BARC, Julien; TADROS, Rafik; GLINGE, Charlotte; CHIANG, David Y; JOUNI, Mariam; SIMONET, Floriane; JURGENS, Sean J; BAUDIC, Manon; NICASTRO, Michele; POTET, Franck; OFFERHAUS, Joost A; WALSH, Roddy; CHOI, Seung Hoan; VERKERK, Arie O; MIZUSAWA, Yuka; ANYS, Soraya; MINOIS, Damien; ARNAUD, Marine; DUCHATEAU, Josselin; WIJEYERATNE, Yanushi D; MUIR, Alison; PAPADAKIS, Michael; CASTELLETTI, Silvia; TORCHIO, Margherita; ORTUÑO, Cristina Gil; LACUNZA, Javier; GIACHINO, Daniela F; CERRATO, Natascia; MARTINS, Raphaël P; CAMPUZANO, Oscar; VAN DOOREN, Sonia; THOLLET, Aurélie; KYNDT, Florence; MAZZANTI, Andrea; CLÉMENTY, Nicolas; BISSON, Arnaud; CORVELEYN, Anniek; STALLMEYER, Birgit; DITTMANN, Sven; SAENEN, Johan; NOËL, Antoine; HONARBAKHSH, Shohreh; RUDIC, Boris; MARZAK, Halim; ROWE, Matthew K; FEDERSPIEL, Claire; LE PAGE, Sophie; PLACIDE, Leslie; MILHEM, Antoine; BARAJAS-MARTINEZ, Hector; BECKMANN, Britt-Maria; KRAPELS, Ingrid P; STEINFURT, Johannes; WINKEL, Bo Gregers; JABBARI, Reza; SHOEMAKER, Moore B; BOUKENS, Bas J; ŠKORIĆ-MILOSAVLJEVIĆ, Doris; BIKKER, Hennie; MANEVY, Federico; LICHTNER, Peter; RIBASÉS, Marta; MEITINGER, Thomas; MÜLLER-NURASYID, Martina; VELDINK, Jan H; VAN DEN BERG, Leonard H; VAN DAMME, Philip; CUSI, Daniele; LANZANI, Chiara; RIGADE, Sidwell; CHARPENTIER, Eric; BARON, Estelle; BONNAUD, Stéphanie; LECOINTE, Simon; DONNART, Audrey; LE MAREC, Hervé; CHATEL, Stéphanie; KARAKACHOFF, Matilde; BÉZIEAU, Stéphane; LONDON, Barry; TFELT-HANSEN, Jacob; RODEN, Dan; ODENING, Katja E; CERRONE, Marina; CHINITZ, Larry A; VOLDERS, Paul G; VAN DE BERG, Maarten P; LAURENT, Gabriel; FAIVRE, Laurence; ANTZELEVITCH, Charles; KÄÄB, Stefan; ARNAOUT, Alain Al; DUPUIS, Jean-Marc; PASQUIE, Jean-Luc; BILLON, Olivier; ROBERTS, Jason D; JESEL, Laurence; BORGGREFE, Martin; LAMBIASE, Pier D; MANSOURATI, Jacques; LOEYS, Bart; LEENHARDT, Antoine; GUICHENEY, Pascale; MAURY, Philippe; SCHULZE-BAHR, Eric; ROBYNS, Tomas; BRECKPOT, Jeroen; BABUTY, Dominique; PRIORI, Silvia G; NAPOLITANO, Carlo; DE ASMUNDIS, Carlo; BRUGADA, Pedro; BRUGADA, Ramon; ARBELO, Elena; BRUGADA, Josep; MABO, Philippe; BEHAR, Nathalie; GIUSTETTO, Carla; MOLINA, Maria Sabater; GIMENO, Juan R; HASDEMIR, Can; SCHWARTZ, Peter J; CROTTI, Lia; MCKEOWN, Pascal P; SHARMA, Sanjay; BEHR, Elijah R; HAISSAGUERRE, Michel; SACHER, Frédéric; ROORYCK, Caroline; TAN, Hanno L; REMME, Carol A; POSTEMA, Pieter G; DELMAR, Mario; ELLINOR, Patrick T; LUBITZ, Steven A; GOURRAUD, Jean-Baptiste; TANCK, Michael W; GEORGE, Alfred L; MACRAE, Calum A; BURRIDGE, Paul W; DINA, Christian; PROBST, Vincent; WILDE, Arthur A; SCHOTT, Jean-Jacques; REDON, Richard; BEZZINA, Connie R

doi:10.1038/s41588-021-01007-6

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Article de revue

Ce document a été publié dans

Nature Genetics. vol. 54, n° 3, p. 232-239

Résumé en anglais

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 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.< Réduire

Mots clés en anglais

Alleles

Brugada Syndrome

Disease Susceptibility

Genetic Predisposition to Disease

Genome-Wide Association Study

Humans

Microtubule-Associated Proteins

Mutation

NAV1.5 Voltage-Gated Sodium Channel

Young Adult

URI

https://oskar-bordeaux.fr/handle/20.500.12278/186976

DOI

http://dx.doi.org/10.1038/s41588-021-01007-6

Unités de recherche

Maladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211

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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.

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Résumé en anglais

Mots clés en anglais

URI

DOI

Unités de recherche