6533b7defe1ef96bd12769e7
RESEARCH PRODUCT
Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization
Peter W. MacfarlaneNiels GrarupRuth J. F. LoosMarcus DörrPeter P. PramstallerTorben HansenJames F. WilsonLu-chen WengLu-chen WengEduardo Tarazona-santosHonghuang LinYong QianJeffrey R. O'connellMaria Pina ConcasClaudia SchurmannClaudia SchurmannMichele OriniJoshua C. BisArchie CampbellSusan R. HeckbertJie YaoEulalia CatamoClaus GraffJames G. WilsonJames G. WilsonPashupati P. MishraMassimo ManginoMartina Müller-nurasyidBorbala MifsudBorbala MifsudLinda RepettoStephan B. FelixJulia RamirezRebecca D. JacksonEric BoerwinkleEric BoerwinkleMonika StollMonika StollElsayed Z. SolimanMaryam KavousiDavid J. PorteousNina MononenDan E. ArkingLaura AndreasenLaura AndreasenLorenz RischAntonio Luiz Pinho RibeiroPier D. LambiaseMika KähönenXia ShenXia ShenXia ShenKenneth RiceEric A. WhitselNona SotoodehniaVictor NauffalVictor NauffalKonstantin StrauchJørgen K. KantersHenry VölzkeDaniel S. EvansJonas L. IsaksenAlessandro De GrandiHao MeiAlexander P. ReinerAlexander P. ReinerChristy L. AveryThiago P. LealThiago P. LealAlanna C. MorrisonChristian FuchsbergerChristian FuchsbergerM. Arfan IkramMoritz SinnerYongmei LiuBruno H. StrickerFrancesco CuccaAllan LinnebergAllan LinnebergPatricia B. MunroeChristina EllervikChristina EllervikChristina EllervikOlli T. RaitakariOlli T. RaitakariMelanie WaldenbergerReem SalmanXiuqing GuoXiuqing GuoXiuqing GuoSandosh PadmanabhanThuyvy DuongDawood DarbarStefan WeissArden MoscatiAlvaro AlonsoCornelia M. Van DuijnCornelia M. Van DuijnGianfranco SinagraLuisa FocoMatthias NauckKathleen A. RyanKjell NikusGustav AhlbergGustav AhlbergHelen R. WarrenKent D. TaylorKent D. TaylorKent D. TaylorNiek VerweijRebecca FreudlingCristian PattaroMichael PreussCharles KooperbergAnne RichmondDavid ConenOliver HinesOliver HinesJuhani JunttilaLeo-pekka LyytikäinenNina Hutri-kähönenKirill V. TarasovUlrich SchottenM. Benjamin ShoemakerMarten E. Van Den BergJerome I. RotterJerome I. RotterJerome I. RotterMichael J. CutlerAdolfo CorreaBruce M. PsatyCaroline HaywardYalda JamshidiPau NavarroJ W BenjaminsPatrick T. EllinorPatrick T. EllinorMassimo MezzavillaWilliam J YoungWilliam J YoungStefan KääbLars LindAntonio De LucaHeikki V. HuikuriMarjo-riitta JärvelinGuillaume ParéStefan Van DuijvenbodenUwe VölkerM Fernanda Lima-costaPhilippe FroguelPhilippe FroguelPhilippe FroguelJan A. KorsAnnette PetersDavid SchlessingerChristopher Newton-chehJ. Wouter JukemaAndrew TinkerDennis O. Mook-kanamoriAntoine R BaldassariStefanie AeschbacherMariaelisa GraffNajim LahrouchiNajim LahrouchiHenry J. LinHenry J. LinHenry J. LinGiorgia GirottoGiulia PelliccioneJeffrey HaesslerAaron IsaacsRebecca N. MitchellCarolina RoselliCarolina RoselliMassimiliano CoccaSina A. GharibRozenn N. LemaitreRaymond NoordamMorten S. OlesenSteven A. LubitzSteven A. LubitzJun DingMay E. MontasserJennifer A. BrodyStella TrompetTraci M. BartzDania RazaDania RazaThomas MeitingerAndrew P. MorrisAndrew P. MorrisAndrew P. MorrisJames P. CookSébastien ThériaultSébastien ThériaultMartin GögeleAndré G. UitterlindenPim Van Der HarstPim Van Der HarstAlan PittmanFarah AhmedSimin LiuCasia NursyifaPaul L. HuangKristen K. PattonTerho Lehtimäkisubject
medicine.medical_specialtybusiness.industryLocus (genetics)Atrial fibrillationmedicine.diseaseQT intervalGenetic architectureSudden cardiac deathQRS complexInternal medicinecardiovascular systemmedicineCardiologyRepolarizationcardiovascular diseasesbusinessVentricular depolarizationdescription
AbstractThe QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-11-04 |