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

Julien Barc; Rafik Tadros; Charlotte Glinge; David Chiang; Mariam Jouni; Floriane Simonet; Sean Jurgens; Manon Baudic; Michele Nicastro; Franck Potet; Joost Offerhaus; Roddy Walsh; Seung Hoan Choi; Arie Verkerk; Yuka Mizusawa; Soraya Anys; Damien Minois; Marine Arnaud; Josselin Duchateau; Yanushi Wijeyeratne; Alison Muir; Michael Papadakis; Silvia Castelletti; Margherita Torchio; Cristina Gil Ortuño; Javier Lacunza; Daniela Giachino; Natascia Cerrato; Raphaël 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 Rowe; Claire Federspiel; Sophie Le Page; Leslie Placide; Antoine Milhem; Hector Barajas-Martinez; Britt-Maria Beckmann; Ingrid Krapels; Johannes Steinfurt; Bo Gregers Winkel; Reza Jabbari; Moore Shoemaker; Bas Boukens; Doris Škorić-Milosavljević; Hennie Bikker; Federico Manevy; Peter Lichtner; Marta Ribasés; Thomas Meitinger; Martina Müller-Nurasyid; Konstantin Strauch; Annette Peters; Holger Schulz; Lars Schwettmann; Reiner Leidl; Margit Heier; Jan Veldink; Leonard 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 Odening; Marina Cerrone; Larry Chinitz; Paul Volders; Maarten van de Berg; Gabriel Laurent; Laurence Faivre; Charles Antzelevitch; Stefan Kääb; Alain Al Arnaout; Jean-Marc Dupuis; Jean Luc Pasquié; Olivier Billon; Jason Roberts; Laurence Jesel; Martin Borggrefe; Pier Lambiase; Jacques Mansourati; Bart Loeys; Antoine Leenhardt; Pascale Guicheney; Philippe Maury; Eric Schulze-Bahr; Tomas Robyns; Jeroen Breckpot; Dominique Babuty; Silvia Priori; Carlo Napolitano; Pascal Defaye; Frédéric Anselme; Jean Philippe Darmon; François Wiart; Carlo de Asmundis; Pedro Brugada; Ramon Brugada; Elena Arbelo; Josep Brugada; Philippe Mabo; Nathalie Behar; Carla Giustetto; Maria Sabater Molina; Juan Gimeno; Can Hasdemir; Peter Schwartz; Lia Crotti; Pascal Mckeown; Sanjay Sharma; Elijah Behr; Michel Haissaguerre; Frédéric Sacher; Caroline Rooryck; Hanno Tan; Carol Remme; Pieter Postema; Mario Delmar; Patrick Ellinor; Steven Lubitz; Jean-Baptiste Gourraud; Michael Tanck; Alfred George; Calum Macrae; Paul Burridge; Christian Dina; Vincent Probst; Arthur Wilde; Jean-Jacques Schott; Richard Redon; Connie Bezzina

doi:10.1038/s41588-021-01007-6

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

Julien Barc, Rafik Tadros, Charlotte Glinge, David Chiang, Mariam Jouni, Floriane Simonet, Sean Jurgens, Manon Baudic, Michele Nicastro, Franck Potet, …

Nature Genetics, Vol.54(3)

03/2022

DOI: https://doi.org/10.1038/s41588-021-01007-6

PMID: 35210625

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.

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Title: Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility
Creators - without role: Julien Barc - Inserm
Rafik Tadros - Amsterdam University Medical Centers
Charlotte Glinge - Amsterdam University Medical Centers
David Chiang - Brigham and Women's Hospital
Mariam Jouni - Northwestern University
Floriane Simonet - Institut du Thorax
Sean Jurgens - Broad Institute
Manon Baudic - Institut du Thorax
Michele Nicastro - Amsterdam Neuroscience
Franck Potet - Northwestern University
Joost Offerhaus - Amsterdam University Medical Centers
Roddy Walsh - Amsterdam Neuroscience
Seung Hoan Choi - Broad Institute
Arie Verkerk - University of Amsterdam
Yuka Mizusawa - ERN GUARD-Heart
Soraya Anys - Institut du Thorax
Damien Minois - Institut du Thorax
Marine Arnaud - Institut du Thorax
Josselin Duchateau - Electrophysiology and Heart Modeling Institute
Yanushi Wijeyeratne - ERN GUARD-Heart
Alison Muir - Belfast Health and Social Care Trust
Michael Papadakis - St George's, University of London
Silvia Castelletti - IRCCS Istituto Auxologico Italiano
Margherita Torchio - IRCCS Istituto Auxologico Italiano
Cristina Gil Ortuño
Javier Lacunza - Hospital Universitario Virgen de la Arrixaca
Daniela Giachino - University of Turin
Natascia Cerrato - University of Turin
Raphaël Martins - Centre Hospitalier Universitaire de Rennes
Oscar Campuzano - Institut d'Investigació Biomèdica de Girona
Sonia van Dooren - ERN GUARD-Heart
Aurélie Thollet - Institut du Thorax
Florence Kyndt - Institut du Thorax
Andrea Mazzanti - ERN GUARD-Heart
Nicolas Clémenty - Centre Hospitalier Universitaire de Tours
Arnaud Bisson - Centre Hospitalier Universitaire de Tours
Anniek Corveleyn - KU Leuven
Birgit Stallmeyer - University Hospital Münster
Sven Dittmann - University Hospital Münster
Johan Saenen - Antwerp University Hospital
Antoine Noël - Centre Hospitalier Régional Universitaire de Brest
Shohreh Honarbakhsh - British Heart Foundation
Boris Rudic - Heidelberg University
Halim Marzak - Université de Strasbourg
Matthew Rowe - Western University
Claire Federspiel - Centre Hospitalier Départemental Vendée
Sophie Le Page - Centre Hospitalier Universitaire d'Angers
Leslie Placide - Centre Hospitalier Universitaire de Montpellier
Antoine Milhem - Centre Hospitalier de La Rochelle
Hector Barajas-Martinez - Lankenau Institute for Medical Research
Britt-Maria Beckmann - LMU Klinikum
Ingrid Krapels
Johannes Steinfurt - University of Freiburg
Bo Gregers Winkel - ERN GUARD-Heart
Reza Jabbari - ERN GUARD-Heart
Moore Shoemaker
Bas Boukens - Amsterdam University Medical Centers
Doris Škorić-Milosavljević - Amsterdam University Medical Centers
Hennie Bikker - ERN GUARD-Heart
Federico Manevy - Amsterdam University Medical Centers
Peter Lichtner - Helmholtz Zentrum München
Marta Ribasés - Universitat Autònoma de Barcelona
Thomas Meitinger - Helmholtz Zentrum München
Martina Müller-Nurasyid - Helmholtz Zentrum München
Konstantin Strauch - Helmholtz Zentrum München
Annette Peters - Helmholtz Zentrum München
Holger Schulz - Helmholtz Zentrum München
Lars Schwettmann - Helmholtz Zentrum München
Reiner Leidl - Helmholtz Zentrum München
Margit Heier - Helmholtz Zentrum München
Jan Veldink - University Medical Center Utrecht
Leonard van den Berg - University Medical Center Utrecht
Philip van Damme - VIB-KU Leuven Center for Brain & Disease Research
Daniele Cusi - Bio4Dreams
Chiara Lanzani - Vita-Salute San Raffaele University
Sidwell Rigade - Institut du Thorax
Eric Charpentier - Institut du Thorax
Estelle Baron - Centre National de la Recherche Scientifique
Stéphanie Bonnaud - Institut du Thorax
Simon Lecointe - Institut du Thorax
Audrey Donnart - Institut du Thorax
Hervé Le Marec - Institut du Thorax
Stéphanie Chatel - Institut du Thorax
Matilde Karakachoff - Institut du Thorax
Stéphane Bézieau - Inserm
Barry London - University of Iowa
Jacob Tfelt-Hansen - Copenhagen University Hospital
Dan Roden - Vanderbilt University Medical Center
Katja Odening - University of Freiburg
Marina Cerrone - New York University
Larry Chinitz - New York University
Paul Volders
Maarten van de Berg
Gabriel Laurent - Maison des Sciences de l’Homme de Dijon
Laurence Faivre
Charles Antzelevitch - Lankenau Institute for Medical Research
Stefan Kääb - ERN GUARD-Heart
Alain Al Arnaout
Jean-Marc Dupuis
Jean Luc Pasquié - Université de Montpellier, Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Olivier Billon - Roche
Jason Roberts - Western University
Laurence Jesel - Université de Strasbourg
Martin Borggrefe - University Medical Centre Mannheim
Pier Lambiase - British Heart Foundation
Jacques Mansourati - Centre Hospitalier Régional Universitaire de Brest
Bart Loeys - Antwerp University Hospital
Antoine Leenhardt - ERN GUARD-Heart
Pascale Guicheney - Université Sorbonne Nouvelle
Philippe Maury - Hôpital Rangueil
Eric Schulze-Bahr - University Hospital Münster
Tomas Robyns - ERN GUARD-Heart
Jeroen Breckpot - KU Leuven
Dominique Babuty - Centre Hospitalier Universitaire de Tours
Silvia Priori - University of Pavia
Carlo Napolitano - University of Pavia
Pascal Defaye - Centre Hospitalier Universitaire de Grenoble
Frédéric Anselme - Université de Rouen Normandie
Jean Philippe Darmon - Centre Hospitalier du Mans
François Wiart - Centre Hospitalier Universitaire de La Réunion
Carlo de Asmundis - Centro de Investigación Biomédica en Red
Pedro Brugada - Universitair Ziekenhuis Brussel
Ramon Brugada - Institut d'Investigació Biomèdica de Girona
Elena Arbelo - Universitat de Barcelona
Josep Brugada - Universitat de Barcelona
Philippe Mabo - Centre Hospitalier Universitaire de Rennes
Nathalie Behar - Centre Hospitalier Universitaire de Rennes
Carla Giustetto - University of Turin
Maria Sabater Molina
Juan Gimeno - Universidad de Murcia
Can Hasdemir - Ege University
Peter Schwartz - Istituti di Ricovero e Cura a Carattere Scientifico
Lia Crotti - Istituti di Ricovero e Cura a Carattere Scientifico
Pascal Mckeown - Queen's University Belfast
Sanjay Sharma - St George’s University Hospitals NHS Foundation Trust
Elijah Behr - St George’s University Hospitals NHS Foundation Trust
Michel Haissaguerre
Frédéric Sacher
Caroline Rooryck - Centre Hospitalier Universitaire de Bordeaux
Hanno Tan - Netherlands Heart Institute
Carol Remme - Amsterdam University Medical Centers
Pieter Postema - Amsterdam Neuroscience
Mario Delmar - New York University
Patrick Ellinor - Massachusetts General Hospital
Steven Lubitz - Broad Institute
Jean-Baptiste Gourraud
Michael Tanck
Alfred George - Northwestern University
Calum Macrae - Brigham and Women's Hospital
Paul Burridge - Northwestern University
Christian Dina - Institut du Thorax
Vincent Probst - ERN GUARD-Heart
Arthur Wilde - Amsterdam University Medical Centers
Jean-Jacques Schott - Institut du Thorax
Richard Redon - ERN GUARD-Heart
Connie Bezzina - Amsterdam University Medical Centers
Publication Details: Nature Genetics, Vol.54(3)
Grant note: The MINE study (J.H.V.) has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 772376—EScORIAL). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public–private partnerships. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. J. Barc is supported by the research program Etoiles montantes des Pays de la Loire REGIOCARD RPH081-U1087-REG-PDL, ANR JCJC LEARN (R21006NN, RPV21014NNA) and by the H2020-MSCA-IF-2014 Program of the European Commission (RISTRAD-661617). R.T. is supported by the Canadian Heart Rhythm Society’s George Mines Award, the European Society of Cardiology research award, and the Philippa and Marvin Carsley Cardiology Chair. D.Y.C. is supported by Fondation Leducq and National Institutes of Health (NIH) NHGRI T32 (no. 1T32HG010464-01). M. Baudic was supported by IRP—VERACITIES—New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES, an I-SITE NExT health and engineering initiative (Ecole Centrale and Nantes University) and by the IRP—GAINES—Genetic Architecture IN cardiovascular disEaSes funded by INSERM and CNRS. R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. S.C. is supported by the NHLBI BioData Catalyst Fellows Program. C.A.R. is supported by Fondation Leducq, the Dutch Heart Foundation (CVON PREDICT2) and the Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw; 91714371). Y.D.W. is supported by the Robert Lancaster Memorial Fund. M.P. is supported by Cardiac Risk in the Young. S.V.D. is supported by Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel, project ‘Unravelling the molecular genetic pathways of Brugada Syndrome by cardiomics research’, VUB IRP project ‘IMAGica: an Integrative personalized Medical Approach for Genetic diseases, Inherited Cardia Arrhythmias as a model’ and Innoviris BRIDGE 2017, project ‘IGenCare: Integrated Personalised Medical Genomics Care Solution for Patients with Rare Genetic Diseases’. S.H. is supported by the Barts BRC. B.R. is supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). B.G.W. is supported by the Danish Heart Foundation. M.B.S. is supported by K23HL127704. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga België, the National Lottery of Belgium and the KU Leuven Opening the Future Fund. D.C. and C.L. are supported by HYPERGENES (HEALTH-F4-2007). D.R. is supported by R01 HL149826, P50 GM115305. P.J.S. acknowledges the support of Leducq Foundation for Cardiovascular Research grant 18CVD05. P.V.D. is supported by the Netherlands CardioVascular Research Initiative (CVON PREDICT2). C.A. is supported by NIH HL47678 and HL138103, W.W. Smith Charitable Trust and Wistar Morris Fund. M.B. is Supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). P.D.L. is supported by UCL/UCLH Biomedicine NIHR and Barts BRC. B.L. is supported by GOA—Antigone 33933. J.B. is supported by a Senior Clinical Fellowship of the Flemish Science Foundation (FWO). E.B. is supported by the British Heart Foundation including BHF Clinical Research Training Fellowship (FS/11/71/28918: Future diagnostic role and new genetic loci in SADS), Cardiac Risk in the Young and Robert Lancaster Memorial fund sponsored by McColl’s Ltd. Retail Group. H.L.T. is supported by the European Union’s Horizon 2020 research and innovation program under acronym ESCAPE-NET, registered under grant agreement no. 733381, and the Dutch Heart Foundation (CVON RESCUED and PREDICT2 projects). M.D. is supported by NIH-RO1 HL134328. P.T.E. was supported by the Fondation Leducq (14CVD01), the NIH (1RO1HL092577, R01HL128914, K24HL105780), the American Heart Association (18SFRN34110082) and by a research grant from Bayer AG to the Broad Institute. S.A.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. J.-B.G. received a grant from the Fédération Française de Cardiologie (PREVENT project). A.L.G. is supported by the Fondation Leducq. C.A.M.R. is supported by the Leducq Foundation and Burroughs Wellecome Fund. A.A.W. is supported by the Dutch Heart Foundation (CVON PREDICT2 project). J.-J.S. is supported by the Fondation pour la Recherche Médicale (DEQ20140329545). R.R. and P.G. are supported by the National Agency for Research (ANR-GENSUD-14-CE10-0001). C.R.B. is supported by the Dutch Heart Foundation (CVON PREDICT2 project), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq (17CVD02).
Identifiers: 9939550909311
Academic Unit: Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Language: English
Resource Type: Journal article
Local Fields: hal-03589076