Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.
Julien BarcRafik TadrosCharlotte GlingeDavid Y ChiangMariam JouniFloriane SimonetSean Joseph JurgensManon BaudicMichele NicastroFranck PotetJoost A OfferhausRoddy WalshSeung Hoan ChoiArjan C HouwelingYuka MizusawaSoraya AnysDamien MinoisMarine ArnaudJosselin DuchateauYanushi D WijeyeratneAlison MuirMichael PapadakisSilvia CastellettiMargherita TorchioCristina Gil OrtuñoJavier LacunzaDaniela Francesca GiachinoNatascia CerratoRaphaël P MartinsÒscar CampuzanoSonia Van DoorenAurélie TholletFlorence KyndtAndrea MazzantiNicolas ClémentyArnaud BissonAnniek CorveleynBirgit StallmeyerSven DittmannJohan SaenenAntoine NoëlShohreh HonarbakhshBoris RudicHalim MarzakMatthew K RoweClaire FederspielSophie Le PageLeslie PlacideAntoine MilhemHector Barajas-MartinezBritt-Maria BeckmannIngrid P KrapelsJohannes SteinfurtBo Gregers WinkelReza JabbariMoore B ShoemakerBas J BoukensDoris Škorić-MilosavljevićHennie BikkerFederico ManevyPeter LichtnerMarta RibasésThomas MeitingerMartina Müller-Nuraysidnull nullJan Herman VeldinkLeonard H van den BergPhilip Van DammeDaniele CusiChiara LanzaniSidwell RigadeEric CharpentierEstelle BaronStéphanie BonnaudSimon LecointeAudrey DonnartHervé Le MarecStéphanie ChatelMatilde KarakachoffStephane BezieauBarry LondonJacob Tfelt-HansenDan RodenKatja E OdeningMarina CerroneLarry A ChinitzPaul G VoldersMaarten P van den BergGabriel LaurentLaurence FaivreCharles AntzelevitchStefan KääbAlain Al ArnaoutJean-Marc DupuisJean-Luc PasquieOlivier BillonJason D RobertsLaurence JeselMartin BorggrefePier D LambiaseJacques MansouratiBart LoeysAntoine LeenhardtPascale GuicheneyPhilippe MauryEric Schulze-BahrTomas RobynsJeroen BreckpotDominique BabutySilvia G PrioriCarlo Napolitanonull nullCarlos De AsmundisPedro BrugadaRamon BrugadaElena ArbeloJosep BrugadaPhilippe MaboNathalie BeharCarla GiustettoMaria Sabater MolinaJuan R GimenoCan HasdemirPeter J SchwartzLia CrottiPascal P McKeownSanjay SharmaElijah R BehrMichel HaissaguerreFrédéric SacherCaroline RooryckHanno L TanCarol A RemmePieter G PostemaMario DelmarPatrick T EllinorSteven A LubitzJean-Baptiste GourraudMichael W T TanckAlfred L GeorgeCalum A MacRaeMaged M CostantineChristian DinaVincent ProbstArthur A WildeJean-Jacques SchottRichard RedonConnie R BezzinaPublished in: Nature genetics (2022)
Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na V 1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na V 1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings.