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

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 t...

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Autores: Lahrouchi, Najim, Tadros, Rafik|||0000-0002-1472-0258, Crotti, Lia, Mizusawa, Yuka, Postema, Pieter G., Beekman, Leander, Walsh, Roddy, Hasegawa, Kanae, Barc, Julien, Ernsting, Marko, Turkowski, Kari L., Mazzanti, Andrea|||0000-0002-0208-2172, Beckmann, Britt M., Shimamoto, Keiko, Diamant, Ulla-Britt, Wijeyeratne, Yanushi D., Kucho, Yu, Robyns, Tomas, Ishikawa, Taisuke, Arbelo, Elena|||0000-0003-0424-6393, Christiansen, Michael, Winbo, Annika, Jabbari, Reza, Lubitz, Steven A., Steinfurt, Johannes, Rudic, Boris, Loeys, Bart, Shoemaker, M. Ben, Weeke, Peter E., Pfeiffer, Ryan, Davies, Brianna|||0000-0001-9469-7109, Andorin, Antoine, Hofman, Nynke, Dagradi, Federica, Pedrazzini, Matteo, Tester, David J., Bos, J. Martijn, Sarquella-Brugada, Georgia|||0000-0002-6857-8904, Campuzano, Óscar|||0000-0001-5298-5276, Platonov, Pyotr G., Stallmeyer, Birgit, Zumhagen, Sven, Nannenberg, Eline A., Veldink, Jan|||0000-0001-5572-9657, van den Berg, Leonard H., Al-Chalabi, Ammar|||0000-0002-4924-7712, Shaw, Christopher E., Shaw, Pamela J., Morrison, Karen E.|||0000-0003-0216-5717, Andersen, Peter Munch|||0000-0003-0094-5429, Müller-Nurasyid, Martina|||0000-0003-3793-5910, Cusi, Daniele|||0000-0002-1006-7597, Barlassina, Cristina|||0000-0001-7407-2697, Galan, Pilar, Lathrop, Mark, Munter, Markus, Werge, Thomas|||0000-0003-1829-0766, Ribasés Haro, Marta|||0000-0003-1039-1116, Aung, Tin, Khor, Chiea Chuen|||0000-0002-1128-4729, Ozaki, Mineo, Lichtner, Peter, Meitinger, Thomas|||0000-0002-8838-8403, Van Tintelen, J. Peter|||0000-0003-3854-6749, Hoedemaekers, Yvonne, Denjoy, Isabelle, Leenhardt, Antoine, Napolitano, Carlo, Shimizu, Wataru, Schott, Jean-Jacques, Gourraud, Jean Baptiste|||0000-0002-6961-2131, Makiyama, Takeru, Ohno, Seiko, Itoh, Hideki, Krahn, Andrew D.|||0000-0002-7982-1586, Antzelevitch, Charles, Roden, Dan M., Saenen, Johan, Borggrefe, Martin, Odening, Katja E., Ellinor, Patrick T., Tfelt-Hansen, Jacob, Skinner, Jonathan R., van den Berg, Maarten P., Olesen, Morten Salling, Brugada, Josep|||0000-0002-5662-8302, Brugada, Ramon|||0000-0001-6607-3032, Makita, Naomasa, Breckpot, Jeroen, Yoshinaga, Masao, Behr, Elijah R., Rydberg, Annika, Aiba, Takeshi, Kääb, Stefan|||0000-0001-8824-3581, Priori, Silvia G., Guicheney, Pascale, Tan, Hanno L., Newton-Cheh, Christopher, Ackerman, Michael J., Schwartz, Peter J., Schulze-Bahr, Eric, Probst, Vincent, Horie, Minoru, Wilde, Arthur A., Tanck, Michael W. T., Bezzina, Connie R.
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:231227
Acceso en línea:https://ddd.uab.cat/record/231227
https://dx.doi.org/urn:doi:10.1161/CIRCULATIONAHA.120.045956
Access Level:acceso abierto
Palabra clave:Genome-wide association study
Inheritance patterns
Long QT syndrome
Descripción
Sumario: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.

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