CC BYMichiel RienstraLuisa FocoAlessandro De GrandiCatriona L. K. BarnesOzren PolasekStephanie M. GogartenBorbala MifsudChristian FuchsbergerBarry LondonLorenz RischM. Abdullah SaidMark ChaffinBlair H. SmithMuhammad B. RiazGardar SveinbjornssonTerho LehtimäkiIgor RudanThibaud BoutinAlbert V. SmithDaniel LevySébastien ThériaultJames J. CranleyCornelia M. van DuijnNathan R. TuckerMassimo ManginoAndrew P. MorrisAndrew A. HicksPier D. LambiaseStefan WeissAmelia W. HallJ. Wouter JukemaStefan van DuijvenbodenCristian PattaroMaria Fernanda Lima-CostaElsayed Z. SolimanMika KähönenStella TrompetNiek VerweijYalda JamshidiPeter P. PramstallerAnnette PetersMichele OriniLu-Chen WengMaria Pina ConcasMichael R. BarnesFabiola Del Greco MMichael PreussYordi J. van de VegteVilmundur GudnasonRenan P. SouzaAndré G. UitterlindenPashupati P. MishraMartina Müller-NurasyidEmelia J. BenjaminRuth J. F. LoosJames H. CartwrightKathryn L. LunettaJ. Gustav SmithLenore J. LaunerJames G. WilsonJulia RamirezNathalia M. AraujoHelen R. WarrenJonathan MartenRenée de MutsertBorbala MifsudUlrike PetersJennifer A. BrodyStefan KääbYong QianMelanie WaldenbergerAdolfo CorreaSusan R. HeckbertMuhammad B. RiazStephan B. FelixJie YaoOlli T. RaitakariAnna F. DominiczakDiane FatkinPaolo GaspariniHonghuang LinGudmar ThorleifssonPeter W. MacfarlaneSandosh PadmanabhanCecilia M. LindgrenNina MononenSébastien ThériaultLars LindErik IngelssonKatri SääksjärviIvana KolcicAlexander P. ReinerEric A. WhitselChristy L. AveryXiuqing GuoMark J. CaulfieldNathan R. TuckerMassimo ManginoDavid J. PorteousJeffrey HaesslerKjell NikusMorten S. OlesenAndrew P. MorrisAaron IsaacsDavíð O. ArnarAnubha MahajanMarcus DörrIan FordCaroline HaywardUnnur ThorsteinsdottirSheila UliviBruce M. PsatyAmelia W. HallMichael J. CutlerAlan R. ShuldinerStefan van DuijvenbodenGianfranco SinagraTim D. SpectorPeter K. JoshiPatrick SulemRebecca D. JacksonHilma HolmKatharina SchrammDan E. ArkingAlvaro AlonsoMoritz F. SinnerKent D. TaylorStefanie AeschbacherJerome I. RotterM. Yldau van der EndeGeorg EhretBruno H. StrickerMary L. BiggsDaniel F. GudbjartssonArie C. MaanKathleen A. RyanEric BoerwinkleKathleen F. KerrMay E. MontasserAlison D. MurrayKari StefanssonJoshua C. BisChristopher Newton-ChehUwe VölkerDavid ConenLeo-Pekka LyytikäinenKonstantin StrauchHenry J. LinLu-Chen WengMarten E. van den BergIoanna NtallaAntonio Luiz Pinho RibeiroNilesh J. SamaniMichael R. BarnesEdward G. LakattaTamara B. HarrisKirill V. TarasovCharles KooperbergHarry CampbellKenneth RiceCathy C. LaurieJames F. WilsonAndrew TinkerGirish N. NadkarniHao MeiErwin P. BottingerJohan SundströmVilmantas GiedraitisAntti JulaVeikko SalomaaSeung Hoan ChoiSolmaz AssaAmanda A. SeyerleM. Benjamin ShoemakerAdrienne M. StilpSteven A. LubitzJun DingDennis O. Mook-KanamoriNina Hutri-Kähönen2025-06-162025-06-162020-05-212041-172310.1038/s41467-020-15706-x10.17863/cam.5368410.17615/q73n-j671https://ror.circle-u.eu/handle/123456789/592317<jats:title>Abstract</jats:title><jats:p>The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (<jats:italic>N</jats:italic> = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.</jats:p>OPENMaleMultifactorial InheritanceSupplementary DataEMC NIHES-03-77-01Arrhythmias, Cardiac / physiopathologyGeneral Physics and AstronomyGene ExpressionArrhythmiasCardiovascularGenome-wide association studiesPublic health care science, environmental and occupational healthMedical Genetics and GenomicsCALCINEURINElectrocardiographyinfo:eu-repo/classification/ddc/616Cardiovascular Diseasename=General Biochemistry,Genetics and Molecular BiologyELEMENTS2.1 Biological and endogenous factorsGWASCardiac and Cardiovascular SystemsAetiologyCardiovascular Diseases / physiopathologycardiovascular geneticsGenetic Loci / geneticsRISKDECREASE/dk/atira/pure/subjectarea/asjc/1300/1300KardiologiQRBiological SciencesMedicinsk genetik och genomikEndophenotypeHeart DiseaseCardiovascular diseasesArrhythmias, Cardiac; Cardiovascular Diseases; Endophenotypes; Female; Gene Expression; Genetic Loci; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Male; Multifactorial Inheritance; Quantitative Trait Loci; Electrocardiographyname=General Physics and AstronomyGenetics, developmental biology, physiologyCardiovascular DiseasesFemaleMedical GeneticsCardiac/dk/atira/pure/subjectarea/asjc/1600/1600Cardiology and Cardiovascular DiseaseBiotechnologyCardiovascular Diseases / geneticsHumanEndophenotypesScienceGeneral Biochemistry,Genetics and Molecular BiologyDURATIONEMC OR-01GENOME-WIDE ASSOCIATION ; ATRIAL-FIBRILLATION ; MUTATIONS ; RISK ; DURATION ; CARDIOMYOPATHY ; CALCINEURIN ; BRADYCARDIA ; DECREASE ; ELEMENTSQuantitative Trait Loci610R MedicineQuantitative Trait Loci / geneticsArticleSDG 3 - Good Health and Well-beingKardiologi och kardiovaskulära sjukdomarGeneticsHumansGenetic Predisposition to DiseaseGENOME-WIDE ASSOCIATIONMedicinsk genetikCARDIOMYOPATHYBiomedical and Clinical SciencesMUTATIONSHuman GenomeArrhythmias, Cardiac / geneticsGenetic VariationArrhythmias, CardiacGeneral ChemistryCardiovascular geneticsGenetic Predisposition to Disease / geneticscardiovascular diseasesGood Health and Well BeingGenetic Locigenome-wide association studiesATRIAL-FIBRILLATIONBRADYCARDIA/dk/atira/pure/subjectarea/asjc/3100/3100name=General ChemistryGenome-Wide Association Studypublication0301 basic medicine0303 health sciences03 medical and health sciences3. Good healthdoi_dedup___PMC72423313243990011368/298024611370/2ff3fb3e-fa6e-44cc-85f2-e63823a002471887/318121220.500.14243/42211810138/31627020.500.11820/7dbc060f-8590-4ae8-a7e0-055dd5996c222164/14604