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Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

dc.rights.licenseopenen_US
dc.contributor.authorBARC, Julien
dc.contributor.authorTADROS, Rafik
dc.contributor.authorGLINGE, Charlotte
dc.contributor.authorCHIANG, David Y
dc.contributor.authorJOUNI, Mariam
dc.contributor.authorSIMONET, Floriane
dc.contributor.authorJURGENS, Sean J
dc.contributor.authorBAUDIC, Manon
dc.contributor.authorNICASTRO, Michele
dc.contributor.authorPOTET, Franck
dc.contributor.authorOFFERHAUS, Joost A
dc.contributor.authorWALSH, Roddy
dc.contributor.authorCHOI, Seung Hoan
dc.contributor.authorVERKERK, Arie O
dc.contributor.authorMIZUSAWA, Yuka
dc.contributor.authorANYS, Soraya
dc.contributor.authorMINOIS, Damien
dc.contributor.authorARNAUD, Marine
dc.contributor.authorDUCHATEAU, Josselin
dc.contributor.authorWIJEYERATNE, Yanushi D
dc.contributor.authorMUIR, Alison
dc.contributor.authorPAPADAKIS, Michael
dc.contributor.authorCASTELLETTI, Silvia
dc.contributor.authorTORCHIO, Margherita
dc.contributor.authorORTUÑO, Cristina Gil
dc.contributor.authorLACUNZA, Javier
dc.contributor.authorGIACHINO, Daniela F
dc.contributor.authorCERRATO, Natascia
dc.contributor.authorMARTINS, Raphaël P
dc.contributor.authorCAMPUZANO, Oscar
dc.contributor.authorVAN DOOREN, Sonia
dc.contributor.authorTHOLLET, Aurélie
dc.contributor.authorKYNDT, Florence
dc.contributor.authorMAZZANTI, Andrea
dc.contributor.authorCLÉMENTY, Nicolas
dc.contributor.authorBISSON, Arnaud
dc.contributor.authorCORVELEYN, Anniek
dc.contributor.authorSTALLMEYER, Birgit
dc.contributor.authorDITTMANN, Sven
dc.contributor.authorSAENEN, Johan
dc.contributor.authorNOËL, Antoine
dc.contributor.authorHONARBAKHSH, Shohreh
dc.contributor.authorRUDIC, Boris
dc.contributor.authorMARZAK, Halim
dc.contributor.authorROWE, Matthew K
dc.contributor.authorFEDERSPIEL, Claire
dc.contributor.authorLE PAGE, Sophie
dc.contributor.authorPLACIDE, Leslie
dc.contributor.authorMILHEM, Antoine
dc.contributor.authorBARAJAS-MARTINEZ, Hector
dc.contributor.authorBECKMANN, Britt-Maria
dc.contributor.authorKRAPELS, Ingrid P
dc.contributor.authorSTEINFURT, Johannes
dc.contributor.authorWINKEL, Bo Gregers
dc.contributor.authorJABBARI, Reza
dc.contributor.authorSHOEMAKER, Moore B
dc.contributor.authorBOUKENS, Bas J
dc.contributor.authorŠKORIĆ-MILOSAVLJEVIĆ, Doris
dc.contributor.authorBIKKER, Hennie
dc.contributor.authorMANEVY, Federico
dc.contributor.authorLICHTNER, Peter
dc.contributor.authorRIBASÉS, Marta
dc.contributor.authorMEITINGER, Thomas
dc.contributor.authorMÜLLER-NURASYID, Martina
dc.contributor.authorVELDINK, Jan H
dc.contributor.authorVAN DEN BERG, Leonard H
dc.contributor.authorVAN DAMME, Philip
dc.contributor.authorCUSI, Daniele
dc.contributor.authorLANZANI, Chiara
dc.contributor.authorRIGADE, Sidwell
dc.contributor.authorCHARPENTIER, Eric
dc.contributor.authorBARON, Estelle
dc.contributor.authorBONNAUD, Stéphanie
dc.contributor.authorLECOINTE, Simon
dc.contributor.authorDONNART, Audrey
dc.contributor.authorLE MAREC, Hervé
dc.contributor.authorCHATEL, Stéphanie
dc.contributor.authorKARAKACHOFF, Matilde
dc.contributor.authorBÉZIEAU, Stéphane
dc.contributor.authorLONDON, Barry
dc.contributor.authorTFELT-HANSEN, Jacob
dc.contributor.authorRODEN, Dan
dc.contributor.authorODENING, Katja E
dc.contributor.authorCERRONE, Marina
dc.contributor.authorCHINITZ, Larry A
dc.contributor.authorVOLDERS, Paul G
dc.contributor.authorVAN DE BERG, Maarten P
dc.contributor.authorLAURENT, Gabriel
dc.contributor.authorFAIVRE, Laurence
dc.contributor.authorANTZELEVITCH, Charles
dc.contributor.authorKÄÄB, Stefan
dc.contributor.authorARNAOUT, Alain Al
dc.contributor.authorDUPUIS, Jean-Marc
dc.contributor.authorPASQUIE, Jean-Luc
dc.contributor.authorBILLON, Olivier
dc.contributor.authorROBERTS, Jason D
dc.contributor.authorJESEL, Laurence
dc.contributor.authorBORGGREFE, Martin
dc.contributor.authorLAMBIASE, Pier D
dc.contributor.authorMANSOURATI, Jacques
dc.contributor.authorLOEYS, Bart
dc.contributor.authorLEENHARDT, Antoine
dc.contributor.authorGUICHENEY, Pascale
dc.contributor.authorMAURY, Philippe
dc.contributor.authorSCHULZE-BAHR, Eric
dc.contributor.authorROBYNS, Tomas
dc.contributor.authorBRECKPOT, Jeroen
dc.contributor.authorBABUTY, Dominique
dc.contributor.authorPRIORI, Silvia G
dc.contributor.authorNAPOLITANO, Carlo
dc.contributor.authorDE ASMUNDIS, Carlo
dc.contributor.authorBRUGADA, Pedro
dc.contributor.authorBRUGADA, Ramon
dc.contributor.authorARBELO, Elena
dc.contributor.authorBRUGADA, Josep
dc.contributor.authorMABO, Philippe
dc.contributor.authorBEHAR, Nathalie
dc.contributor.authorGIUSTETTO, Carla
dc.contributor.authorMOLINA, Maria Sabater
dc.contributor.authorGIMENO, Juan R
dc.contributor.authorHASDEMIR, Can
dc.contributor.authorSCHWARTZ, Peter J
dc.contributor.authorCROTTI, Lia
dc.contributor.authorMCKEOWN, Pascal P
dc.contributor.authorSHARMA, Sanjay
dc.contributor.authorBEHR, Elijah R
dc.contributor.authorHAISSAGUERRE, Michel
dc.contributor.authorSACHER, Frédéric
hal.structure.identifierService de génétique médicale
hal.structure.identifierCentre Hospitalier Universitaire de Bordeaux [CHU Bordeaux]
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorROORYCK, Caroline
dc.contributor.authorTAN, Hanno L
dc.contributor.authorREMME, Carol A
dc.contributor.authorPOSTEMA, Pieter G
dc.contributor.authorDELMAR, Mario
dc.contributor.authorELLINOR, Patrick T
dc.contributor.authorLUBITZ, Steven A
dc.contributor.authorGOURRAUD, Jean-Baptiste
dc.contributor.authorTANCK, Michael W
dc.contributor.authorGEORGE, Alfred L
dc.contributor.authorMACRAE, Calum A
dc.contributor.authorBURRIDGE, Paul W
dc.contributor.authorDINA, Christian
dc.contributor.authorPROBST, Vincent
dc.contributor.authorWILDE, Arthur A
dc.contributor.authorSCHOTT, Jean-Jacques
dc.contributor.authorREDON, Richard
dc.contributor.authorBEZZINA, Connie R
dc.date.accessioned2024-01-09T13:55:40Z
dc.date.available2024-01-09T13:55:40Z
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/186976
dc.description.abstractEnBrugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, 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 Na1.5 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.
dc.language.isoENen_US
dc.subject.enAlleles
dc.subject.enBrugada Syndrome
dc.subject.enDisease Susceptibility
dc.subject.enGenetic Predisposition to Disease
dc.subject.enGenome-Wide Association Study
dc.subject.enHumans
dc.subject.enMicrotubule-Associated Proteins
dc.subject.enMutation
dc.subject.enNAV1.5 Voltage-Gated Sodium Channel
dc.subject.enYoung Adult
dc.title.enGenome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.
dc.typeArticle de revueen_US
dc.identifier.doi10.1038/s41588-021-01007-6en_US
dc.subject.halSciences du Vivant [q-bio]/Médecine humaine et pathologieen_US
dc.identifier.pubmed35210625en_US
bordeaux.journalNature Geneticsen_US
bordeaux.page232-239en_US
bordeaux.volume54en_US
bordeaux.hal.laboratoriesMaladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211en_US
bordeaux.issue3en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcepubmed
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exportfalse
workflow.import.sourcepubmed
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Nature%20Genetics&rft.volume=54&rft.issue=3&rft.spage=232-239&rft.epage=232-239&rft.au=BARC,%20Julien&TADROS,%20Rafik&GLINGE,%20Charlotte&CHIANG,%20David%20Y&JOUNI,%20Mariam&rft.genre=article


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