-K897Tisassociated
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17. Olson,T.M.etal.Sodiumchannelmutationsandsusceptibilitytoheartfailureandatrial
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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.
Page21of41
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