Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
Dan E ArkingSara L PulitLia CrottiPim van der HarstPatricia B MunroeTamara T KoopmannNona SotoodehniaElizabeth J RossinMichael MorleyXinchen WangAndrew D JohnsonAlicia LundbyDaníel F GudbjartssonPeter A NoseworthyMark EijgelsheimYuki BradfordKirill V TarasovMarcus DörrMartina Müller-NurasyidAnnukka M LahtinenIlja M NolteAlbert Vernon SmithJoshua C BisAaron IsaacsStephen J NewhouseDaniel S EvansWendy S PostDaryl WaggottLeo-Pekka LyytikäinenAndrew A HicksLewin EiseleDavid EllinghausCaroline HaywardPau NavarroSheila UliviToshiko TanakaDavid J TesterStéphanie ChatelStefan GustafssonMeena KumariRichard W MorrisÅsa T NaluaiSandosh PadmanabhanAlexander KluttigBernhard StrohmerAndrie G PanayiotouMaria TorresMichael KnoflachJaroslav A HubacekKamil SlowikowskiSoumya RaychaudhuriRunjun D KumarTamara B HarrisLenore J LaunerAlan R ShuldinerAlvaro AlonsoJoel S BaderGeorg EhretHailiang HuangW H Linda KaoJames B StraitPeter W MacfarlaneMorris BrownMark J CaulfieldNilesh J SamaniFlorian KronenbergJohann Willeitnull nullnull nullJ Gustav SmithKarin H GreiserHenriette Meyer Zu SchwabedissenKarl WerdanMassimo CarellaLeopoldo ZelanteSusan R HeckbertBruce M PsatyJerome I RotterIvana KolcicOzren PolašekAlan F WrightMaura GriffinMark J Dalynull nullDavid O ArnarHilma HólmUnnur Thorsteinsdottirnull nullJoshua C DennyDan M RodenRebecca L ZuvichValur EmilssonAndrew S PlumpMartin G LarsonChristopher J O'DonnellXiaoyan YinMarco BobboAdamo P D'AdamoAnnamaria IorioGianfranco SinagraAngel CarracedoSteven R CummingsMichael A NallsAntti JulaKimmo K KontulaAnnukka MarjamaaLasse OikarinenMarkus PerolaKimmo PorthanRaimund ErbelPer HoffmannKarl-Heinz JöckelHagen KälschMarkus M Nöthennull nullMarcel den HoedRuth J F LoosDag S ThelleChristian GiegerThomas MeitingerSiegfried PerzAnnette PetersHanna PruchaMoritz F SinnerMelanie WaldenbergerRudolf A de BoerLude FrankePieter A van der VleutenBritt Maria BeckmannEimo MartensAbdennasser BardaiNynke HofmanArthur A M WildeElijah R BehrChrysoula DalageorgouJohn R GiudicessiArgelia Medeiros-DomingoJulien BarcFlorence KyndtVincent ProbstAlice GhidoniRoberto InsoliaRobert M HamiltonStephen W SchererJeffrey BrandimartoKenneth MarguliesChristine E MoravecFabiola del Greco MChristian FuchsbergerJeffrey R O'ConnellWai K LeeGraham C M WattHarry CampbellSarah H WildNour E El MokhtariNorbert FreyFolkert W AsselbergsIrene Mateo LeachGerjan NavisMaarten P van den BergDirk J van VeldhuisenManolis KellisBouwe P KrijtheOscar H FrancoAlbert HofmanJan A KorsAndré G UitterlindenJacqueline C M WittemanLyudmyla KedenkoClaudia LaminaBen A OostraGonçalo R AbecasisEdward G LakattaAntonella MulasMarco OrrúDavid SchlessingerManuela UdaMarcello R P MarkusUwe VölkerHarold SniederTimothy D SpectorJohan ÄrnlövLars LindJohan SundströmAnn-Christine SyvänenMika KivimakiMika KähönenNina MononenOlli T RaitakariJorma S ViikariVera AdamkovaStefan KiechlMaria BrionAndrew N NicolaidesBernhard PaulweberJohannes HaertingAnna F DominiczakFredrik NybergPeter H WhincupAroon D HingoraniJean-Jacques SchottConnie R BezzinaErik IngelssonLuigi FerrucciPaolo GaspariniJames F WilsonIgor RudanAndre FrankeThomas W MühleisenPeter P PramstallerTerho J LehtimäkiAndrew D PatersonAfshin ParsaYongmei LiuCornelia M van DuijnDavid S SiscovickVilmundur GudnasonYalda JamshidiVeikko SalomaaStephan B FelixSerena SannaMarylyn DeRiggi RitchieBruno H StrickerKari StefanssonLaurie A BoyerThomas P CappolaJesper V OlsenKasper LagePeter J SchwartzStefan KääbAravinda ChakravartiMichael J AckermanArne PfeuferPaul I W de BakkerChristopher Newton-ChehPublished in: Nature genetics (2014)
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.