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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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      Nature genetics
      Springer Science and Business Media LLC

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          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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          Author and article information

          Journal
          Nat Genet
          Nature genetics
          Springer Science and Business Media LLC
          1546-1718
          1061-4036
          March 2022
          : 54
          : 3
          Affiliations
          [1 ] Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France. julien.barc@univ-nantes.fr.
          [2 ] European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart, . julien.barc@univ-nantes.fr.
          [3 ] Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
          [4 ] Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute and Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
          [5 ] The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
          [6 ] Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
          [7 ] Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
          [8 ] Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
          [9 ] The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
          [10 ] Department of Medical Biology, University of Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
          [11 ] European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.
          [12 ] IHU Liryc, Electrophysiology and Heart Modeling Institute, fondation Bordeaux Université, Pessac-Bordeaux, France.
          [13 ] Université Bordeaux, Centre de recherche Cardio-Thoracique de Bordeaux, Bordeaux, France.
          [14 ] INSERM, Centre de recherche Cardio-Thoracique de Bordeaux, Bordeaux, France.
          [15 ] Electrophysiology and Ablation Unit, Bordeaux University Hospital (CHU), Pessac, France.
          [16 ] Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK.
          [17 ] Cardiology Clinical Academic Group, St. George's University Hospitals' NHS Foundation Trust, London, UK.
          [18 ] Cardiology, Belfast Health and Social Care Trust and Queen's University Belfast, Belfast, UK.
          [19 ] Center for Cardiac Arrhythmias of Genetic Origin, Istituto Auxologico Italiano IRCCS, Milan, Italy.
          [20 ] Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano IRCCS, Cusano Milanino, Italy.
          [21 ] Cardiogenetic, Unidad de Cardiopatías Familiares, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, Murcia, Spain.
          [22 ] Cardiology, Unidad de Cardiopatías Familiares, Hospital Universitario Virgen de la Arrixaca, Universidad de Murcia, Murcia, Spain.
          [23 ] Clinical and Biological Sciences, Medical Genetics, University of Torino, Orbassano, Italy.
          [24 ] Medical Genetics, San Luigi Gonzaga University Hospital, Orbassano, Italy.
          [25 ] Medical Sciences, Cardiology, University of Torino, Torino, Italy.
          [26 ] Cardiologie et Maladies vasculaires, Université Rennes1 - CHU Rennes, Rennes, France.
          [27 ] Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.
          [28 ] Medical Science Department, University of Girona, Girona, Spain.
          [29 ] Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
          [30 ] Biochemistry and Molecular Genetics Department, Hospital Clinic, University of Barcelona-IDIBAPS, Barcelona, Spain.
          [31 ] Centre for Medical Genetics, research group Reproduction and Genetics, research cluster Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.
          [32 ] Molecular Cardiology, ICS Maugeri, IRCCS and Department of Molecular Medicine, University of Pavia, Pavia, Italy.
          [33 ] Department of Cardiology, CHU Tours, Tours, France.
          [34 ] Department of Human Genetics, Catholic University Leuven, Leuven, Belgium.
          [35 ] University Hospital Münster, Institute for Genetics of Heart Diseases (IfGH), Münster, Germany.
          [36 ] Cardiology, Electrophysiology - Cardiogenetics, University of Antwerp/Antwerp University Hospital, Edegem, Belgium.
          [37 ] Department of Cardiology, University Hospital of Brest, Brest, France.
          [38 ] Cardiology, Medicine, Barts Heart Centre, London, UK.
          [39 ] Department 1st of Medicine, Cardiology, University Medical Center Mannheim, Mannheim, Germany.
          [40 ] German Center for Cardiovascular Research (DZHK), Mannheim, Germany.
          [41 ] Department of Cardiology, University Hospital of Strasbourg, Strasbourg, France.
          [42 ] Medicine, Cardiology, Western University, London, Ontario, Canada.
          [43 ] Department of Cardiovascular Medicine, Vendée Hospital, Service de Cardiologie, La Roche sur Yon, France.
          [44 ] Service de cardiologie, CHU Angers, Angers, France.
          [45 ] Department of Cardiology, CHU Montpellier, Montpellier, France.
          [46 ] Department of Cardiology, CH La Rochelle, La Rochelle, France.
          [47 ] Lankenau Institute for Medical Research, Wynnewood, PA, USA.
          [48 ] Department of Medicine I, University Hospital, LMU Munich, Munich, Germany.
          [49 ] University Hospital of the Johann Wolfgang Goethe University Frankfurt, Institute of Legal Medicine, Frankfurt, Germany.
          [50 ] Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
          [51 ] Department of Cardiology and Angiology I, Heart Center, University Freiburg, Freiburg, Germany.
          [52 ] Medicine, Cardiology, Vanderbilt University Medical Center, Nashville, TN, USA.
          [53 ] Genome Diagnostics Laboratory, Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands.
          [54 ] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
          [55 ] Psychiatric Genetics Unit, Institute Vall d'Hebron Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
          [56 ] Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
          [57 ] IBE, LMU Munich, Munich, Germany.
          [58 ] Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany.
          [59 ] Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
          [60 ] Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
          [61 ] Neurology Department University Hospital Leuven, Neuroscience Department KU Leuven, Center for Brain & Disease Research VIB, Leuven, Belgium.
          [62 ] Scientific Unit, Bio4Dreams - Business Nursery for Life Sciences, Milan, Italy.
          [63 ] Nephrology, Genomics of Renal Diseases and Hypertension Unit, Università Vita Salute San Raffaele, Milan, Italy.
          [64 ] Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, Nantes, France.
          [65 ] Department of Internal Medicine, Division of Cardiovascular Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
          [66 ] Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark.
          [67 ] Medicine, Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
          [68 ] Medicine, Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
          [69 ] Medicine, Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
          [70 ] Department of Cardiology, Translational Cardiology, University Hospital Bern, Bern, Switzerland.
          [71 ] Medicine, Leon H. Charney Division of Cardiology, Heart Rhythm Center and Cardiovascular Genetics Program, New York University School of Medicine, New York, NY, USA.
          [72 ] Department of Cardiology, CARIM, Maastricht University Medical Center, Maastricht, The Netherlands.
          [73 ] Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
          [74 ] Cardiology Department, ImVia lab team IFTIM, University Hospital Dijon, Dijon, France.
          [75 ] Centre de Génétique, FHU TRANSLAD, Dijon, France.
          [76 ] German Center for Cardiovascular Research (DZHK), Partnersite Munich, Munich, Germany.
          [77 ] Department of Cardiology, CNRS UMR9214 - Inserm U1046 - PHYMEDEXP, Université de Montpellier et CHU Montpellier, Montpellier, France.
          [78 ] INSERM 1260 - Regenerative Nanomedecine, University of Strasbourg, Strasbourg, France.
          [79 ] Institute of Cardiovasculr Science, UCL, Population Health, UCL, London, UK.
          [80 ] Center for Medical Genetics, Cardiogenetics, University of Antwerp/Antwerp University Hospital, Edegem, Belgium.
          [81 ] Department of Cardiology, Hopital Bichat, Paris, France.
          [82 ] Sorbonne Université, Paris, France.
          [83 ] UMR_S1166, Faculté de médecine, Sorbonne Université, INSERM, Paris, France.
          [84 ] Service de cardiologie, Hôpital Rangueil, CHU de Toulouse, Toulouse, France.
          [85 ] Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium.
          [86 ] Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
          [87 ] Heart Rhythm Management Center, Postgraduate Program in Cardiac Electrophysiology and Pacing Universitair Ziekenhuis, Brussel-Vrije Universiteit Brussel, ERN Heart Guard Center, Brussels, Belgium.
          [88 ] IDIBAPS, Institut d'Investigació August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
          [89 ] Heart Rhythm Management Center, UZ Brussel-VUB, Brussels, Belgium.
          [90 ] Hospital Trueta, CiberCV, University of Girona, IDIBGI, Girona, Spain, Barcelona, Spain.
          [91 ] Arrhythmia Section, Cardiology Department, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
          [92 ] Cardiovascular Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain.
          [93 ] Department of Cardiology, Ege University School of Medicine, Bornova, Turkey.
          [94 ] Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Istituto Auxologico Italiano IRCCS, Milan, Italy.
          [95 ] Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
          [96 ] CHU Bordeaux, Service de Génétique Médicale, Bordeaux, France.
          [97 ] Université de Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Bordeaux, France.
          [98 ] Netherlands Heart Institute, Utrecht, The Netherlands.
          [99 ] Medicine, Cardiology, New York University School of Medicine, New York, NY, USA.
          [100 ] Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital and Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Boston, MA, USA.
          [101 ] Clinical Epidemiology, Biostatistics and Bioinformatics, Clinical Methods and Public Health, Amsterdam Public Health, Amsterdam, The Netherlands.
          [102 ] Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
          [103 ] Medicine, Cardiovascular Medicine, Genetics and Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
          [104 ] European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart, . c.r.bezzina@amsterdamumc.nl.
          [105 ] Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. c.r.bezzina@amsterdamumc.nl.
          Article
          10.1038/s41588-021-01007-6
          10.1038/s41588-021-01007-6
          35210625
          2acbe4c3-b786-4fab-a2f3-33b2ac693425
          History

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