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1. SCN5A Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in SCN5A Families.

Author

Wijeyeratne YD, Tanck MW, Mizusawa Y, Batchvarov V, Barc J, Crotti L, Bos JM, Tester DJ, Muir A, Veltmann C, Ohno S, Page SP, Galvin J, Tadros R, Muggenthaler M, Raju H, Denjoy I, Schott JJ, Gourraud JB, Skoric-Milosavljevic D, Nannenberg EA, Redon R, Papadakis M, Kyndt F, Dagradi F, Castelletti S, Torchio M, Meitinger T, Lichtner P, Ishikawa T, Wilde AAM, Takahashi K, Sharma S, Roden DM, Borggrefe MM, McKeown PP, Shimizu W, Horie M, Makita N, Aiba T, Ackerman MJ, Schwartz PJ, Probst V, Bezzina CR, and Behr ER

Subjects
Adult, Alleles, Female, Genetic Association Studies, Haploinsufficiency genetics, Humans, Likelihood Functions, Loss of Function Mutation genetics, Male, Phenotype, Risk Factors, Brugada Syndrome genetics, Genetic Predisposition to Disease, Mutation genetics, NAV1.5 Voltage-Gated Sodium Channel genetics
Abstract

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations., Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles)., Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; P =0.0078). Among SCN5A -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; P =0.0846). In SCN5A -negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; P =0.0146). Among E1784K- SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; P =0.0011)., Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.

Published
2020
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2. Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Author

Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, Postema PG, Beekman L, Walsh R, Hasegawa K, Barc J, Ernsting M, Turkowski KL, Mazzanti A, Beckmann BM, Shimamoto K, Diamant UB, Wijeyeratne YD, Kucho Y, Robyns T, Ishikawa T, Arbelo E, Christiansen M, Winbo A, Jabbari R, Lubitz SA, Steinfurt J, Rudic B, Loeys B, Shoemaker MB, Weeke PE, Pfeiffer R, Davies B, Andorin A, Hofman N, Dagradi F, Pedrazzini M, Tester DJ, Bos JM, Sarquella-Brugada G, Campuzano Ó, Platonov PG, Stallmeyer B, Zumhagen S, Nannenberg EA, Veldink JH, van den Berg LH, Al-Chalabi A, Shaw CE, Shaw PJ, Morrison KE, Andersen PM, Müller-Nurasyid M, Cusi D, Barlassina C, Galan P, Lathrop M, Munter M, Werge T, Ribasés M, Aung T, Khor CC, Ozaki M, Lichtner P, Meitinger T, van Tintelen JP, Hoedemaekers Y, Denjoy I, Leenhardt A, Napolitano C, Shimizu W, Schott JJ, Gourraud JB, Makiyama T, Ohno S, Itoh H, Krahn AD, Antzelevitch C, Roden DM, Saenen J, Borggrefe M, Odening KE, Ellinor PT, Tfelt-Hansen J, Skinner JR, van den Berg MP, Olesen MS, Brugada J, Brugada R, Makita N, Breckpot J, Yoshinaga M, Behr ER, Rydberg A, Aiba T, Kääb S, Priori SG, Guicheney P, Tan HL, Newton-Cheh C, Ackerman MJ, Schwartz PJ, Schulze-Bahr E, Probst V, Horie M, Wilde AA, Tanck MWT, and Bezzina CR

Subjects
Adolescent, Adult, Age of Onset, Alleles, Case-Control Studies, Electrocardiography, Genetic Association Studies, Genotype, Humans, Long QT Syndrome diagnosis, Long QT Syndrome mortality, Long QT Syndrome therapy, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Prognosis, Severity of Illness Index, Young Adult, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Long QT Syndrome genetics
Abstract

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility., Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score., Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance ( P <5×10 -8 ) near NOS1AP , KCNQ1 , and KLF12 , and 1 missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold ( P <10 -6 ). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r g =0.40; P =3.2×10 -3 ). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls ( P <10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive ( P <0.005)., Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

Published
2020
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3. Brugada syndrome.

Author

Mizusawa Y and Wilde AA

Subjects
Biopsy, Diagnostic Imaging, Humans, Myocardium pathology, Brugada Syndrome diagnosis, Brugada Syndrome genetics, Brugada Syndrome physiopathology, Electrocardiography methods, Genetic Predisposition to Disease
Published
2012
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4. Genome-wide association analyses identify novel Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Author

Barc, Julien, Tadros, Rafik, Glinge, Charlotte, Chiang, David Y., Jouni, Mariam, Simonet, Floriane, Jurgens, Sean J., Baudic, Manon, Nicastro, Michele, Potet, Franck, Offerhaus, Joost A., Walsh, Roddy, Choi, Seung Hoan, Verkerk, Arie O., Mizusawa, Yuka, Anys, Soraya, Minois, Damien, Arnaud, Marine, Duchateau, Josselin, Wijeyeratne, Yanushi D., Muir, Alison, Papadakis, Michael, Castelletti, Silvia, Torchio, Margherita, Ortuño, Cristina Gil, Lacunza, Javier, Giachino, Daniela F., Cerrato, Natascia, Martins, Raphaël P., Campuzano, Oscar, Van Dooren, Sonia, Thollet, Aurélie, Kyndt, Florence, Mazzanti, Andrea, Clémenty, Nicolas, Bisson, Arnaud, Corveleyn, Anniek, Stallmeyer, Birgit, Dittmann, Sven, Saenen, Johan, Noël, Antoine, Honarbakhsh, Shohreh, Rudic, Boris, Marzak, Halim, Rowe, Matthew K., Federspiel, Claire, Le Page, Sophie, Placide, Leslie, Milhem, Antoine, Barajas-Martinez, Hector, Beckmann, Britt-Maria, Krapels, Ingrid P., Steinfurt, Johannes, Winkel, Bo Gregers, Jabbari, Reza, Shoemaker, Moore B., Boukens, Bas J., Škorić-Milosavljević, Doris, Bikker, Hennie, Manevy, Federico, Lichtner, Peter, Ribasés, Marta, Meitinger, Thomas, Müller-Nurasyid, Martina, Strauch, Konstantin, Peters, Annette, Schulz, Holger, Schwettmann, Lars, Leidl, Reiner, Heier, Margit, Veldink, Jan H., van den Berg, Leonard H., Van Damme, Philip, Cusi, Daniele, Lanzani, Chiara, Rigade, Sidwell, Charpentier, Eric, Baron, Estelle, Bonnaud, Stéphanie, Lecointe, Simon, Donnart, Audrey, Le Marec, Hervé, Chatel, Stéphanie, Karakachoff, Matilde, Bézieau, Stéphane, London, Barry, Tfelt-Hansen, Jacob, Roden, Dan, Odening, Katja E., Cerrone, Marina, Chinitz, Larry A., Volders, Paul G., van de Berg, Maarten P., Laurent, Gabriel, Faivre, Laurence, Antzelevitch, Charles, Kääb, Stefan, Arnaout, Alain Al, Dupuis, Jean-Marc, Pasquie, Jean-Luc, Billon, Olivier, Roberts, Jason D., Jesel, Laurence, Borggrefe, Martin, Lambiase, Pier D., Mansourati, Jacques, Loeys, Bart, Leenhardt, Antoine, Guicheney, Pascale, Maury, Philippe, Schulze-Bahr, Eric, Robyns, Tomas, Breckpot, Jeroen, Babuty, Dominique, Priori, Silvia G., Napolitano, Carlo, Defaye, Pascal, Anselme, Frédéric, Darmon, Jean Philippe, Wiart, François, de Asmundis, Carlo, Brugada, Pedro, Brugada, Ramon, Arbelo, Elena, Brugada, Josep, Mabo, Philippe, Behar, Nathalie, Giustetto, Carla, Molina, Maria Sabater, Gimeno, Juan R., Hasdemir, Can, Schwartz, Peter J., Crotti, Lia, McKeown, Pascal P., Sharma, Sanjay, Behr, Elijah R., Haissaguerre, Michel, Sacher, Frédéric, Rooryck, Caroline, Tan, Hanno L., Remme, Carol A., Postema, Pieter G., Delmar, Mario, Ellinor, Patrick T., Lubitz, Steven A., Gourraud, Jean-Baptiste, Tanck, Michael W., George, Alfred L., MacRae, Calum A., Burridge, Paul W., Dina, Christian, Probst, Vincent, Wilde, Arthur A., Schott, Jean-Jacques, Redon, Richard, Bezzina, Connie R., KORA-Study Group, Nantes Referral Ctr Inherited Card, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé - François Bonamy, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Amsterdam UMC - Amsterdam University Medical Center, 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)., Barc, J, Tadros, R, Glinge, C, Chiang, D, Jouni, M, Simonet, F, Jurgens, S, Baudic, M, Nicastro, M, Potet, F, Offerhaus, J, Walsh, R, Hoan Choi, S, Verkerk, A, Mizusawa, Y, Anys, S, Minois, D, Arnaud, M, Duchateau, J, Wijeyeratne, Y, Muir, A, Papadakis, M, Castelletti, S, Torchio, M, Gil Ortuño, C, Lacunza, J, Giachino, D, Cerrato, N, Martins, R, Campuzano, O, Van Dooren, S, Thollet, A, Kyndt, F, Mazzanti, A, Clémenty, N, Bisson, A, Corveleyn, A, Stallmeyer, B, Dittmann, S, Saenen, J, Noël, A, Honarbakhsh, S, Rudic, B, Marzak, H, Rowe, M, Federspiel, C, Le Page, S, Placide, L, Milhem, A, Barajas-Martinez, H, Beckmann, B, Krapels, I, Steinfurt, J, Gregers Winkel, B, Jabbari, R, Shoemaker, M, Boukens, B, Škorić-Milosavljević, D, Bikker, H, Manevy, F, Lichtner, P, Ribasés, M, Meitinger, T, Müller-Nurasyid, M, Group, K, Veldink, J, van den Berg, L, Van Damme, P, Cusi, D, Lanzani, C, Rigade, S, Charpentier, E, Baron, E, Bonnaud, S, Lecointe, S, Donnart, A, Le Marec, H, Chatel, S, Karakachoff, M, Bézieau, S, London, B, Tfelt-Hansen, J, Roden, D, Odening, K, Cerrone, M, Chinitz, L, Volders, P, van de Berg, M, Laurent, G, Faivre, L, Antzelevitch, C, Kääb, S, Al Arnaout, A, Dupuis, J, Pasquie, J, Billon, O, Roberts, J, Jesel, L, Borggrefe, M, Lambiase, P, Mansourati, J, Loeys, B, Leenhardt, A, Guicheney, P, Maury, P, Schulze-Bahr, E, Robyns, T, Breckpot, J, Babuty, D, Priori, S, Napolitano, C, Referral Center for inherited cardiac arrhythmia, N, de Asmundis, C, Brugada, P, Brugada, R, Arbelo, E, Brugada, J, Mabo, P, Behar, N, Giustetto, C, Sabater Molina, M, Gimeno, J, Hasdemir, C, Schwartz, P, Crotti, L, Mckeown, P, Sharma, S, Behr, E, Haissaguerre, M, Sacher, F, Rooryck, C, Tan, H, Remme, C, Postema, P, Delmar, M, Ellinor, P, Lubitz, S, Gourraud, J, Tanck, M, L. George Jr., A, Macrae, C, Burridge, P, Dina, C, Probst, V, Wilde, A, Schott, J, Redon &amp, R, Bezzina, C, Cardiology, Graduate School, Medical Biology, ACS - Amsterdam Cardiovascular Sciences, ACS - Heart failure & arrhythmias, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, APH - Methodology, Epidemiology and Data Science, MUMC+: DA KG Polikliniek (9), RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H04 Arrhythmogenesis and cardiogenetics, and Cardiovascular Centre (CVC)

Subjects
EXPRESSION, [SDV]Life Sciences [q-bio], DIAGNOSIS, GUIDELINES, ANNOTATION, Article, NAV1.5 Voltage-Gated Sodium Channel, Young Adult, MANAGEMENT, Genetics, GWAS, Humans, Genetic Predisposition to Disease, 610 Medicine & health, SCN5A, Alleles, Brugada Syndrome, Allele, [SDV.GEN]Life Sciences [q-bio]/Genetics, HERITABILITY, Microtubule-Associated Protein, Brugada Syndrome, GWAS, SNPs, COMMON VARIANTS, Mutation, Disease Susceptibility, Human medicine, ENRICHMENT, Microtubule-Associated Proteins, SNPs, Human, GENERATION, Genome-Wide Association Study
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(V)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(V)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. Genome-wide association analyses identify new susceptibility loci for Brugada syndrome. Functional studies implicate microtubule-related trafficking effects on sodium channel expression as an underlying molecular mechanism., European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [772376-EScORIAL]; Health~Holland; Top Sector Life Sciences Health; Wellcome Trust [076113, 085475, 090355]; Helmholtz Zentrum Munchen-German Research Center for Environmental Health - German Federal Ministry of Education and Research; State of Bavaria; Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ; research program Etoiles montantes des Pays de la Loire [REGIOCARD RPH081-U1087-REG-PDL]; ANR JCJC LEARN [R21006NN, RPV21014NNA]; H2020-MSCA-IF-2014 Program of the European Commission [RISTRAD-661617]; Canadian Heart Rhythm Society's George Mines Award; European Society of Cardiology research award; Philippa and Marvin Carsley Cardiology Chair; Fondation Leducq; National Institutes of Health (NIH) NHGRI T32 [1T32HG010464-01]; IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES an I-SITE NExT health and engineering initiative (Ecole Centrale); IRP-VERACITIES-New Mechanisms for VEntricular ARrhythmia And CardIomeTabolic DIseasES an I-SITE NExT health and engineering initiative (Nantes University); IRP-GAINES-Genetic Architecture IN cardiovascular disEaSes - INSERM; CNRS; Amsterdam Cardiovascular Sciences fellowship; NHLBI BioData Catalyst Fellows Program; Dutch Heart Foundation [CVON PREDICT2]; Innovational Research Incentives Scheme Vidi grant from the Netherlands Organisation for Health Research and Development (ZonMw) [91714371]; Robert Lancaster Memorial Fund; Cardiac Risk in the Young; Wetenschappelijk Fonds Willy Gepts VUB-UZ Brussel; 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'; Barts BRC; DZHK (German Centre for Cardiovascular Research); BMBF (German Ministry of Education and Research); Danish Heart Foundation; IWT [140935]; ALS Liga Belgie; National Lottery of Belgium; KU Leuven Opening the Future Fund; HYPERGENES [HEALTH-F4-2007]; Leducq Foundation for Cardiovascular Research grant [18CVD05]; Netherlands CardioVascular Research Initiative [CVON PREDICT2]; NIH [HL47678, HL138103, 1RO1HL092577, R01HL128914, K24HL105780]; W.W. Smith Charitable Trust; Wistar Morris Fund; GOA-Antigone [33933]; Senior Clinical Fellowship of the Flemish Science Foundation (FWO); British Heart Foundation; BHF Clinical Research Training Fellowship [FS/11/71/28918]; Cardiac Risk in the Young and Robert Lancaster Memorial fund - McColl's Ltd. Retail Group; European Union's Horizon 2020 research and innovation program under acronym ESCAPE-NET [733381]; Dutch Heart Foundation; Fondation Leducq [14CVD01, 17CVD02]; American Heart Association [18SFRN34110082, 18SFRN34250007]; Bayer AG; NIH grant [1R01HL139731]; Federation Francaise de Cardiologie (PREVENT project); Leducq Foundation; Burroughs Wellecome Fund; Fondation pour la Recherche Medicale [DEQ20140329545]; National Agency for Research [ANR-GENSUD-14-CE10-0001]; Netherlands Organization for Scientific Research (VICI fellowship) [016.150.610]; [K23HL127704]; [R01 HL149826]; [P50 GM115305]; [NIH-RO1 HL134328], We are greatly indebted to the patients included in the study. We thank V. Cotard, C. Goutsmedt, M.-F. Le Cunff and N. Bourgeais for assistance in patient recruitment and L. Beekman for his technical support. We thank the biological resource centre for biobanking (CHU Nantes, Nantes Universite, Centre de ressources biologiques (BB0033-00040), F-44000 Nantes, France) for applying the following guidelines68. We are most grateful to the Genomics and Bioinformatics Core Facility of Nantes (GenoBiRD, Biogenouest, IFB) for its technical support. This research has been conducted using the UK Biobank resource; we are grateful to UK Biobank participants. 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 Munchen-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-Universitat, 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 Belgie, 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 Federation Francaise 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 Medicale (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).

Published
2022
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5. Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

Author

Yvonne M. Hoedemaekers, M. Ben Shoemaker, Pascale Guicheney, Antoine Leenhardt, Andrea Mazzanti, Minoru Horie, Jan H. Veldink, Isabelle Denjoy, Yu Kucho, Chiea Chuen Khor, Tomas Robyns, Carlo Napolitano, Peter Weeke, J. Martijn Bos, David J. Tester, Hanno L. Tan, Annika Rydberg, Patrick T. Ellinor, Pilar Galan, Taisuke Ishikawa, Seiko Ohno, Peter J. Schwartz, Masao Yoshinaga, Thomas Werge, Marta Ribasés, Bart Loeys, Jean-Jacques Schott, Jacob Tfelt-Hansen, Ulla-Britt Diamant, Marko Ernsting, Georgia Sarquella-Brugada, Yuka Mizusawa, Michael Christiansen, Pyotr G. Platonov, Annika Winbo, Thomas Meitinger, Keiko Shimamoto, Cristina Barlassina, Pieter G. Postema, Takeru Makiyama, Maarten P. van den Berg, Yanushi D. Wijeyeratne, Wataru Shimizu, Charles Antzelevitch, Christopher Newton-Cheh, Martina Müller-Nurasyid, Dan M. Roden, Vincent Probst, Takeshi Aiba, Lia Crotti, Daniele Cusi, Britt M. Beckmann, Johan Saenen, Peter Lichtner, Oscar Campuzano, Tin Aung, Nynke Hofman, Morten S. Olesen, Matteo Pedrazzini, Elijah R. Behr, Karen E. Morrison, Najim Lahrouchi, Katja E. Odening, Andrew D. Krahn, Kari L. Turkowski, J. Peter van Tintelen, Steven A. Lubitz, Federica Dagradi, Josep Brugada, Julien Barc, Birgit Stallmeyer, Stefan Kääb, Sven Zumhagen, Jonathan R. Skinner, Michael W.T. Tanck, Christopher Shaw, Brianna Davies, Eric Schulze-Bahr, Mineo Ozaki, Roddy Walsh, Antoine Andorin, Leonard H. van den Berg, Silvia G. Priori, Johannes Steinfurt, Jean-Baptiste Gourraud, Eline A. Nannenberg, Mark Lathrop, Rafik Tadros, Ramon Brugada, Leander Beekman, Peter M. Andersen, Ryan Pfeiffer, Boris Rudic, Reza Jabbari, Kanae Hasegawa, Jeroen Breckpot, Naomasa Makita, Michael J. Ackerman, Arthur A.M. Wilde, Hideki Itoh, Martin Borggrefe, Elena Arbelo, Connie R. Bezzina, Pamela J. Shaw, Ammar Al-Chalabi, Markus Munter, Cardiology, Graduate School, ACS - Heart failure & arrhythmias, ACS - Amsterdam Cardiovascular Sciences, Human Genetics, Epidemiology and Data Science, APH - Methodology, ACS - Atherosclerosis & ischemic syndromes, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences. Amsterdam University Medical Center, University of Amsterdam, European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart (ERN GUARD-Heart), Institut de Cardiologie de Montreal, Université de Montréal (UdeM), Istituto Auxologico Italiano, Shiga University of Medical Science, University of Fukui [Bunkyo], Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Lahrouchi, N, Tadros, R, Crotti, L, Mizusawa, Y, Postema, P, Beekman, L, Walsh, R, Hasegawa, K, Barc, J, Ernsting, M, Turkowski, K, Mazzanti, A, Beckmann, B, Shimamoto, K, Diamant, U, Wijeyeratne, Y, Kucho, Y, Robyns, T, Ishikawa, T, Arbelo, E, Christiansen, M, Winbo, A, Jabbari, R, Lubitz, S, Steinfurt, J, Rudic, B, Loeys, B, Shoemaker, M, Weeke, P, Pfeiffer, R, Davies, B, Andorin, A, Hofman, N, Dagradi, F, Pedrazzini, M, Tester, D, Bos, J, Sarquella-Brugada, G, Campuzano, Ó, Platonov, P, Stallmeyer, B, Zumhagen, S, Nannenberg, E, Veldink, J, van den Berg, L, Al-Chalabi, A, Shaw, C, Shaw, P, Morrison, K, Andersen, P, Müller-Nurasyid, M, Cusi, D, Barlassina, C, Galan, P, Lathrop, M, Munter, M, Werge, T, Ribasés, M, Aung, T, Khor, C, Ozaki, M, Lichtner, P, Meitinger, T, van Tintelen, J, Hoedemaekers, Y, Denjoy, I, Leenhardt, A, Napolitano, C, Shimizu, W, Schott, J, Gourraud, J, Makiyama, T, Ohno, S, Itoh, H, Krahn, A, Antzelevitch, C, Roden, D, Saenen, J, Borggrefe, M, Odening, K, Ellinor, P, Tfelt-Hansen, J, Skinner, J, van den Berg, M, Olesen, M, Brugada, J, Brugada, R, Makita, N, Breckpot, J, Yoshinaga, M, Behr, E, Rydberg, A, Aiba, T, Kääb, S, Priori, S, Guicheney, P, Tan, H, Newton-Cheh, C, Ackerman, M, Schwartz, P, Schulze-Bahr, E, Probst, V, Horie, M, Wilde, A, Tanck, M, Bezzina, C, and Cardiovascular Centre (CVC)

Subjects
Multifactorial Inheritance, [SDV]Life Sciences [q-bio], Genome-wide association study, 030204 cardiovascular system & hematology, Severity of Illness Index, Sudden cardiac death, Electrocardiography, 0302 clinical medicine, inheritance pattern, Medicine, Cardiac and Cardiovascular Systems, Age of Onset, Genetics, 0303 health sciences, Kardiologi, Genetic disorder, genome-wide association study, Prognosis, 3. Good health, Phenotype, Medical genetics, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Genotype, Long QT syndrome, 610 Medicine & health, BIO/18 - GENETICA, QT interval, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, Physiology (medical), long QT syndrome, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Alleles, Genetic Association Studies, MED/01 - STATISTICA MEDICA, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, inheritance patterns, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, Heritability, medicine.disease, Genetic architecture, Genome-wide Association Study, Inheritance Patterns, Long Qt Syndrome, Case-Control Studies, Human medicine, business
Abstract

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance ( P −8 ) near NOS1AP , KCNQ1 , and KLF12 , and 1 missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold ( P −6 ). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r g =0.40; P =3.2×10 −3 ). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls ( P P Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

Published
2020
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6. Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

Author

Jade Violleau, Stefan Kääb, Susan Bartkowiak, Richard Redon, Antoine Leenhardt, Hanno L. Tan, Jean-Baptiste Gourraud, Peter Weeke, Rachel Bastiaenen, Rianne Wolswinkel, Federica Dagradi, Vincent M. Christoffels, Jacob Tfelt-Hansen, Jean-Jacques Schott, Hervé Le Marec, Manfred Gessler, Françoise Gros, Pascale Guicheney, Julien Barc, Arthur A.M. Wilde, Simon Lecointe, Akihiko Nogami, Tohru Minamino, Sven Zumhagen, Margherita Torchio, Elijah R. Behr, Rainer Schimpf, Carol Ann Remme, Florence Kyndt, Lia Crotti, Yuka Mizusawa, Morten S. Olesen, Vincent Probst, Naoto Endo, Naomasa Makita, Eric Charpentier, Philippe Froguel, Arie O. Verkerk, Minoru Horie, Takeshi Aiba, Christian Dina, Peter J. Schwartz, Kanae Hasegawa, Floriane Simonet, Véronique Fressart, Seiko Ohno, Cornelia Wiese, Eric Schulze-Bahr, Stéphane Bézieau, Hiroshi Watanabe, Vincent Portero, Wataru Shimizu, Beverley Balkau, Martin Borggrefe, Britt M. Beckmann, Charles Antzelevitch, Bas J. Boukens, Dan M. Roden, Pierre Lindenbaum, Aurore Despres, David Weber, Olivier Lantieri, Connie R. Bezzina, Stéphanie Chatel, Ruben Coronel, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Medical Biology, Other departments, ARD - Amsterdam Reproduction and Development, Bezzina, C, Barc, J, Mizusawa, Y, Remme, C, Gourraud, J, Simonet, F, Verkerk, A, Schwartz, P, Crotti, L, Dagradi, F, Guicheney, P, Fressart, V, Leenhardt, A, Antzelevitch, C, Bartkowiak, S, Borggrefe, M, Schimpf, R, Schulze-Bahr, E, Zumhagen, S, Behr, E, Bastiaenen, R, Tfelt-Hansen, J, Olesen, M, Kääb, S, Beckmann, B, Weeke, P, Watanabe, H, Endo, N, Minamino, T, Horie, M, Ohno, S, Hasegawa, K, Makita, N, Nogami, A, Shimizu, W, Aiba, T, Froguel, P, Balkau, B, Lantieri, O, Torchio, M, Wiese, C, Weber, D, Wolswinkel, R, Coronel, R, Boukens, B, Bézieau, S, Charpentier, E, Chatel, S, Despres, A, Gros, F, Kyndt, F, Lecointe, S, Lindenbaum, P, Portero, V, Violleau, J, Gessler, M, Tan, H, Roden, D, Christoffels, V, Le Marec, H, Wilde, A, Probst, V, Schott, J, Dina, C, and Redon, R

Subjects
Male, Qrs Duration, Bioinformatics, Sodium Channels, NAV1.5 Voltage-Gated Sodium Channel, Sudden cardiac death, Genome-Wide Association, Mice, Atrial Gene-Expression, Basic Helix-Loop-Helix Transcription Factors, Odds Ratio, Brugada Syndrome, Brugada syndrome, Mice, Knockout, St-Segment Elevation, SECS-S/01 - STATISTICA, cardiovascular system, Cardiology, Chromosomes, Human, Pair 6, Female, Chromosomes, Human, Pair 3, medicine.medical_specialty, Bundle-Branch Block, BIO/18 - GENETICA, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, NAV1.8 Voltage-Gated Sodium Channel, Internal medicine, Genetic variation, Cardiac conduction, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, cardiovascular diseases, HEY2, Alleles, Heart-Rate, Genetic Variation, Cardiac arrhythmia, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Qt Interval Duration, Repressor Proteins, Ventricular-Fibrillation, Pr Interval, Death, Sudden, Cardiac, Case-Control Studies, Conduction System, Genome-Wide Association Study, Rare disease
Abstract

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10(-68); rs9388451, P = 5.1 × 10(-17)) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10(-14)). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10(-81)). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

Published
2013
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7. Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study

Author

Peter Weeke, Bram P. Prins, Yalda Jamshidi, Stefan Kääb, Margherita Torchio, Evmorfia Petropoulou, Dan M. Roden, Sanjay Sharma, Eline A. Nannenberg, Lia Crotti, Pascale Guicheney, Javad Jabbari, Julien Barc, Tao Yang, Peter J. Schwartz, Anders G. Holst, Eleonora Savio-Galimberti, Morten S. Olesen, Michael J. Ackerman, Connie R. Bezzina, Vincent Probst, Yuka Mizusawa, Dawood Darbar, Elijah R. Behr, Arthur A.M. Wilde, Myriam Berthet, Rachel Bastiaenan, Richard Redon, Antoine Leenhardt, Federica Dagradi, Stig Haunsø, Jacob Tfelt-Hansen, Behr, E, Savio-Galimberti, E, Barc, J, Holst, A, Petropoulou, E, Prins, B, Jabbari, J, Torchio, M, Berthet, M, Mizusawa, Y, Yang, T, Nannenberg, E, Dagradi, F, Weeke, P, Bastiaenan, R, Ackerman, M, Haunso, S, Leenhardt, A, Kääb, S, Probst, V, Redon, R, Sharma, S, Wilde, A, Tfelt-Hansen, J, Schwartz, P, Roden, D, Bezzina, C, Olesen, M, Darbar, D, Guicheney, P, Crotti, L, Jamshidi, Y, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Chemical Engineering [Anshan], University of Science and Technology LiaoNing (USTL), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Service de Cardiologie, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-Centre de Référence Maladies Cardiaques Héréditaires, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Cardiology, ACS - Amsterdam Cardiovascular Sciences, and Human Genetics

Subjects
Male, SCN10A, Candidate gene, QRS duration, Heredity, Physiology, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Action Potentials, Gene Frequency, Risk Factors, Databases, Genetic, Odds Ratio, humans, Exome sequencing, Brugada syndrome, Genetics, adult, Single Nucleotide, Middle Aged, Pedigree, 3. Good health, Europe, Phenotype, Female, Corrigendum, Cardiology and Cardiovascular Medicine, Saudi Arabia, BIO/18 - GENETICA, Biology, Transfection, Polymorphism, Single Nucleotide, Sudden death, Cell Line, NAV1.8 Voltage-Gated Sodium Channel, Databases, Genetic, Physiology (medical), Cardiac conduction, medicine, Genetic Predisposition to Disease, Polymorphism, Allele, Allele frequency, Genetic Association Studies, MED/01 - STATISTICA MEDICA, Aged, Genetic heterogeneity, Computational Biology, Rare variant, Rare variants, Original Articles, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, United States, Case-Control Studies
Abstract

International audience; AIMS: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration. METHODS AND RESULTS: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF \textless1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970). CONCLUSION: Rare variants in the screened QRS-associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients.

Published
2015
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8. Characterization of SEMA3A-encoded semaphorin as a naturally occurring Kv4.3 protein inhibitor and its contribution to Brugada syndrome

Author

Wei Wang, Dan Ye, Jeanne M. Nerbonne, Peter J. Schwartz, Marielle Alders, David J. Tester, John R. Giudicessi, Lia Crotti, Michael J. Ackerman, Yuka Mizusawa, Federica Dagradi, Eric K. Johnson, Nicole J. Boczek, Margherita Torchio, Arthur A.M. Wilde, Boczek, N, Ye, D, Johnson, E, Wang, W, Crotti, L, Tester, D, Dagradi, F, Mizusawa, Y, Torchio, M, Alders, M, Giudicessi, J, Wilde, A, Schwartz, P, Nerbonne, J, Ackerman, M, Cardiology, ACS - Amsterdam Cardiovascular Sciences, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Other Research, and Human Genetics

Subjects
Adult, Male, Physiology, DNA Mutational Analysis, Mutation, Missense, BIO/18 - GENETICA, Biology, Transfection, Article, Membrane Potentials, Electrocardiography, Semaphorin, medicine, Potassium Channel Blockers, Humans, Immunoprecipitation, Hanatoxin, Genetic Predisposition to Disease, Myocytes, Cardiac, Brugada syndrome, Patch clamp, Ion channel, Genetics, Dose-Response Relationship, Drug, Brugada Syndrome, Ion Channels, Medical, Potassium Channels, Semaphorin-3a, HEK 293 cells, SEMA3A, semaphorin-3A, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, Middle Aged, medicine.disease, Molecular biology, Potassium channel, Kinetics, HEK293 Cells, Phenotype, Shal Potassium Channels, ion channel, cardiovascular system, genetics, medical, Female, Cardiology and Cardiovascular Medicine, Protein Binding, Signal Transduction, potassium channel
Abstract

Rationale : Semaphorin 3A ( SEMA3A )-encoded semaphorin is a chemorepellent that disrupts neural patterning in the nervous and cardiac systems. In addition, SEMA3A has an amino acid motif that is analogous to hanatoxin, an inhibitor of voltage-gated K + channels. SEMA3A -knockout mice exhibit an abnormal ECG pattern and are prone to ventricular arrhythmias and sudden cardiac death. Objective : Our aim was to determine whether SEMA3A is a naturally occurring protein inhibitor of K v 4.3 (I to ) channels and its potential contribution to Brugada syndrome. Methods and Results : K v 4.3, Na v 1.5, Ca v 1.2, or K v 4.2 were coexpressed or perfused with SEMA3A in HEK293 cells, and electrophysiological properties were examined via whole-cell patch clamp technique. SEMA3A selectively altered K v 4.3 by significantly reducing peak current density without perturbing K v 4.3 cell surface protein expression. SEMA3A also reduced I to current density in cardiomyocytes derived from human-induced pluripotent stem cells. Disruption of a putative toxin binding domain on K v 4.3 was used to assess physical interactions between SEMA3A and K v 4.3. These findings in combination with coimmunoprecipitations of SEMA3A and K v 4.3 revealed a potential direct binding interaction between these proteins. Comprehensive mutational analysis of SEMA3A was performed on 198 unrelated SCN5A genotype–negative patients with Brugada syndrome, and 2 rare SEMA3A missense mutations were identified. The SEMA3A mutations disrupted SEMA3A’s ability to inhibit K v 4.3 channels, resulting in a significant gain of K v 4.3 current compared with wild-type SEMA3A. Conclusions : This study is the first to demonstrate SEMA3A as a naturally occurring protein that selectively inhibits K v 4.3 and SEMA3A as a possible Brugada syndrome susceptibility gene through a K v 4.3 gain-of-function mechanism.

Published
2014

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