Journal article
Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility
Nature genetics, Vol.54(3), pp.232-239
03/2022
DOI: 10.1038/s41588-021-01007-6
PMCID: PMC9376964
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 Na
1.5, 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 Na
1.5 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.
Details
- Title: Subtitle
- Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility
- Creators
- Julien Barc - ERN GUARD-HeartRafik Tadros - University of AmsterdamCharlotte Glinge - University of AmsterdamDavid Y Chiang - Brigham and Women's HospitalMariam Jouni - Northwestern University Feinberg School of MedicineFloriane Simonet - Institut du ThoraxSean J Jurgens - Broad InstituteManon Baudic - Institut du ThoraxMichele Nicastro - University of AmsterdamFranck Potet - Northwestern University Feinberg School of MedicineJoost A Offerhaus - University of AmsterdamRoddy Walsh - University of AmsterdamSeung Hoan Choi - Broad InstituteArie O Verkerk - University of AmsterdamYuka Mizusawa - University of AmsterdamSoraya Anys - Institut du ThoraxDamien Minois - Institut du ThoraxMarine Arnaud - Institut du ThoraxJosselin Duchateau - Bordeaux University Hospital (CHU)Yanushi D Wijeyeratne - ERN GUARD-HeartAlison Muir - Belfast Health and Social Care TrustMichael Papadakis - St George’s University Hospitals NHS Foundation TrustSilvia Castelletti - Istituto Auxologico ItalianoMargherita Torchio - Istituto Auxologico ItalianoCristina Gil Ortuño - Cardiogenetic, Unidad de Cardiopatías Familiares, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, Murcia, SpainJavier Lacunza - Hospital Universitario Virgen de la ArrixacaDaniela F Giachino - Gonzaga UniversityNatascia Cerrato - University of TurinRaphaël P Martins - University of Rennes 1Oscar Campuzano - Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV)Sonia Van Dooren - ERN GUARD-HeartAurélie Thollet - Institut du ThoraxFlorence Kyndt - Institut du ThoraxAndrea Mazzanti - ERN GUARD-HeartNicolas Clémenty - Centre Hospitalier Universitaire de ToursArnaud Bisson - Centre Hospitalier Universitaire de ToursAnniek Corveleyn - KU LeuvenBirgit Stallmeyer - University Hospital MünsterSven Dittmann - University Hospital MünsterJohan Saenen - University of Antwerp/Antwerp University HospitalAntoine Noël - Centre Hospitalier Régional Universitaire de BrestShohreh Honarbakhsh - Barts Heart CentreBoris Rudic - German Centre for Cardiovascular ResearchHalim Marzak - University Hospital of StrasbourgMatthew K Rowe - Western UniversityClaire Federspiel - Betanien HospitalSophie Le Page - Centre Hospitalier Universitaire d'AngersLeslie Placide - CHU MontpellierAntoine Milhem - Centre Hospitalier de La RochelleHector Barajas-Martinez - Lankenau Institute for Medical ResearchBritt-Maria Beckmann - UberIngrid P Krapels - Maastricht UniversityJohannes Steinfurt - University Medical Center FreiburgBo Gregers Winkel - Copenhagen University HospitalReza Jabbari - Copenhagen University HospitalMoore B Shoemaker - Vanderbilt University Medical CenterBas J Boukens - Department of Medical Biology, University of Amsterdam, Amsterdam University Medical Centers, Amsterdam, The NetherlandsDoris Škorić-Milosavljević - University of AmsterdamHennie Bikker - Amsterdam University Medical CentersFederico Manevy - University of AmsterdamPeter Lichtner - Institute of Human Genetics, Helmholtz Zentrum MünchenMarta Ribasés - Autonomous University of BarcelonaThomas Meitinger - Institute of Human Genetics, Helmholtz Zentrum MünchenMartina Müller-Nurasyid - Ludwig-Maximilians-Universität MünchenJan H Veldink - University College UtrechtLeonard H van den Berg - University College UtrechtPhilip Van Damme - VIB-KU Leuven Center for Brain & Disease ResearchDaniele Cusi - Center for Life SciencesChiara Lanzani - Vita-Salute San Raffaele UniversitySidwell Rigade - Institut du ThoraxEric Charpentier - Institut du ThoraxEstelle Baron - Institut du ThoraxStéphanie Bonnaud - Institut du ThoraxSimon Lecointe - Institut du ThoraxAudrey Donnart - Institut du ThoraxHervé Le Marec - Institut du ThoraxStéphanie Chatel - Institut du ThoraxMatilde Karakachoff - Institut du ThoraxStéphane Bézieau - Institut du ThoraxBarry London - University of IowaJacob Tfelt-Hansen - Copenhagen University HospitalDan Roden - Vanderbilt University Medical CenterKatja E Odening - University Medical Center FreiburgMarina Cerrone - New York UniversityLarry A Chinitz - New York UniversityPaul G Volders - Maastricht UniversityMaarten P van de Berg - Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The NetherlandsGabriel Laurent - Centre Hospitalier Universitaire Dijon BourgogneLaurence Faivre - Centre de Génétique MoléculaireCharles Antzelevitch - Lankenau Institute for Medical ResearchStefan Kääb - ERN GUARD-HeartAlain Al Arnaout - Department of Cardiology, CH La Rochelle, La Rochelle, FranceJean-Marc Dupuis - Centre Hospitalier Universitaire d'AngersJean-Luc Pasquie - University of MontpellierOlivier Billon - Betanien HospitalJason D Roberts - Western UniversityLaurence Jesel - University Hospital of StrasbourgMartin Borggrefe - German Centre for Cardiovascular ResearchPier D Lambiase - Barts Heart CentreJacques Mansourati - Centre Hospitalier Régional Universitaire de BrestBart Loeys - University of Antwerp/Antwerp University HospitalAntoine Leenhardt - ERN GUARD-HeartPascale Guicheney - Sorbonne UniversitéPhilippe Maury - Centre Hospitalier Universitaire de ToulouseEric Schulze-Bahr - ERN GUARD-HeartTomas Robyns - ERN GUARD-HeartJeroen Breckpot - KU LeuvenDominique Babuty - Centre Hospitalier Universitaire de ToursSilvia G Priori - ERN GUARD-HeartCarlo Napolitano - ERN GUARD-HeartCarlo de Asmundis - Vrije Universiteit BrusselPedro Brugada - UZ Brussel-VUBRamon Brugada - University of GironaElena Arbelo - University of BarcelonaJosep Brugada - University of BarcelonaPhilippe Mabo - University of Rennes 1Nathalie Behar - University of Rennes 1Carla Giustetto - University of TurinMaria Sabater Molina - Cardiogenetic, Unidad de Cardiopatías Familiares, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, Murcia, SpainJuan R Gimeno - ERN GUARD-HeartCan Hasdemir - Ege UniversityPeter J Schwartz - ERN GUARD-HeartLia Crotti - ERN GUARD-HeartPascal P McKeown - Belfast Health and Social Care TrustSanjay Sharma - St George’s University Hospitals NHS Foundation TrustElijah R Behr - ERN GUARD-HeartMichel Haissaguerre - Bordeaux University Hospital (CHU)Frédéric Sacher - Bordeaux University Hospital (CHU)Caroline Rooryck - Centre Hospitalier Universitaire de BordeauxHanno L Tan - University of AmsterdamCarol A Remme - University of AmsterdamPieter G Postema - University of AmsterdamMario Delmar - New York UniversityPatrick T Ellinor - Broad InstituteSteven A Lubitz - Broad InstituteJean-Baptiste Gourraud - ERN GUARD-HeartMichael W Tanck - Amsterdam Public HealthAlfred L George Jr - Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL, USACalum A MacRae - Brigham and Women's HospitalPaul W Burridge - Northwestern University Feinberg School of MedicineChristian Dina - Institut du ThoraxVincent Probst - ERN GUARD-HeartArthur A Wilde - University of AmsterdamJean-Jacques Schott - ERN GUARD-HeartRichard Redon - ERN GUARD-HeartConnie R Bezzina - University of AmsterdamNantes Referral Center for inherited cardiac arrhythmia
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.54(3), pp.232-239
- DOI
- 10.1038/s41588-021-01007-6
- PMID
- 35210625
- PMCID
- PMC9376964
- NLM abbreviation
- Nat Genet
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Grant note
- 090355 / Wellcome Trust R01 HL128914 / NHLBI NIH HHS K23 HL127704 / NHLBI NIH HHS FS/11/71/28918 / British Heart Foundation P50 GM115305 / NIGMS NIH HHS R01 HL139731 / NHLBI NIH HHS 085475 / Wellcome Trust T32 HG010464 / NHGRI NIH HHS R01 HL149826 / NHLBI NIH HHS K24 HL105780 / NHLBI NIH HHS 076113 / Wellcome Trust
- Language
- English
- Date published
- 03/2022
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984297505402771
Metrics
19 Record Views