Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.
| Title: | 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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| Authors: | Barc J; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France. julien.barc@univ-nantes.fr.; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart, . julien.barc@univ-nantes.fr.; Tadros R; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute and Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.; Glinge C; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Chiang DY; Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Jouni M; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Simonet F; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Jurgens SJ; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Baudic M; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Nicastro M; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Potet F; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Offerhaus JA; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Walsh R; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Choi SH; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Verkerk AO; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Department of Medical Biology, University of Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Mizusawa Y; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Anys S; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Minois D; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Arnaud M; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Duchateau J; IHU Liryc, Electrophysiology and Heart Modeling Institute, fondation Bordeaux Université, Pessac-Bordeaux, France.; Université Bordeaux, Centre de recherche Cardio-Thoracique de Bordeaux, Bordeaux, France.; INSERM, Centre de recherche Cardio-Thoracique de Bordeaux, Bordeaux, France.; Electrophysiology and Ablation Unit, Bordeaux University Hospital (CHU), Pessac, France.; Wijeyeratne YD; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK.; Cardiology Clinical Academic Group, St. George's University Hospitals' NHS Foundation Trust, London, UK.; Muir A; Cardiology, Belfast Health and Social Care Trust and Queen's University Belfast, Belfast, UK.; Papadakis M; Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK.; Cardiology Clinical Academic Group, St. George's University Hospitals' NHS Foundation Trust, London, UK.; Castelletti S; Center for Cardiac Arrhythmias of Genetic Origin, Istituto Auxologico Italiano IRCCS, Milan, Italy.; Torchio M; Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano IRCCS, Cusano Milanino, Italy.; Ortuño CG; Cardiogenetic, Unidad de Cardiopatías Familiares, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, Murcia, Spain.; Lacunza J; Cardiology, Unidad de Cardiopatías Familiares, Hospital Universitario Virgen de la Arrixaca, Universidad de Murcia, Murcia, Spain.; Giachino DF; Clinical and Biological Sciences, Medical Genetics, University of Torino, Orbassano, Italy.; Medical Genetics, San Luigi Gonzaga University Hospital, Orbassano, Italy.; Cerrato N; Medical Sciences, Cardiology, University of Torino, Torino, Italy.; Martins RP; Cardiologie et Maladies vasculaires, Université Rennes1 - CHU Rennes, Rennes, France.; Campuzano O; Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.; Medical Science Department, University of Girona, Girona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.; Biochemistry and Molecular Genetics Department, Hospital Clinic, University of Barcelona-IDIBAPS, Barcelona, Spain.; Van Dooren S; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; 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.; Thollet A; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Kyndt F; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Mazzanti A; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Molecular Cardiology, ICS Maugeri, IRCCS and Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Clémenty N; Department of Cardiology, CHU Tours, Tours, France.; Bisson A; Department of Cardiology, CHU Tours, Tours, France.; Corveleyn A; Department of Human Genetics, Catholic University Leuven, Leuven, Belgium.; Stallmeyer B; University Hospital Münster, Institute for Genetics of Heart Diseases (IfGH), Münster, Germany.; Dittmann S; University Hospital Münster, Institute for Genetics of Heart Diseases (IfGH), Münster, Germany.; Saenen J; Cardiology, Electrophysiology - Cardiogenetics, University of Antwerp/Antwerp University Hospital, Edegem, Belgium.; Noël A; Department of Cardiology, University Hospital of Brest, Brest, France.; Honarbakhsh S; Cardiology, Medicine, Barts Heart Centre, London, UK.; Rudic B; Department 1st of Medicine, Cardiology, University Medical Center Mannheim, Mannheim, Germany.; German Center for Cardiovascular Research (DZHK), Mannheim, Germany.; Marzak H; Department of Cardiology, University Hospital of Strasbourg, Strasbourg, France.; Rowe MK; Medicine, Cardiology, Western University, London, Ontario, Canada.; Federspiel C; Department of Cardiovascular Medicine, Vendée Hospital, Service de Cardiologie, La Roche sur Yon, France.; Le Page S; Service de cardiologie, CHU Angers, Angers, France.; Placide L; Department of Cardiology, CHU Montpellier, Montpellier, France.; Milhem A; Department of Cardiology, CH La Rochelle, La Rochelle, France.; Barajas-Martinez H; Lankenau Institute for Medical Research, Wynnewood, PA, USA.; Beckmann BM; Department of Medicine I, University Hospital, LMU Munich, Munich, Germany.; University Hospital of the Johann Wolfgang Goethe University Frankfurt, Institute of Legal Medicine, Frankfurt, Germany.; Krapels IP; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.; Steinfurt J; Department of Cardiology and Angiology I, Heart Center, University Freiburg, Freiburg, Germany.; Winkel BG; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Jabbari R; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Shoemaker MB; Medicine, Cardiology, Vanderbilt University Medical Center, Nashville, TN, USA.; Boukens BJ; Department of Medical Biology, University of Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands.; Škorić-Milosavljević D; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Bikker H; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Genome Diagnostics Laboratory, Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands.; Manevy F; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Lichtner P; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.; Ribasés M; Psychiatric Genetics Unit, Institute Vall d'Hebron Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.; Meitinger T; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.; Müller-Nurasyid M; Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.; IBE, LMU Munich, Munich, Germany.; Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg University, Mainz, Germany.; Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.; Veldink JH; Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; van den Berg LH; Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.; Van Damme P; Neurology Department University Hospital Leuven, Neuroscience Department KU Leuven, Center for Brain & Disease Research VIB, Leuven, Belgium.; Cusi D; Scientific Unit, Bio4Dreams - Business Nursery for Life Sciences, Milan, Italy.; Lanzani C; Nephrology, Genomics of Renal Diseases and Hypertension Unit, Università Vita Salute San Raffaele, Milan, Italy.; Rigade S; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Charpentier E; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, Nantes, France.; Baron E; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Bonnaud S; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, Nantes, France.; Lecointe S; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Donnart A; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Université de Nantes, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, Nantes, France.; Le Marec H; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Chatel S; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Karakachoff M; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Bézieau S; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; London B; Department of Internal Medicine, Division of Cardiovascular Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, USA.; Tfelt-Hansen J; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark.; Roden D; Medicine, Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.; Medicine, Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.; Medicine, Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.; Odening KE; Department of Cardiology and Angiology I, Heart Center, University Freiburg, Freiburg, Germany.; Department of Cardiology, Translational Cardiology, University Hospital Bern, Bern, Switzerland.; Cerrone M; Medicine, Leon H. Charney Division of Cardiology, Heart Rhythm Center and Cardiovascular Genetics Program, New York University School of Medicine, New York, NY, USA.; Chinitz LA; Medicine, Leon H. Charney Division of Cardiology, Heart Rhythm Center and Cardiovascular Genetics Program, New York University School of Medicine, New York, NY, USA.; Volders PG; Department of Cardiology, CARIM, Maastricht University Medical Center, Maastricht, The Netherlands.; van de Berg MP; Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.; Laurent G; Cardiology Department, ImVia lab team IFTIM, University Hospital Dijon, Dijon, France.; Faivre L; Centre de Génétique, FHU TRANSLAD, Dijon, France.; Antzelevitch C; Lankenau Institute for Medical Research, Wynnewood, PA, USA.; Kääb S; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Department of Medicine I, University Hospital, LMU Munich, Munich, Germany.; German Center for Cardiovascular Research (DZHK), Partnersite Munich, Munich, Germany.; Arnaout AA; Department of Cardiology, CH La Rochelle, La Rochelle, France.; Dupuis JM; Service de cardiologie, CHU Angers, Angers, France.; Pasquie JL; Department of Cardiology, CNRS UMR9214 - Inserm U1046 - PHYMEDEXP, Université de Montpellier et CHU Montpellier, Montpellier, France.; Billon O; Department of Cardiovascular Medicine, Vendée Hospital, Service de Cardiologie, La Roche sur Yon, France.; Roberts JD; Medicine, Cardiology, Western University, London, Ontario, Canada.; Jesel L; Department of Cardiology, University Hospital of Strasbourg, Strasbourg, France.; INSERM 1260 - Regenerative Nanomedecine, University of Strasbourg, Strasbourg, France.; Borggrefe M; Department 1st of Medicine, Cardiology, University Medical Center Mannheim, Mannheim, Germany.; German Center for Cardiovascular Research (DZHK), Mannheim, Germany.; Lambiase PD; Cardiology, Medicine, Barts Heart Centre, London, UK.; Institute of Cardiovasculr Science, UCL, Population Health, UCL, London, UK.; Mansourati J; Department of Cardiology, University Hospital of Brest, Brest, France.; Loeys B; Center for Medical Genetics, Cardiogenetics, University of Antwerp/Antwerp University Hospital, Edegem, Belgium.; Leenhardt A; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Department of Cardiology, Hopital Bichat, Paris, France.; Guicheney P; Sorbonne Université, Paris, France.; UMR_S1166, Faculté de médecine, Sorbonne Université, INSERM, Paris, France.; Maury P; Service de cardiologie, Hôpital Rangueil, CHU de Toulouse, Toulouse, France.; Schulze-Bahr E; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; University Hospital Münster, Institute for Genetics of Heart Diseases (IfGH), Münster, Germany.; Robyns T; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium.; Cardiovascular Sciences, University of Leuven, Leuven, Belgium.; Breckpot J; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Department of Human Genetics, Catholic University Leuven, Leuven, Belgium.; Babuty D; Department of Cardiology, CHU Tours, Tours, France.; Priori SG; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Molecular Cardiology, ICS Maugeri, IRCCS and Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Napolitano C; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Molecular Cardiology, ICS Maugeri, IRCCS and Department of Molecular Medicine, University of Pavia, Pavia, Italy.; de Asmundis C; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.; Heart Rhythm Management Center, Postgraduate Program in Cardiac Electrophysiology and Pacing Universitair Ziekenhuis, Brussel-Vrije Universiteit Brussel, ERN Heart Guard Center, Brussels, Belgium.; IDIBAPS, Institut d'Investigació August Pi i Sunyer (IDIBAPS), Barcelona, Spain.; Brugada P; Heart Rhythm Management Center, UZ Brussel-VUB, Brussels, Belgium.; Brugada R; Hospital Trueta, CiberCV, University of Girona, IDIBGI, Girona, Spain, Barcelona, Spain.; Arbelo E; Arrhythmia Section, Cardiology Department, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.; Brugada J; Cardiovascular Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain.; Mabo P; Cardiologie et Maladies vasculaires, Université Rennes1 - CHU Rennes, Rennes, France.; Behar N; Cardiologie et Maladies vasculaires, Université Rennes1 - CHU Rennes, Rennes, France.; Giustetto C; Medical Sciences, Cardiology, University of Torino, Torino, Italy.; Molina MS; Cardiogenetic, Unidad de Cardiopatías Familiares, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, Murcia, Spain.; Gimeno JR; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Cardiology, Unidad de Cardiopatías Familiares, Hospital Universitario Virgen de la Arrixaca, Universidad de Murcia, Murcia, Spain.; Hasdemir C; Department of Cardiology, Ege University School of Medicine, Bornova, Turkey.; Schwartz PJ; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Center for Cardiac Arrhythmias of Genetic Origin, Istituto Auxologico Italiano IRCCS, Milan, Italy.; Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano IRCCS, Cusano Milanino, Italy.; Crotti L; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Center for Cardiac Arrhythmias of Genetic Origin, Istituto Auxologico Italiano IRCCS, Milan, Italy.; Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano IRCCS, Cusano Milanino, Italy.; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Istituto Auxologico Italiano IRCCS, Milan, Italy.; Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.; McKeown PP; Cardiology, Belfast Health and Social Care Trust and Queen's University Belfast, Belfast, UK.; Sharma S; Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK.; Cardiology Clinical Academic Group, St. George's University Hospitals' NHS Foundation Trust, London, UK.; Behr ER; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK.; Cardiology Clinical Academic Group, St. George's University Hospitals' NHS Foundation Trust, London, UK.; Haissaguerre M; IHU Liryc, Electrophysiology and Heart Modeling Institute, fondation Bordeaux Université, Pessac-Bordeaux, France.; Université Bordeaux, Centre de recherche Cardio-Thoracique de Bordeaux, Bordeaux, France.; INSERM, Centre de recherche Cardio-Thoracique de Bordeaux, Bordeaux, France.; Electrophysiology and Ablation Unit, Bordeaux University Hospital (CHU), Pessac, France.; Sacher F; IHU Liryc, Electrophysiology and Heart Modeling Institute, fondation Bordeaux Université, Pessac-Bordeaux, France.; Université Bordeaux, Centre de recherche Cardio-Thoracique de Bordeaux, Bordeaux, France.; INSERM, Centre de recherche Cardio-Thoracique de Bordeaux, Bordeaux, France.; Electrophysiology and Ablation Unit, Bordeaux University Hospital (CHU), Pessac, France.; Rooryck C; CHU Bordeaux, Service de Génétique Médicale, Bordeaux, France.; Université de Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Bordeaux, France.; Tan HL; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Netherlands Heart Institute, Utrecht, The Netherlands.; Remme CA; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Postema PG; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Delmar M; Medicine, Cardiology, New York University School of Medicine, New York, NY, USA.; Ellinor PT; Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital and Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Boston, MA, USA.; Lubitz SA; Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital and Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Boston, MA, USA.; Gourraud JB; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Tanck MW; Clinical Epidemiology, Biostatistics and Bioinformatics, Clinical Methods and Public Health, Amsterdam Public Health, Amsterdam, The Netherlands.; George AL Jr; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; MacRae CA; Medicine, Cardiovascular Medicine, Genetics and Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Burridge PW; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Dina C; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; Probst V; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Wilde AA; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Schott JJ; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Redon R; Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart.; Bezzina CR; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart, . c.r.bezzina@amsterdamumc.nl.; Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. c.r.bezzina@amsterdamumc.nl. |
| Corporate Authors: | KORA-Study Group; Nantes Referral Center for inherited cardiac arrhythmia |
| Source: | Nature genetics [Nat Genet] 2022 Mar; Vol. 54 (3), pp. 232-239. Date of Electronic Publication: 2022 Feb 24. |
| Publication Type: | Journal Article; Meta-Analysis; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Nature Pub. Co Country of Publication: United States NLM ID: 9216904 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1718 (Electronic) Linking ISSN: 10614036 NLM ISO Abbreviation: Nat Genet Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: New York, NY : Nature Pub. Co., c1992- |
| MeSH Terms: | Brugada Syndrome*/complications ; Brugada Syndrome*/genetics ; Brugada Syndrome*/metabolism; Disease Susceptibility/complications ; Microtubule-Associated Proteins/genetics ; NAV1.5 Voltage-Gated Sodium Channel/genetics ; NAV1.5 Voltage-Gated Sodium Channel/metabolism ; Alleles ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Mutation ; Young Adult |
| 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.; (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.) |
| Comments: | Erratum in: Nat Genet. 2022 May;54(5):735. doi: 10.1038/s41588-022-01079-y.. (PMID: 35474365) |
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| Grant Information: | R01 HL047678 United States HL NHLBI NIH HHS; R01 HL139731 United States HL NHLBI NIH HHS; R01 HL092577 United States HL NHLBI NIH HHS; T32 HG010464 United States HG NHGRI NIH HHS; R01 HL134328 United States HL NHLBI NIH HHS; P50 GM115305 United States GM NIGMS NIH HHS; R01 HL152201 United States HL NHLBI NIH HHS; R01 HL149826 United States HL NHLBI NIH HHS; K24 HL105780 United States HL NHLBI NIH HHS; K23 HL127704 United States HL NHLBI NIH HHS; 076113 United Kingdom WT_ Wellcome Trust; R56 HL138103 United States HL NHLBI NIH HHS; FS/11/71/28918 United Kingdom BHF_ British Heart Foundation; R01 HL128914 United States HL NHLBI NIH HHS; 085475 United Kingdom WT_ Wellcome Trust; United Kingdom WT_ Wellcome Trust; 090355 United Kingdom WT_ Wellcome Trust |
| Contributed Indexing: | Investigator: K Strauch; A Peters; H Schulz; L Schwettmann; R Leidl; M Heier; P Defaye; F Anselme; JP Darmon; F Wiart |
| Substance Nomenclature: | 0 (MAPRE2 protein, human); 0 (Microtubule-Associated Proteins); 0 (NAV1.5 Voltage-Gated Sodium Channel) |
| Entry Date(s): | Date Created: 20220225 Date Completed: 20220427 Latest Revision: 20221018 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC9376964 |
| DOI: | 10.1038/s41588-021-01007-6 |
| PMID: | 35210625 |
| Database: | MEDLINE |
Journal Article; Meta-Analysis; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't