Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome. / 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; 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; Andorin, Antoine; Hofman, Nynke; Dagradi, Federica; Pedrazzini, Matteo; Tester, David J; Bos, J Martijn; Sarquella-Brugada, Georgia; Campuzano, Óscar; Platonov, Pyotr G; Stallmeyer, Birgit; Zumhagen, Sven; Nannenberg, Eline A; Veldink, Jan H; van den Berg, Leonard H; Al-Chalabi, Ammar; Shaw, Christopher E; Shaw, Pamela J; Morrison, Karen E; Andersen, Peter M; Müller-Nurasyid, Martina; Cusi, Daniele; Barlassina, Cristina; Galan, Pilar; Lathrop, Mark; Munter, Markus; Werge, Thomas; Ribasés, Marta; Aung, Tin; Khor, Chiea C; Ozaki, Mineo; Lichtner, Peter; Meitinger, Thomas; van Tintelen, J Peter; Hoedemaekers, Yvonne; Denjoy, Isabelle; Leenhardt, Antoine; Napolitano, Carlo; Shimizu, Wataru; Schott, Jean-Jacques; Gourraud, Jean-Baptiste; Makiyama, Takeru; Ohno, Seiko; Itoh, Hideki; Krahn, Andrew D; 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; Brugada, Ramón; Makita, Naomasa; Breckpot, Jeroen; Yoshinaga, Masao; Behr, Elijah R; Rydberg, Annika; Aiba, Takeshi; Kääb, Stefan; 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.
In: Circulation, Vol. 142, No. 4, 2020, p. 324-338.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
AU - Lahrouchi, Najim
AU - Tadros, Rafik
AU - Crotti, Lia
AU - Mizusawa, Yuka
AU - Postema, Pieter G
AU - Beekman, Leander
AU - Walsh, Roddy
AU - Hasegawa, Kanae
AU - Barc, Julien
AU - Ernsting, Marko
AU - Turkowski, Kari L
AU - Mazzanti, Andrea
AU - Beckmann, Britt M
AU - Shimamoto, Keiko
AU - Diamant, Ulla-Britt
AU - Wijeyeratne, Yanushi D
AU - Kucho, Yu
AU - Robyns, Tomas
AU - Ishikawa, Taisuke
AU - Arbelo, Elena
AU - Christiansen, Michael
AU - Winbo, Annika
AU - Jabbari, Reza
AU - Lubitz, Steven A
AU - Steinfurt, Johannes
AU - Rudic, Boris
AU - Loeys, Bart
AU - Shoemaker, M Ben
AU - Weeke, Peter E
AU - Pfeiffer, Ryan
AU - Davies, Brianna
AU - Andorin, Antoine
AU - Hofman, Nynke
AU - Dagradi, Federica
AU - Pedrazzini, Matteo
AU - Tester, David J
AU - Bos, J Martijn
AU - Sarquella-Brugada, Georgia
AU - Campuzano, Óscar
AU - Platonov, Pyotr G
AU - Stallmeyer, Birgit
AU - Zumhagen, Sven
AU - Nannenberg, Eline A
AU - Veldink, Jan H
AU - van den Berg, Leonard H
AU - Al-Chalabi, Ammar
AU - Shaw, Christopher E
AU - Shaw, Pamela J
AU - Morrison, Karen E
AU - Andersen, Peter M
AU - Müller-Nurasyid, Martina
AU - Cusi, Daniele
AU - Barlassina, Cristina
AU - Galan, Pilar
AU - Lathrop, Mark
AU - Munter, Markus
AU - Werge, Thomas
AU - Ribasés, Marta
AU - Aung, Tin
AU - Khor, Chiea C
AU - Ozaki, Mineo
AU - Lichtner, Peter
AU - Meitinger, Thomas
AU - van Tintelen, J Peter
AU - Hoedemaekers, Yvonne
AU - Denjoy, Isabelle
AU - Leenhardt, Antoine
AU - Napolitano, Carlo
AU - Shimizu, Wataru
AU - Schott, Jean-Jacques
AU - Gourraud, Jean-Baptiste
AU - Makiyama, Takeru
AU - Ohno, Seiko
AU - Itoh, Hideki
AU - Krahn, Andrew D
AU - Antzelevitch, Charles
AU - Roden, Dan M
AU - Saenen, Johan
AU - Borggrefe, Martin
AU - Odening, Katja E
AU - Ellinor, Patrick T
AU - Tfelt-Hansen, Jacob
AU - Skinner, Jonathan R
AU - van den Berg, Maarten P
AU - Olesen, Morten Salling
AU - Brugada, Josep
AU - Brugada, Ramón
AU - Makita, Naomasa
AU - Breckpot, Jeroen
AU - Yoshinaga, Masao
AU - Behr, Elijah R
AU - Rydberg, Annika
AU - Aiba, Takeshi
AU - Kääb, Stefan
AU - Priori, Silvia G
AU - Guicheney, Pascale
AU - Tan, Hanno L
AU - Newton-Cheh, Christopher
AU - Ackerman, Michael J
AU - Schwartz, Peter J
AU - Schulze-Bahr, Eric
AU - Probst, Vincent
AU - Horie, Minoru
AU - Wilde, Arthur A
AU - Tanck, Michael W T
AU - Bezzina, Connie R
PY - 2020
Y1 - 2020
N2 - 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 (GWAS) followed by transethnic meta-analysis in 1,656 unrelated LQTS patients of European or Japanese ancestry and 9,890 controls to identify susceptibility single nucleotide polymorphisms (SNPs). We estimated the SNP heritability (h2SNP) of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 SNPs previously associated with QTc in the general population using a polygenic risk score (PRSQT). Results: Genome-wide association analysis identified three loci associated with LQTS at genome-wide statistical significance (P<5x10-8) near NOS1AP, KCNQ1 and KLF12, and one 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 [SE] 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT interval in the general population (rg=0.40, P=3.2x10-3). PRSQT was greater in LQTS cases compared to controls (P<10-13), and notably, among LQTS patients PRSQT was greater in genotype negative compared to genotype positive patients (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.
AB - 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 (GWAS) followed by transethnic meta-analysis in 1,656 unrelated LQTS patients of European or Japanese ancestry and 9,890 controls to identify susceptibility single nucleotide polymorphisms (SNPs). We estimated the SNP heritability (h2SNP) of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 SNPs previously associated with QTc in the general population using a polygenic risk score (PRSQT). Results: Genome-wide association analysis identified three loci associated with LQTS at genome-wide statistical significance (P<5x10-8) near NOS1AP, KCNQ1 and KLF12, and one 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 [SE] 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT interval in the general population (rg=0.40, P=3.2x10-3). PRSQT was greater in LQTS cases compared to controls (P<10-13), and notably, among LQTS patients PRSQT was greater in genotype negative compared to genotype positive patients (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.
U2 - 10.1161/CIRCULATIONAHA.120.045956
DO - 10.1161/CIRCULATIONAHA.120.045956
M3 - Journal article
C2 - 32429735
VL - 142
SP - 324
EP - 338
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 4
ER -
ID: 241885318