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

Abstract

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 NaV1.5, 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 NaV1.5 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.

• Authors: Julien Barc, Rafik Tadros, Charlotte Glinge, David Y Chiang, Mariam Jouni, Floriane Simonet, Sean J Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, Joost A Offerhaus, Roddy Walsh, Seung Hoan Choi, Arie O Verkerk, Yuka Mizusawa, Soraya Anys, Damien Minois, Marine Arnaud, Josselin Duchateau, Yanushi D Wijeyeratne, Alison Muir, Michael Papadakis, Silvia Castelletti, Margherita Torchio, Cristina Gil Ortuño, Javier Lacunza, Daniela F Giachino, Natascia Cerrato, Raphaël P Martins, Oscar Campuzano, Sonia Van Dooren, Aurélie Thollet, Florence Kyndt, Andrea Mazzanti, Nicolas Clémenty, Arnaud Bisson, Anniek Corveleyn, Birgit Stallmeyer, Sven Dittmann, Johan Saenen, Antoine Noël, Shohreh Honarbakhsh, Boris Rudic, Halim Marzak, Matthew K Rowe, Claire Federspiel, Sophie Le Page, Leslie Placide, Antoine Milhem, Hector Barajas-Martinez, Britt-Maria Beckmann, Ingrid P Krapels, Johannes Steinfurt, Bo Gregers Winkel, Reza Jabbari, Moore B Shoemaker, Bas J Boukens, Doris Škorić-Milosavljević, Hennie Bikker, Federico Manevy, Peter Lichtner, Marta Ribasés, Thomas Meitinger, Martina Müller-Nurasyid, KORA-Study Group, Jan H Veldink, Leonard H van den Berg, Philip Van Damme, Daniele Cusi, Chiara Lanzani, Sidwell Rigade, Eric Charpentier, Estelle Baron, Stéphanie Bonnaud, Simon Lecointe, Audrey Donnart, Hervé Le Marec, Stéphanie Chatel, Matilde Karakachoff, Stéphane Bézieau, Barry London, Jacob Tfelt-Hansen, Dan Roden, Katja E Odening, Marina Cerrone, Larry A Chinitz, Paul G Volders, Maarten P van de Berg, Gabriel Laurent, Laurence Faivre, Charles Antzelevitch, Stefan Kääb, Alain Al Arnaout, Jean-Marc Dupuis, Jean-Luc Pasquie, Olivier Billon, Jason D Roberts, Laurence Jesel, Martin Borggrefe, Pier D Lambiase, Jacques Mansourati, Bart Loeys, Antoine Leenhardt, Pascale Guicheney, Philippe Maury, Eric Schulze-Bahr, Tomas Robyns, Jeroen Breckpot, Dominique Babuty, Silvia G Priori, Carlo Napolitano, Nantes Referral Center for inherited cardiac arrhythmia, Carlo de Asmundis, Pedro Brugada, Ramon Brugada, Elena Arbelo, Josep Brugada, Philippe Mabo, Nathalie Behar, Carla Giustetto, Maria Sabater Molina, Juan R Gimeno, Can Hasdemir, Peter J Schwartz, Lia Crotti, Pascal P McKeown, Sanjay Sharma, Elijah R Behr, Michel Haissaguerre, Frédéric Sacher, Caroline Rooryck, Hanno L Tan, Carol A Remme, Pieter G Postema, Mario Delmar, Patrick T Ellinor, Steven A Lubitz, Jean-Baptiste Gourraud, Michael W Tanck, Alfred L George Jr, Calum A MacRae, Paul W Burridge, Christian Dina, Vincent Probst, Arthur A Wilde, Jean-Jacques Schott, Richard Redon, Connie R Bezzina
• Journal: Nature genetics (Nat Genet) Vol. 54 Issue 3 Pg. 232-239 (03 2022) ISSN: 1546-1718 [Electronic] United States
• PMID: 35210625 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• MAPRE2 protein, human
• Microtubule-Associated Proteins
• NAV1.5 Voltage-Gated Sodium Channel

Topics

• Alleles
• Brugada Syndrome (complications, genetics, metabolism)
• Disease Susceptibility (complications)
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Microtubule-Associated Proteins (genetics)
• Mutation
• NAV1.5 Voltage-Gated Sodium Channel (genetics, metabolism)
• Young Adult