Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
Lahrouchi, Najim (University of Amsterdam)
Tadros, Rafik (Université de Montréal)
Crotti, Lia (University of Milano-Bicocca)
Mizusawa, Yuka (University of Amsterdam)
Postema, Pieter G. (University of Amsterdam)
Beekman, Leander (University of Amsterdam)
Walsh, Roddy (University of Amsterdam)
Hasegawa, Kanae (Shiga University of Medical Science, Otsu, Japan)
Barc, Julien (Inserm, France)
Ernsting, Marko (University Hospital Muenster (Alemanya))
Turkowski, Kari L. (Mayo Clinic, Rochester)
Mazzanti, Andrea (University of Pavia)
Beckmann, Britt M. (University Hospital of the Ludwig Maximilians University, Munich)
Shimamoto, Keiko (National Cerebral and Cardiovascular Center, Osaka)
Diamant, Ulla-Britt (Umeå University, Sweden)
Wijeyeratne, Yanushi D. (St George's University of London)
Kucho, Yu (National Hospital Organization Kagoshima Medical Center, Japan)
Robyns, Tomas (University Hospitals Leuven (Bèlgica))
Ishikawa, Taisuke (National Cerebral and Cardiovascular Center, Osaka)
Arbelo, Elena (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Christiansen, Michael (Statens Serum Institute, Copenhagen)
Winbo, Annika (The University of Auckland)
Jabbari, Reza (Copenhagen University Hospital)
Lubitz, Steven A. (Massachusetts General Hospital (Boston))
Steinfurt, Johannes (Heart Center University of Freiburg)
Rudic, Boris (University Medical Center Mannheim)
Loeys, Bart (University Hospital Antwerp (Bèlgica))
Shoemaker, M. Ben (Vanderbilt University Medical Center, Nashville)
Weeke, Peter E. (Vanderbilt University Medical Center, Nashville)
Pfeiffer, Ryan (Masonic Medical Research Institute, Utica, NY)
Davies, Brianna (University of British Columbia, Vancouver)
Andorin, Antoine (St George's University of London)
Hofman, Nynke (University of Amsterdam)
Dagradi, Federica (Istituto Auxologico Italiano - IRCCS, Milan)
Pedrazzini, Matteo (Istituto Auxologico Italiano - IRCCS, Milan)
Tester, David J. (Mayo Clinic, Rochester)
Bos, J. Martijn (Mayo Clinic, Rochester)
Sarquella-Brugada, Georgia (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Campuzano, Óscar (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Platonov, Pyotr G. (Lund University, Sweden)
Stallmeyer, Birgit (University Hospital Muenster (Alemanya))
Zumhagen, Sven (University Hospital Muenster (Alemanya))
Nannenberg, Eline A. (University of Amsterdam)
Veldink, Jan (University Medical Center Utrecht)
van den Berg, Leonard H. (University Medical Center Utrecht)
Al-Chalabi, Ammar (King's College Hospital NHS Foundation Trust)
Shaw, Christopher E. (King's College London)
Shaw, Pamela J. (Istituto Auxologico Italiano - IRCCS, Milan)
Morrison, Karen E. (University of Southampton)
Andersen, Peter Munch (Ulm University, Germany)
Müller-Nurasyid, Martina (University Hospital of the Ludwig Maximilians University, Munich)
Cusi, Daniele (University of Milan)
Barlassina, Cristina (University of Milan)
Galan, Pilar (Inserm, France)
Lathrop, Mark (McGill University and Génome Québec Innovation Centre, Montréal)
Munter, Markus (McGill University and Génome Québec Innovation Centre, Montréal)
Werge, Thomas (The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen)
Ribasés Haro, Marta (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Aung, Tin (Singapore Eye Research Institute)
Khor, Chiea Chuen (Genome Institute of Singapore)
Ozaki, Mineo (Ozaki Eye Hospital, Miyazaki, Japan)
Lichtner, Peter (Helmholtz Zentrum München, Neuherberg, Germany)
Meitinger, Thomas (Helmholtz Zentrum München, Neuherberg, Germany)
van Tintelen, J. Peter (University of Amsterdam)
Hoedemaekers, Yvonne (University Medical Centre Groningen)
Denjoy, Isabelle (Université de Paris Inserm)
Leenhardt, Antoine (Université de Paris Inserm)
Napolitano, Carlo (ICS Maugeri - IRCCS, Pavia)
Shimizu, Wataru (National Cerebral and Cardiovascular Center, Osaka)
Schott, Jean-Jacques (Inserm, France)
Gourraud, Jean-Baptiste (Inserm, France)
Makiyama, Takeru (Kyoto University Graduate School of Medicine)
Ohno, Seiko (University of Milano-Bicocca)
Itoh, Hideki (Shiga University of Medical Science, Otsu, Japan)
Krahn, Andrew D. (University of British Columbia, Vancouver)
Antzelevitch, Charles (Lankenau Institute for Medical Research, Wynnewood, PA)
Roden, Dan M. (Vanderbilt University Medical Center, Nashville)
Saenen, Johan (University Hospital Antwerp (Bèlgica))
Borggrefe, Martin (University Medical Center Mannheim)
Odening, Katja E. (Heart Center University of Freiburg, Germany)
Ellinor, Patrick T. (Massachusetts General Hospital (Boston))
Tfelt-Hansen, Jacob (Copenhagen University Hospital)
Skinner, Jonathan R. (Starship Children's Hospital (Auckland, Nova Zelanda))
van den Berg, Maarten P. (University Medical Center Groningen)
Olesen, Morten Salling (Copenhagen University Hospital)
Brugada, Josep 1958- (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Brugada, Ramon (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Makita, Naomasa (National Cerebral and Cardiovascular Center Research Institute, Osaka)
Breckpot, Jeroen (University Hospitals Leuven (Bèlgica))
Yoshinaga, Masao (National Hospital Organization Kagoshima Medical Center, Japan)
Behr, Elijah R. (St George's University of London)
Rydberg, Annika (Umeå University, Sweden)
Aiba, Takeshi (National Cerebral and Cardiovascular Center, Osaka)
Kääb, Stefan (University Hospital of the Ludwig Maximilians University, Munich)
Priori, Silvia G. (ICS Maugeri - IRCCS, Pavia)
Guicheney, Pascale (Inserm, France)
Tan, Hanno L. (University of Amsterdam)
Newton-Cheh, Christopher (Massachusetts General Hospital (Boston))
Ackerman, Michael J. (Mayo Clinic, Rochester)
Schwartz, Peter J. (European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart)
Schulze-Bahr, Eric (University Hospital Muenster (Alemanya))
Probst, Vincent (Inserm, France)
Horie, Minoru (Shiga University of Medical Science, Otsu, Japan)
Wilde, Arthur A. (University of Amsterdam)
Tanck, Michael W. T. (University of Amsterdam)
Bezzina, Connie R. (University of Amsterdam)
Universitat Autònoma de Barcelona

Fecha:	2020
Resumen:	Supplemental Digital Content is available in the text. 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. 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=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). 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.
Ayudas:	European Commission 733381 European Commission 661617 Instituto de Salud Carlos III PI16-01203 Instituto de Salud Carlos III PI17-01690
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Genome-wide association study ; Inheritance patterns ; Long QT syndrome
Publicado en:	Circulation, Vol. 142 (may 2020) , p. 324-338, ISSN 1524-4539

DOI: 10.1161/CIRCULATIONAHA.120.045956
PMID: 32429735

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