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

Najim Lahrouchi, Rafik Tadros, Lia Crotti, Yuka Mizusawa, Pieter G Postema, Leander Beekman, Roddy Walsh, Kanae Hasegawa, Julien Barc, Marko Ernsting, Kari L Turkowski, Andrea Mazzanti, Britt M Beckmann, Keiko Shimamoto, Ulla-Britt Diamant, Yanushi D Wijeyeratne, Yu Kucho, Tomas Robyns, Taisuke Ishikawa, Elena ArbeloMichael Christiansen, Annika Winbo, Reza Jabbari, Steven A Lubitz, Johannes Steinfurt, Boris Rudic, Bart Loeys, M Ben Shoemaker, Peter E Weeke, Ryan Pfeiffer, Brianna Davies, Antoine Andorin, Nynke Hofman, Federica Dagradi, Matteo Pedrazzini, David J Tester, J Martijn Bos, Georgia Sarquella-Brugada, Óscar Campuzano, Pyotr G Platonov, Birgit Stallmeyer, Sven Zumhagen, Eline A Nannenberg, Jan H Veldink, Leonard H van den Berg, Ammar Al-Chalabi, Christopher E Shaw, Pamela J Shaw, Karen E Morrison, Peter M Andersen, Martina Müller-Nurasyid, Daniele Cusi, Cristina Barlassina, Pilar Galan, Mark Lathrop, Markus Munter, Thomas Werge, Marta Ribasés, Tin Aung, Chiea C Khor, Mineo Ozaki, Peter Lichtner, Thomas Meitinger, J Peter van Tintelen, Yvonne Hoedemaekers, Isabelle Denjoy, Antoine Leenhardt, Carlo Napolitano, Wataru Shimizu, Jean-Jacques Schott, Jean-Baptiste Gourraud, Takeru Makiyama, Seiko Ohno, Hideki Itoh, Andrew D Krahn, Charles Antzelevitch, Dan M Roden, Johan Saenen, Martin Borggrefe, Katja E Odening, Patrick T Ellinor, Jacob Tfelt-Hansen, Jonathan R Skinner, Maarten P van den Berg, Morten Salling Olesen, Josep Brugada, Ramón Brugada, Naomasa Makita, Jeroen Breckpot, Masao Yoshinaga, Elijah R Behr, Annika Rydberg, Takeshi Aiba, Stefan Kääb, Silvia G Priori, Pascale Guicheney, Hanno L Tan, Christopher Newton-Cheh, Michael J Ackerman, Peter J Schwartz, Eric Schulze-Bahr, Vincent Probst, Minoru Horie, Arthur A Wilde, Michael W T Tanck, Connie R Bezzina

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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 (rg=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.

Original languageEnglish
Pages (from-to)324-338
Number of pages15
Issue number4
Early online date20-May-2020
Publication statusPublished - 28-Jul-2020


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