Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Dan E. Arking; Sara L. Pulit; Lia Crotti; Pim Van Der Harst; Patricia B. Munroe; Tamara T. Koopmann; Nona Sotoodehnia; Elizabeth J. Rossin; Michael Morley; Xinchen Wang; Andrew D. Johnson; Alicia Lundby; Daníel F. Gudbjartsson; Peter A. Noseworthy; Mark Eijgelsheim; Yuki Bradford; Kirill V. Tarasov; Marcus Dörr; Martina Müller-Nurasyid; Annukka M. Lahtinen; Ilja M. Nolte; Albert Vernon Smith; Joshua C. Bis; Aaron Isaacs; Stephen J. Newhouse; Daniel S. Evans; Wendy S. Post; Daryl Waggott; Leo Pekka Lyytikäinen; Andrew A. Hicks; Lewin Eisele; David Ellinghaus; Caroline Hayward; Pau Navarro; Sheila Ulivi; Toshiko Tanaka; David J. Tester; Stéphanie Chatel; Stefan Gustafsson; Meena Kumari; Richard W. Morris; Asa T. Naluai; Sandosh Padmanabhan; Alexander Kluttig; Bernhard Strohmer; Andrie G. Panayiotou; Maria Torres; Michael Knoflach; Jaroslav A. Hubacek; Kamil Slowikowski; Soumya Raychaudhuri; Runjun D. Kumar; Tamara B. Harris; Lenore J. Launer; Alan R. Shuldiner; Alvaro Alonso; Joel S. Bader; Georg Ehret; Hailiang Huang; W. H.Linda Kao; James B. Strait; Peter W. Macfarlane; Morris Brown; Mark J. Caulfield; Nilesh J. Samani; Florian Kronenberg; Johann Willeit; J. Gustav Smith; Karin H. Greiser; Henriette Meyer Zu Schwabedissen; Karl Werdan; Massimo Carella; Leopoldo Zelante; Susan R. Heckbert; Bruce M. Psaty; Jerome I. Rotter; Ivana Kolcic; Ozren Polašek; Alan F. Wright; Maura Griffin; Mark J. Daly; David O. Arnar; Hilma Hólm; Unnur Thorsteinsdottir; Joshua C. Denny; Dan M. Roden; Rebecca L. Zuvich; Valur Emilsson; Andrew S. Plump; Martin G. Larson; Christopher J. O'Donnell; Xiaoyan Yin; Marco Bobbo; Adamo P. D'Adamo; Annamaria Iorio; Gianfranco Sinagra; Angel Carracedo; Steven R. Cummings; Michael A. Nalls; Antti Jula; Kimmo K. Kontula; Annukka Marjamaa; Lasse Oikarinen; Markus Perola; Kimmo Porthan; Raimund Erbel; Per Hoffmann; Karl Heinz Jöckel; Hagen Kälsch; Markus M. Nöthen; Marcel Den Hoed; Ruth J.F. Loos; Dag S. Thelle; Christian Gieger; Thomas Meitinger; Siegfried Perz; Annette Peters; Hanna Prucha; Moritz F. Sinner; Melanie Waldenberger; Rudolf A. De Boer; Lude Franke; Pieter A. Van Der Vleuten; Britt Maria Beckmann; Eimo Martens; Abdennasser Bardai; Nynke Hofman; Arthur A.M. Wilde; Elijah R. Behr; Chrysoula Dalageorgou; John R. Giudicessi; Argelia Medeiros-Domingo; Julien Barc; Florence Kyndt; Vincent Probst; Alice Ghidoni; Roberto Insolia; Robert M. Hamilton; Stephen W. Scherer; Jeffrey Brandimarto; Kenneth Margulies; Christine E. Moravec; Fabiola Del Greco M; Christian Fuchsberger; Jeffrey R. O'Connell; Wai K. Lee; Graham C.M. Watt; Harry Campbell; Sarah H. Wild; Nour E. El Mokhtari; Norbert Frey; Folkert W. Asselbergs; Irene Mateo Leach; Gerjan Navis; Maarten P. Van Den Berg; Dirk J. Van Veldhuisen; Manolis Kellis; Bouwe P. Krijthe; Oscar H. Franco; Albert Hofman; Jan A. Kors; André G. Uitterlinden; Jacqueline C.M. Witteman; Lyudmyla Kedenko; Claudia Lamina; Ben A. Oostra; Gonçalo R. Abecasis; Edward G. Lakatta; Antonella Mulas; Marco Orrú; David Schlessinger; Manuela Uda; Marcello R.P. Markus; Uwe Völker; Harold Snieder; Timothy D. Spector; Johan Ärnlöv; Lars Lind; Johan Sundström; Ann Christine Syvänen; Mika Kivimaki; Mika Kähönen; Nina Mononen; Olli T. Raitakari; Jorma S. Viikari; Vera Adamkova; Stefan Kiechl; Maria Brion; Andrew N. Nicolaides; Bernhard Paulweber; Johannes Haerting; Anna F. Dominiczak; Fredrik Nyberg; Peter H. Whincup; Aroon D. Hingorani; Jean Jacques Schott; Connie R. Bezzina; Erik Ingelsson; Luigi Ferrucci; Paolo Gasparini; James F. Wilson; Igor Rudan; Andre Franke; Thomas W. Mühleisen; Peter P. Pramstaller; Terho J. Lehtimäki; Andrew D. Paterson; Afshin Parsa; Yongmei Liu; Cornelia M. Van Duijn; David S. Siscovick; Vilmundur Gudnason; Yalda Jamshidi; Veikko Salomaa; Stephan B. Felix; Serena Sanna; Marylyn D. Ritchie; Bruno H. Stricker; Kari Stefansson; Laurie A. Boyer; Thomas P. Cappola; Jesper V. Olsen; Kasper Lage; Peter J. Schwartz; Stefan Kääb; Aravinda Chakravarti; Michael J. Ackerman; Arne Pfeufer; Paul I.W. De Bakker; Christopher Newton-Cheh

doi:10.1038/ng.3014

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Dan E. Arking, Sara L. Pulit, Lia Crotti, Pim Van Der Harst, Patricia B. Munroe, Tamara T. Koopmann, Nona Sotoodehnia, Elizabeth J. Rossin, Michael Morley, Xinchen Wang, Andrew D. Johnson, Alicia Lundby, Daníel F. Gudbjartsson, Peter A. Noseworthy, Mark Eijgelsheim, Yuki Bradford, Kirill V. Tarasov, Marcus Dörr, Martina Müller-Nurasyid, Annukka M. LahtinenIlja M. Nolte, Albert Vernon Smith, Joshua C. Bis, Aaron Isaacs, Stephen J. Newhouse, Daniel S. Evans, Wendy S. Post, Daryl Waggott, Leo Pekka Lyytikäinen, Andrew A. Hicks, Lewin Eisele, David Ellinghaus, Caroline Hayward, Pau Navarro, Sheila Ulivi, Toshiko Tanaka, David J. Tester, Stéphanie Chatel, Stefan Gustafsson, Meena Kumari, Richard W. Morris, Asa T. Naluai, Sandosh Padmanabhan, Alexander Kluttig, Bernhard Strohmer, Andrie G. Panayiotou, Maria Torres, Michael Knoflach, Jaroslav A. Hubacek, Kamil Slowikowski, Soumya Raychaudhuri, Runjun D. Kumar, Tamara B. Harris, Lenore J. Launer, Alan R. Shuldiner, Alvaro Alonso, Joel S. Bader, Georg Ehret, Hailiang Huang, W. H.Linda Kao, James B. Strait, Peter W. Macfarlane, Morris Brown, Mark J. Caulfield, Nilesh J. Samani, Florian Kronenberg, Johann Willeit, J. Gustav Smith, Karin H. Greiser, Henriette Meyer Zu Schwabedissen, Karl Werdan, Massimo Carella, Leopoldo Zelante, Susan R. Heckbert, Bruce M. Psaty, Jerome I. Rotter, Ivana Kolcic, Ozren Polašek, Alan F. Wright, Maura Griffin, Mark J. Daly, David O. Arnar, Hilma Hólm, Unnur Thorsteinsdottir, Joshua C. Denny, Dan M. Roden, Rebecca L. Zuvich, Valur Emilsson, Andrew S. Plump, Martin G. Larson, Christopher J. O'Donnell, Xiaoyan Yin, Marco Bobbo, Adamo P. D'Adamo, Annamaria Iorio, Gianfranco Sinagra, Angel Carracedo, Steven R. Cummings, Michael A. Nalls, Antti Jula, Kimmo K. Kontula, Annukka Marjamaa, Lasse Oikarinen, Markus Perola, Kimmo Porthan, Raimund Erbel, Per Hoffmann, Karl Heinz Jöckel, Hagen Kälsch, Markus M. Nöthen, Marcel Den Hoed, Ruth J.F. Loos, Dag S. Thelle, Christian Gieger, Thomas Meitinger, Siegfried Perz, Annette Peters, Hanna Prucha, Moritz F. Sinner, Melanie Waldenberger, Rudolf A. De Boer, Lude Franke, Pieter A. Van Der Vleuten, Britt Maria Beckmann, Eimo Martens, Abdennasser Bardai, Nynke Hofman, Arthur A.M. Wilde, Elijah R. Behr, Chrysoula Dalageorgou, John R. Giudicessi, Argelia Medeiros-Domingo, Julien Barc, Florence Kyndt, Vincent Probst, Alice Ghidoni, Roberto Insolia, Robert M. Hamilton, Stephen W. Scherer, Jeffrey Brandimarto, Kenneth Margulies, Christine E. Moravec, Fabiola Del Greco M, Christian Fuchsberger, Jeffrey R. O'Connell, Wai K. Lee, Graham C.M. Watt, Harry Campbell, Sarah H. Wild, Nour E. El Mokhtari, Norbert Frey, Folkert W. Asselbergs, Irene Mateo Leach, Gerjan Navis, Maarten P. Van Den Berg, Dirk J. Van Veldhuisen, Manolis Kellis, Bouwe P. Krijthe, Oscar H. Franco, Albert Hofman, Jan A. Kors, André G. Uitterlinden, Jacqueline C.M. Witteman, Lyudmyla Kedenko, Claudia Lamina, Ben A. Oostra, Gonçalo R. Abecasis, Edward G. Lakatta, Antonella Mulas, Marco Orrú, David Schlessinger, Manuela Uda, Marcello R.P. Markus, Uwe Völker, Harold Snieder, Timothy D. Spector, Johan Ärnlöv, Lars Lind, Johan Sundström, Ann Christine Syvänen, Mika Kivimaki, Mika Kähönen, Nina Mononen, Olli T. Raitakari, Jorma S. Viikari, Vera Adamkova, Stefan Kiechl, Maria Brion, Andrew N. Nicolaides, Bernhard Paulweber, Johannes Haerting, Anna F. Dominiczak, Fredrik Nyberg, Peter H. Whincup, Aroon D. Hingorani, Jean Jacques Schott, Connie R. Bezzina, Erik Ingelsson, Luigi Ferrucci, Paolo Gasparini, James F. Wilson, Igor Rudan, Andre Franke, Thomas W. Mühleisen, Peter P. Pramstaller, Terho J. Lehtimäki, Andrew D. Paterson, Afshin Parsa, Yongmei Liu, Cornelia M. Van Duijn, David S. Siscovick, Vilmundur Gudnason, Yalda Jamshidi, Veikko Salomaa, Stephan B. Felix, Serena Sanna, Marylyn D. Ritchie, Bruno H. Stricker, Kari Stefansson, Laurie A. Boyer, Thomas P. Cappola, Jesper V. Olsen, Kasper Lage, Peter J. Schwartz, Stefan Kääb, Aravinda Chakravarti, Michael J. Ackerman, Arne Pfeufer, Paul I.W. De Bakker, Christopher Newton-Cheh

Research output: Contribution to journal › Article › peer-review

158 Scopus citations

Abstract

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Original language	English (US)
Pages (from-to)	826-836
Number of pages	11
Journal	Nature genetics
Volume	46
Issue number	8
DOIs	https://doi.org/10.1038/ng.3014
State	Published - Aug 2014

ASJC Scopus subject areas

Genetics

Access to Document

10.1038/ng.3014

Cite this

Arking, D. E., Pulit, S. L., Crotti, L., Van Der Harst, P., Munroe, P. B., Koopmann, T. T., Sotoodehnia, N., Rossin, E. J., Morley, M., Wang, X., Johnson, A. D., Lundby, A., Gudbjartsson, D. F., Noseworthy, P. A., Eijgelsheim, M., Bradford, Y., Tarasov, K. V., Dörr, M., Müller-Nurasyid, M., ... Newton-Cheh, C. (2014). Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nature genetics, 46(8), 826-836. https://doi.org/10.1038/ng.3014

Arking, DE, Pulit, SL, Crotti, L, Van Der Harst, P, Munroe, PB, Koopmann, TT, Sotoodehnia, N, Rossin, EJ, Morley, M, Wang, X, Johnson, AD, Lundby, A, Gudbjartsson, DF, Noseworthy, PA, Eijgelsheim, M, Bradford, Y, Tarasov, KV, Dörr, M, Müller-Nurasyid, M, Lahtinen, AM, Nolte, IM, Smith, AV, Bis, JC, Isaacs, A, Newhouse, SJ, Evans, DS, Post, WS, Waggott, D, Lyytikäinen, LP, Hicks, AA, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, DJ, Chatel, S, Gustafsson, S, Kumari, M, Morris, RW, Naluai, AT, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, AG, Torres, M, Knoflach, M, Hubacek, JA, Slowikowski, K, Raychaudhuri, S, Kumar, RD, Harris, TB, Launer, LJ, Shuldiner, AR, Alonso, A, Bader, JS, Ehret, G, Huang, H, Kao, WHL, Strait, JB, Macfarlane, PW, Brown, M, Caulfield, MJ, Samani, NJ, Kronenberg, F, Willeit, J, Smith, JG, Greiser, KH, Zu Schwabedissen, HM, Werdan, K, Carella, M, Zelante, L, Heckbert, SR, Psaty, BM, Rotter, JI, Kolcic, I, Polašek, O, Wright, AF, Griffin, M, Daly, MJ, Arnar, DO, Hólm, H, Thorsteinsdottir, U, Denny, JC, Roden, DM, Zuvich, RL, Emilsson, V, Plump, AS, Larson, MG, O'Donnell, CJ, Yin, X, Bobbo, M, D'Adamo, AP, Iorio, A, Sinagra, G, Carracedo, A, Cummings, SR, Nalls, MA, Jula, A, Kontula, KK, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, KH, Kälsch, H, Nöthen, MM, Den Hoed, M, Loos, RJF, Thelle, DS, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, MF, Waldenberger, M, De Boer, RA, Franke, L, Van Der Vleuten, PA, Beckmann, BM, Martens, E, Bardai, A, Hofman, N, Wilde, AAM, Behr, ER, Dalageorgou, C, Giudicessi, JR, Medeiros-Domingo, A, Barc, J, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, RM, Scherer, SW, Brandimarto, J, Margulies, K, Moravec, CE, Del Greco M, F, Fuchsberger, C, O'Connell, JR, Lee, WK, Watt, GCM, Campbell, H, Wild, SH, El Mokhtari, NE, Frey, N, Asselbergs, FW, Leach, IM, Navis, G, Van Den Berg, MP, Van Veldhuisen, DJ, Kellis, M, Krijthe, BP, Franco, OH, Hofman, A, Kors, JA, Uitterlinden, AG, Witteman, JCM, Kedenko, L, Lamina, C, Oostra, BA, Abecasis, GR, Lakatta, EG, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, MRP, Völker, U, Snieder, H, Spector, TD, Ärnlöv, J, Lind, L, Sundström, J, Syvänen, AC, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, OT, Viikari, JS, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, AN, Paulweber, B, Haerting, J, Dominiczak, AF, Nyberg, F, Whincup, PH, Hingorani, AD, Schott, JJ, Bezzina, CR, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, JF, Rudan, I, Franke, A, Mühleisen, TW, Pramstaller, PP, Lehtimäki, TJ, Paterson, AD, Parsa, A, Liu, Y, Van Duijn, CM, Siscovick, DS, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, SB, Sanna, S, Ritchie, MD, Stricker, BH, Stefansson, K, Boyer, LA, Cappola, TP, Olsen, JV, Lage, K, Schwartz, PJ, Kääb, S, Chakravarti, A, Ackerman, MJ, Pfeufer, A, De Bakker, PIW & Newton-Cheh, C 2014, 'Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization', Nature genetics, vol. 46, no. 8, pp. 826-836. https://doi.org/10.1038/ng.3014

@article{975fd3e1260b4f0e9877f405d8ce5ac3,

title = "Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization",

abstract = "The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.",

author = "Arking, {Dan E.} and Pulit, {Sara L.} and Lia Crotti and {Van Der Harst}, Pim and Munroe, {Patricia B.} and Koopmann, {Tamara T.} and Nona Sotoodehnia and Rossin, {Elizabeth J.} and Michael Morley and Xinchen Wang and Johnson, {Andrew D.} and Alicia Lundby and Gudbjartsson, {Dan{\'i}el F.} and Noseworthy, {Peter A.} and Mark Eijgelsheim and Yuki Bradford and Tarasov, {Kirill V.} and Marcus D{\"o}rr and Martina M{\"u}ller-Nurasyid and Lahtinen, {Annukka M.} and Nolte, {Ilja M.} and Smith, {Albert Vernon} and Bis, {Joshua C.} and Aaron Isaacs and Newhouse, {Stephen J.} and Evans, {Daniel S.} and Post, {Wendy S.} and Daryl Waggott and Lyytik{\"a}inen, {Leo Pekka} and Hicks, {Andrew A.} and Lewin Eisele and David Ellinghaus and Caroline Hayward and Pau Navarro and Sheila Ulivi and Toshiko Tanaka and Tester, {David J.} and St{\'e}phanie Chatel and Stefan Gustafsson and Meena Kumari and Morris, {Richard W.} and Naluai, {Asa T.} and Sandosh Padmanabhan and Alexander Kluttig and Bernhard Strohmer and Panayiotou, {Andrie G.} and Maria Torres and Michael Knoflach and Hubacek, {Jaroslav A.} and Kamil Slowikowski and Soumya Raychaudhuri and Kumar, {Runjun D.} and Harris, {Tamara B.} and Launer, {Lenore J.} and Shuldiner, {Alan R.} and Alvaro Alonso and Bader, {Joel S.} and Georg Ehret and Hailiang Huang and Kao, {W. H.Linda} and Strait, {James B.} and Macfarlane, {Peter W.} and Morris Brown and Caulfield, {Mark J.} and Samani, {Nilesh J.} and Florian Kronenberg and Johann Willeit and Smith, {J. Gustav} and Greiser, {Karin H.} and {Zu Schwabedissen}, {Henriette Meyer} and Karl Werdan and Massimo Carella and Leopoldo Zelante and Heckbert, {Susan R.} and Psaty, {Bruce M.} and Rotter, {Jerome I.} and Ivana Kolcic and Ozren Pola{\v s}ek and Wright, {Alan F.} and Maura Griffin and Daly, {Mark J.} and Arnar, {David O.} and Hilma H{\'o}lm and Unnur Thorsteinsdottir and Denny, {Joshua C.} and Roden, {Dan M.} and Zuvich, {Rebecca L.} and Valur Emilsson and Plump, {Andrew S.} and Larson, {Martin G.} and O'Donnell, {Christopher J.} and Xiaoyan Yin and Marco Bobbo and D'Adamo, {Adamo P.} and Annamaria Iorio and Gianfranco Sinagra and Angel Carracedo and Cummings, {Steven R.} and Nalls, {Michael A.} and Antti Jula and Kontula, {Kimmo K.} and Annukka Marjamaa and Lasse Oikarinen and Markus Perola and Kimmo Porthan and Raimund Erbel and Per Hoffmann and J{\"o}ckel, {Karl Heinz} and Hagen K{\"a}lsch and N{\"o}then, {Markus M.} and {Den Hoed}, Marcel and Loos, {Ruth J.F.} and Thelle, {Dag S.} and Christian Gieger and Thomas Meitinger and Siegfried Perz and Annette Peters and Hanna Prucha and Sinner, {Moritz F.} and Melanie Waldenberger and {De Boer}, {Rudolf A.} and Lude Franke and {Van Der Vleuten}, {Pieter A.} and Beckmann, {Britt Maria} and Eimo Martens and Abdennasser Bardai and Nynke Hofman and Wilde, {Arthur A.M.} and Behr, {Elijah R.} and Chrysoula Dalageorgou and Giudicessi, {John R.} and Argelia Medeiros-Domingo and Julien Barc and Florence Kyndt and Vincent Probst and Alice Ghidoni and Roberto Insolia and Hamilton, {Robert M.} and Scherer, {Stephen W.} and Jeffrey Brandimarto and Kenneth Margulies and Moravec, {Christine E.} and {Del Greco M}, Fabiola and Christian Fuchsberger and O'Connell, {Jeffrey R.} and Lee, {Wai K.} and Watt, {Graham C.M.} and Harry Campbell and Wild, {Sarah H.} and {El Mokhtari}, {Nour E.} and Norbert Frey and Asselbergs, {Folkert W.} and Leach, {Irene Mateo} and Gerjan Navis and {Van Den Berg}, {Maarten P.} and {Van Veldhuisen}, {Dirk J.} and Manolis Kellis and Krijthe, {Bouwe P.} and Franco, {Oscar H.} and Albert Hofman and Kors, {Jan A.} and Uitterlinden, {Andr{\'e} G.} and Witteman, {Jacqueline C.M.} and Lyudmyla Kedenko and Claudia Lamina and Oostra, {Ben A.} and Abecasis, {Gon{\c c}alo R.} and Lakatta, {Edward G.} and Antonella Mulas and Marco Orr{\'u} and David Schlessinger and Manuela Uda and Markus, {Marcello R.P.} and Uwe V{\"o}lker and Harold Snieder and Spector, {Timothy D.} and Johan {\"A}rnl{\"o}v and Lars Lind and Johan Sundstr{\"o}m and Syv{\"a}nen, {Ann Christine} and Mika Kivimaki and Mika K{\"a}h{\"o}nen and Nina Mononen and Raitakari, {Olli T.} and Viikari, {Jorma S.} and Vera Adamkova and Stefan Kiechl and Maria Brion and Nicolaides, {Andrew N.} and Bernhard Paulweber and Johannes Haerting and Dominiczak, {Anna F.} and Fredrik Nyberg and Whincup, {Peter H.} and Hingorani, {Aroon D.} and Schott, {Jean Jacques} and Bezzina, {Connie R.} and Erik Ingelsson and Luigi Ferrucci and Paolo Gasparini and Wilson, {James F.} and Igor Rudan and Andre Franke and M{\"u}hleisen, {Thomas W.} and Pramstaller, {Peter P.} and Lehtim{\"a}ki, {Terho J.} and Paterson, {Andrew D.} and Afshin Parsa and Yongmei Liu and {Van Duijn}, {Cornelia M.} and Siscovick, {David S.} and Vilmundur Gudnason and Yalda Jamshidi and Veikko Salomaa and Felix, {Stephan B.} and Serena Sanna and Ritchie, {Marylyn D.} and Stricker, {Bruno H.} and Kari Stefansson and Boyer, {Laurie A.} and Cappola, {Thomas P.} and Olsen, {Jesper V.} and Kasper Lage and Schwartz, {Peter J.} and Stefan K{\"a}{\"a}b and Aravinda Chakravarti and Ackerman, {Michael J.} and Arne Pfeufer and {De Bakker}, {Paul I.W.} and Christopher Newton-Cheh",

year = "2014",

month = aug,

doi = "10.1038/ng.3014",

language = "English (US)",

volume = "46",

pages = "826--836",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "8",

}

TY - JOUR

T1 - Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

AU - Arking, Dan E.

AU - Pulit, Sara L.

AU - Crotti, Lia

AU - Van Der Harst, Pim

AU - Munroe, Patricia B.

AU - Koopmann, Tamara T.

AU - Sotoodehnia, Nona

AU - Rossin, Elizabeth J.

AU - Morley, Michael

AU - Wang, Xinchen

AU - Johnson, Andrew D.

AU - Lundby, Alicia

AU - Gudbjartsson, Daníel F.

AU - Noseworthy, Peter A.

AU - Eijgelsheim, Mark

AU - Bradford, Yuki

AU - Tarasov, Kirill V.

AU - Dörr, Marcus

AU - Müller-Nurasyid, Martina

AU - Lahtinen, Annukka M.

AU - Nolte, Ilja M.

AU - Smith, Albert Vernon

AU - Bis, Joshua C.

AU - Isaacs, Aaron

AU - Newhouse, Stephen J.

AU - Evans, Daniel S.

AU - Post, Wendy S.

AU - Waggott, Daryl

AU - Lyytikäinen, Leo Pekka

AU - Hicks, Andrew A.

AU - Eisele, Lewin

AU - Ellinghaus, David

AU - Hayward, Caroline

AU - Navarro, Pau

AU - Ulivi, Sheila

AU - Tanaka, Toshiko

AU - Tester, David J.

AU - Chatel, Stéphanie

AU - Gustafsson, Stefan

AU - Kumari, Meena

AU - Morris, Richard W.

AU - Naluai, Asa T.

AU - Padmanabhan, Sandosh

AU - Kluttig, Alexander

AU - Strohmer, Bernhard

AU - Panayiotou, Andrie G.

AU - Torres, Maria

AU - Knoflach, Michael

AU - Hubacek, Jaroslav A.

AU - Slowikowski, Kamil

AU - Raychaudhuri, Soumya

AU - Kumar, Runjun D.

AU - Harris, Tamara B.

AU - Launer, Lenore J.

AU - Shuldiner, Alan R.

AU - Alonso, Alvaro

AU - Bader, Joel S.

AU - Ehret, Georg

AU - Huang, Hailiang

AU - Kao, W. H.Linda

AU - Strait, James B.

AU - Macfarlane, Peter W.

AU - Brown, Morris

AU - Caulfield, Mark J.

AU - Samani, Nilesh J.

AU - Kronenberg, Florian

AU - Willeit, Johann

AU - Smith, J. Gustav

AU - Greiser, Karin H.

AU - Zu Schwabedissen, Henriette Meyer

AU - Werdan, Karl

AU - Carella, Massimo

AU - Zelante, Leopoldo

AU - Heckbert, Susan R.

AU - Psaty, Bruce M.

AU - Rotter, Jerome I.

AU - Kolcic, Ivana

AU - Polašek, Ozren

AU - Wright, Alan F.

AU - Griffin, Maura

AU - Daly, Mark J.

AU - Arnar, David O.

AU - Hólm, Hilma

AU - Thorsteinsdottir, Unnur

AU - Denny, Joshua C.

AU - Roden, Dan M.

AU - Zuvich, Rebecca L.

AU - Emilsson, Valur

AU - Plump, Andrew S.

AU - Larson, Martin G.

AU - O'Donnell, Christopher J.

AU - Yin, Xiaoyan

AU - Bobbo, Marco

AU - D'Adamo, Adamo P.

AU - Iorio, Annamaria

AU - Sinagra, Gianfranco

AU - Carracedo, Angel

AU - Cummings, Steven R.

AU - Nalls, Michael A.

AU - Jula, Antti

AU - Kontula, Kimmo K.

AU - Marjamaa, Annukka

AU - Oikarinen, Lasse

AU - Perola, Markus

AU - Porthan, Kimmo

AU - Erbel, Raimund

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AU - De Bakker, Paul I.W.

AU - Newton-Cheh, Christopher

PY - 2014/8

Y1 - 2014/8

N2 - The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

AB - The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

UR - http://www.scopus.com/inward/record.url?scp=84905594041&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905594041&partnerID=8YFLogxK

U2 - 10.1038/ng.3014

DO - 10.1038/ng.3014

M3 - Article

C2 - 24952745

AN - SCOPUS:84905594041

SN - 1061-4036

VL - 46

SP - 826

EP - 836

JO - Nature genetics

JF - Nature genetics

IS - 8

ER -

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

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