Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
| Autor: | 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 |
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| Přispěvatelé: | 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, Cardiovascular Centre (CVC) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | Circulation, 142(4), 324-338. Lippincott Williams and Wilkins Circulation Circulation, American Heart Association, 2020, 142 (4), pp.324-338. ⟨10.1161/CIRCULATIONAHA.120.045956⟩ r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu Fundació Sant Joan de Déu Circulation, 142, 4, pp. 324-38 Lahrouchi, N, Tadros, R, Crotti, L, Mizusawa, Y, Postema, P G, Beekman, L, Walsh, R, Hasegawa, K, Barc, J, Ernsting, M, Turkowski, K L, Mazzanti, A, Beckmann, B M, Shimamoto, K, Diamant, U-B, Wijeyeratne, Y D, Kucho, Y, Robyns, T, Ishikawa, T, Arbelo, E, Christiansen, M, Winbo, A, Jabbari, R, Lubitz, S A, Steinfurt, J, Rudic, B, Loeys, B, Shoemaker, M B, Weeke, P E, Pfeiffer, R, Davies, B, Andorin, A, Hofman, N, Dagradi, F, Pedrazzini, M, Tester, D J, Bos, J M, Sarquella-Brugada, G, Campuzano, Ó, Platonov, P G, Stallmeyer, B, Zumhagen, S, Nannenberg, E A, Veldink, J H, van den Berg, L H, Al-Chalabi, A, Shaw, C E, Shaw, P J, Morrison, K E, Andersen, P M, Müller-Nurasyid, M, Cusi, D, Barlassina, C, Galan, P, Lathrop, M, Munter, M, Werge, T, Ribasés, M, Aung, T, Khor, C C, Ozaki, M, Lichtner, P, Meitinger, T, van Tintelen, J P, Hoedemaekers, Y, Denjoy, I, Leenhardt, A, Napolitano, C, Shimizu, W, Schott, J-J, Gourraud, J-B, Makiyama, T, Ohno, S, Itoh, H, Krahn, A D, Antzelevitch, C, Roden, D M, Saenen, J, Borggrefe, M, Odening, K E, Ellinor, P T, Tfelt-Hansen, J, Skinner, J R, van den Berg, M P, Olesen, M S, Brugada, J, Brugada, R, Makita, N, Breckpot, J, Yoshinaga, M, Behr, E R, Rydberg, A, Aiba, T, Kääb, S, Priori, S G, Guicheney, P, Tan, H L, Newton-Cheh, C, Ackerman, M J, Schwartz, P J, Schulze-Bahr, E, Probst, V, Horie, M, Wilde, A A, Tanck, M W T & Bezzina, C R 2020, ' Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome ', Circulation, vol. 142, no. 4, pp. 324-338 . https://doi.org/10.1161/CIRCULATIONAHA.120.045956 r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu instname Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona Circulation 142, 324-338 (2020) Circulation, 142(4), 324-338. LIPPINCOTT WILLIAMS & WILKINS Lahrouchi, Najim; Tadros, Rafik; Crotti, Lia; Mizusawa, Yuka; Postema, Pieter G; Beekman, Leander; Walsh, Roddy; Hasegawa, Kanae; Barc, Julien; Ernsting, Marko; Turkowski, Kari L; Mazzanti, Andrea; Beckmann, Britt M; Shimamoto, Keiko; Diamant, Ulla-Britt; Wijeyeratne, Yanushi D; Kucho, Yu; Robyns, Tomas; Ishikawa, Taisuke; Arbelo, Elena; ... (2020). Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome. Circulation, 142(4), pp. 324-338. American Heart Association 10.1161/CIRCULATIONAHA.120.045956 Circulation, 142, 324-38 |
| ISSN: | 0009-7322 1524-4539 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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