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1. Genetic studies of Long QT syndrome

Author

Dalageorgou, Chrysoula

Subjects
616.128
Abstract

The QT interval is a representation of the cardiac ventricular repolarization process on the electrocardiogram. QT interval varies as a function of age, sex, heart rate, genetic variation and cardiac and non-cardiac drugs. Some individuals may have "normal" QT intervals, but are more susceptible to cardiac arrhythmias, potentially caused by genetic factors underlying QT variability in the general population. A twin study was conducted in which the genetic and environmental influences on QT and corrected QT interval were compared, based on different adjustment formulae. The current report provided evidence that corrected QT interval heritability estimates depend on the specific correction formula applied, as well as that approximately a quarter of the uncorrected QT interval heritability is due to genes specific to QT interval, while the remainder is shared with genes for heart rate. This thesis also aimed to show the penetrance of mutations occurring in the KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 cardiac ion channel genes in clinically '. , diagnosed Long QT Syndrome (LQTS) cases. This study showed that the overall detection rate for mutations in the five defined LQTS genes was approximately 31%. Interestingly, a KCNH2 protein linked C terminal mutation was found to produce a prematurely truncated KCNH2 channel and protein defective trafficking using functional analysis. Page 3 •

Published
2012

7. Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing

Author

Nunn, Laurence M, Lopes, Luis R, Syrris, Petros, Murphy, Cian, Plagnol, Vincent, Firman, Eileen, Dalageorgou, Chrysoula, Zorio, Esther, Domingo, Diana, Murday, Victoria, Findlay, Iain, Duncan, Alexis, Carr-White, Gerry, Robert, Leema, Bueser, Teofila, Langman, Caroline, Fynn, Simon P, Goddard, Martin, White, Anne, Bundgård, Henning, Ferrero-Miliani, Laura, Wheeldon, Nigel, Suvarna, Simon K, O'Beirne, Aliceson, Lowe, Martin D, McKenna, William J, Elliott, Perry M, Lambiase, Pier D, Nunn, Laurence M, Lopes, Luis R, Syrris, Petros, Murphy, Cian, Plagnol, Vincent, Firman, Eileen, Dalageorgou, Chrysoula, Zorio, Esther, Domingo, Diana, Murday, Victoria, Findlay, Iain, Duncan, Alexis, Carr-White, Gerry, Robert, Leema, Bueser, Teofila, Langman, Caroline, Fynn, Simon P, Goddard, Martin, White, Anne, Bundgård, Henning, Ferrero-Miliani, Laura, Wheeldon, Nigel, Suvarna, Simon K, O'Beirne, Aliceson, Lowe, Martin D, McKenna, William J, Elliott, Perry M, and Lambiase, Pier D

Abstract

AIMS: The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible.METHODS AND RESULTS: To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency <0.02% in the NHLBI exome sequencing project and an internal set of control exomes were prioritized for analysis followed by <0.5% frequency threshold secondary analysis. First-degree relatives were offered clinical screening for inherited cardiac conditions. Seven probands (12%) carried very rare (<0.02%) or novel non-sense candidate mutations and 10 probands (17%) had previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands.CONCLUSION: Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution.

Published
2016

8. Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing

Author

Nunn, Laurence M., primary, Lopes, Luis R., additional, Syrris, Petros, additional, Murphy, Cian, additional, Plagnol, Vincent, additional, Firman, Eileen, additional, Dalageorgou, Chrysoula, additional, Zorio, Esther, additional, Domingo, Diana, additional, Murday, Victoria, additional, Findlay, Iain, additional, Duncan, Alexis, additional, Carr-White, Gerry, additional, Robert, Leema, additional, Bueser, Teofila, additional, Langman, Caroline, additional, Fynn, Simon P, additional, Goddard, Martin, additional, White, Anne, additional, Bundgaard, Henning, additional, Ferrero-Miliani, Laura, additional, Wheeldon, Nigel, additional, Suvarna, Simon K., additional, O'Beirne, Aliceson, additional, Lowe, Martin D., additional, McKenna, William J., additional, Elliott, Perry M., additional, and Lambiase, Pier D., additional

Published
2015
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9. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

Author

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

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.

Published
2014
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10. Genome Wide Analysis of Drug-Induced Torsades de Pointes: Lack of Common Variants with Large Effect Sizes

Author

Behr, Elijah R., primary, Ritchie, Marylyn D., additional, Tanaka, Toshihiro, additional, Kääb, Stefan, additional, Crawford, Dana C., additional, Nicoletti, Paola, additional, Floratos, Aris, additional, Sinner, Moritz F., additional, Kannankeril, Prince J., additional, Wilde, Arthur A. M., additional, Bezzina, Connie R., additional, Schulze-Bahr, Eric, additional, Zumhagen, Sven, additional, Guicheney, Pascale, additional, Bishopric, Nanette H., additional, Marshall, Vanessa, additional, Shakir, Saad, additional, Dalageorgou, Chrysoula, additional, Bevan, Steve, additional, Jamshidi, Yalda, additional, Bastiaenen, Rachel, additional, Myerburg, Robert J., additional, Schott, Jean-Jacques, additional, Camm, A. John, additional, Steinbeck, Gerhard, additional, Norris, Kris, additional, Altman, Russ B., additional, Tatonetti, Nicholas P., additional, Jeffery, Steve, additional, Kubo, Michiaki, additional, Nakamura, Yusuke, additional, Shen, Yufeng, additional, George, Alfred L., additional, and Roden, Dan M., additional

Published
2013
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11. Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing.

Author

Nunn, Laurence M., Lopes, Luis R., Syrris, Petros, Murphy, Cian, Plagnol, Vincent, Firman, Eileen, Dalageorgou, Chrysoula, Zorio, Esther, Domingo, Diana, Murday, Victoria, Findlay, Iain, Duncan, Alexis, Carr-White, Gerry, Robert, Leema, Bueser, Teofila, Langman, Caroline, Fynn, Simon P., Goddard, Martin, White, Anne, and Bundgaard, Henning

Subjects
CARDIAC arrest prevention, LONG QT syndrome diagnosis, BRUGADA syndrome diagnosis, AUTOPSY, COMPARATIVE studies, DISEASE susceptibility, GENEALOGY, GENES, GENETIC techniques, GENOMES, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, GENETIC mutation, RESEARCH, GENETIC testing, LONG QT syndrome, EVALUATION research, BRUGADA syndrome, CASE-control method, SEQUENCE analysis, MEMBRANE transport proteins
Abstract

Aims: The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible.Methods and Results: To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency <0.02% in the NHLBI exome sequencing project and an internal set of control exomes were prioritized for analysis followed by <0.5% frequency threshold secondary analysis. First-degree relatives were offered clinical screening for inherited cardiac conditions. Seven probands (12%) carried very rare (<0.02%) or novel non-sense candidate mutations and 10 probands (17%) had previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands.Conclusion: Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Published
2016
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12. Common Variation in the NOS1AP Gene Is Associated With Drug-Induced QT Prolongation and Ventricular Arrhythmia

Author

Jamshidi, Yalda, primary, Nolte, Ilja M., additional, Dalageorgou, Chrysoula, additional, Zheng, Dongling, additional, Johnson, Toby, additional, Bastiaenen, Rachel, additional, Ruddy, Suzanne, additional, Talbott, Daniel, additional, Norris, Kris J., additional, Snieder, Harold, additional, George, Alfred L., additional, Marshall, Vanessa, additional, Shakir, Saad, additional, Kannankeril, Prince J., additional, Munroe, Patricia B., additional, Camm, A. John, additional, Jeffery, Steve, additional, Roden, Dan M., additional, and Behr, Elijah R., additional

Published
2012
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14. Common Genetic Variation Near the Phospholamban Gene Is Associated with Cardiac Repolarisation: Meta- Analysis of Three Genome-Wide Association Studies.

Author

Nolte, Ilja M., Wallace, Chris, Newhouse, Stephen J., Waggott, Daryl, Jingyuan Fu, Soranzo, Nicole, Gwilliam, Rhian, Deloukas, Panos, Savelieva, Irina, Dongling Zheng, Dalageorgou, Chrysoula, Farrall, Martin, Samani, Nilesh J., Connell, John, Brown, Morris, Dominiczak, Anna, Lathrop, Mark, Eleftheria Zeggini, Wain, Louise V., and Newton-Cheh, Christopher

Subjects
META-analysis, ARRHYTHMIA, HEART beat, CARDIAC arrest, HEART diseases, PALPITATION, LOCUS (Genetics)
Abstract

To identify loci affecting the electrocardiographic QT interval, a measure of cardiac repolarisation associated with risk of ventricular arrhythmias and sudden cardiac death, we conducted a meta-analysis of three genome-wide association studies (GWAS) including 3,558 subjects from the TwinsUK and BRIGHT cohorts in the UK and the DCCT/EDIC cohort from North America. Five loci were significantly associated with QT interval at P<1x10-6. To validate these findings we performed an in silico comparison with data from two QT consortia: QTSCD (n = 15,842) and QTGEN (n = 13,685). Analysis confirmed the association between common variants near NOS1AP (P = 1.4x10-83) and the phospholamban (PLN) gene (P = 1.9x10-29). The most associated SNP near NOS1AP (rs12143842) explains 0.82% variance; the SNP near PLN (rs11153730) explains 0.74% variance of QT interval duration. We found no evidence for interaction between these two SNPs (P = 0.99). PLN is a key regulator of cardiac diastolic function and is involved in regulating intracellular calcium cycling, it has only recently been identified as a susceptibility locus for QT interval. These data offer further mechanistic insights into genetic influence on the QT interval which may predispose to life threatening arrhythmias and sudden cardiac death. [ABSTRACT FROM AUTHOR]

Published
2009
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15. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author

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

Subjects
genome-wide association study, QT interval, Long QT Syndrome, sudden cardiac death, myocardial repolarization, arrhythmias
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 QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for 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 novel candidate genes for ventricular arrhythmias, LQTS,and SCD.

Published
2014
Full Text
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16. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Author

Yuki Bradford, Toshiko Tanaka, Jeffrey R. O'Connell, Florence Kyndt, Unnur Thorsteinsdottir, Ivana Kolcic, Xiaoyan Yin, Vincent Probst, Manolis Kellis, Christopher Newton-Cheh, Stefan Kääb, Argelia Medeiros-Domingo, Markus M. Nöthen, Paolo Gasparini, Jean-Jacques Schott, Ruth J. F. Loos, Thomas W. Mühleisen, Annukka Marjamaa, Morris Brown, Igor Rudan, Runjun D. Kumar, Peter J. Schwartz, Lars Lind, Martina Müller-Nurasyid, Xinchen Wang, Joshua C. Denny, Roberto Insolia, Soumya Raychaudhuri, Stephen W. Scherer, Bruno H. Stricker, Alexander Kluttig, Adamo Pio D'Adamo, Laurie A. Boyer, Moritz F. Sinner, Norbert Frey, Nour Eddine El Mokhtari, Thomas Meitinger, Jesper V. Olsen, Gerjan Navis, Steven R. Cummings, Richard W Morris, Nynke Hofman, Marcel den Hoed, Rudolf A. de Boer, Gonçalo R. Abecasis, Mark J. Daly, Dan M. Roden, Christian Gieger, Lyudmyla Kedenko, Marcus Dörr, Thomas P. Cappola, Afshin Parsa, Kari Stefansson, Markus Perola, Mark Eijgelsheim, Fredrik Nyberg, Robert M. Hamilton, Yalda Jamshidi, W. H. Linda Kao, Terho Lehtimäki, Annette Peters, David Schlessinger, Peter P. Pramstaller, James F. Wilson, Vilmundur Gudnason, Florian Kronenberg, Aroon D. Hingorani, Connie R. Bezzina, Abdennasser Bardai, Marylyn D. Ritchie, Andrew S. Plump, Johan Sundström, Daryl Waggott, Chrysoula Dalageorgou, Paul I.W. de Bakker, Uwe Völker, Aaron Isaacs, Oscar H. Franco, Yongmei Liu, Andrew N. Nicolaides, Lia Crotti, Cornelia M. van Duijn, Ben A. Oostra, Arne Pfeufer, Karl Werdan, Michael Morley, Jan A. Kors, Julien Barc, Lewin Eisele, Siegfried Perz, Stéphanie Chatel, Pieter A. van der Vleuten, Sara L. Pulit, Anna F. Dominiczak, Harry Campbell, Alice Ghidoni, Irene Mateo Leach, Nona Sotoodehnia, Nina Mononen, Henriette E. Meyer zu Schwabedissen, Alvaro Alonso, Fabiola Del Greco M, Dan E. Arking, Vera Adamkova, Mike A. Nalls, Valur Emilsson, Edward G. Lakatta, Kirill Tarasov, Alan F. Wright, Lenore J. Launer, Erik Ingelsson, Karin Halina Greiser, Ozren Polasek, Massimo Carella, Daniel F. Gudbjartsson, Bouwe P. Krijthe, Hanna Prucha, Per Hoffmann, Maura Griffin, Stefan Kiechl, Angel Carracedo, Ilja M. Nolte, Christine E. Moravec, Johann Willeit, Joshua C. Bis, Patricia B. Munroe, Marcello Ricardo Paulista Markus, Hailiang Huang, Mika Kähönen, Albert Hofman, Peter H. Whincup, Dirk J. van Veldhuisen, Michael Knoflach, Alicia Lundby, Serena Sanna, Hagen Kälsch, Bernhard Paulweber, Kamil Slowikowski, Luigi Ferrucci, Melanie Waldenberger, Marco Bobbo, Annukka M. Lahtinen, Ann-Christine Syvänen, J. Gustav Smith, Åsa Torinsson Naluai, Jaroslav A. Hubacek, Jeffrey Brandimarto, Wendy S. Post, Lude Franke, Mark J. Caulfield, Folkert W. Asselbergs, André G. Uitterlinden, Stefan Gustafsson, Pim van der Harst, David J. Tester, David S. Siscovick, David O. Arnar, Sarah H Wild, Elizabeth J. Rossin, Albert V. Smith, Bruce M. Psaty, Georg Ehret, Alan R. Shuldiner, Stephen Newhouse, Kimmo Kontula, Maria Brion, Andre Franke, Peter W. Macfarlane, Mika Kivimäki, Tamara B. Harris, Lasse Oikarinen, Tamara T. Koopmann, Kenneth B. Margulies, Aravinda Chakravarti, Gianfranco Sinagra, Maarten P. van den Berg, Veikko Salomaa, Karl-Heinz Jöckel, Daniel S. Evans, Caroline Hayward, Kimmo Porthan, Michael J. Ackerman, Jacqueline C.M. Witteman, Arthur A.M. Wilde, Martin G. Larson, Kasper Lage, Manuela Uda, Susan R. Heckbert, Joel S. Bader, Graham Watt, María Dolores Torres, Stephan B. Felix, Jerome I. Rotter, Pau Navarro, Meena Kumari, Johan Ärnlöv, Andrew D. Paterson, Antti Jula, Olli T. Raitakari, Raimund Erbel, Christopher J. O'Donnell, Britt M. Beckmann, Peter A. Noseworthy, Tim D. Spector, Wai K. Lee, Leopoldo Zelante, Nilesh J. Samani, John R. Giudicessi, Harold Snieder, Dag S. Thelle, David Ellinghaus, Eimo Martens, James B. Strait, Jorma S. A. Viikari, Andrew D. Johnson, Antonella Mulas, Hilma Holm, Johannes Haerting, Annamaria Iorio, Rebecca L. Zuvich, Sheila Ulivi, Andrew A. Hicks, Elijah R. Behr, Leo-Pekka Lyytikäinen, Bernhard Strohmer, Marco Orru, Claudia Lamina, Sandosh Padmanabhan, Christian Fuchsberger, Andrie G. Panayiotou, Ehret, Georg Benedikt, Internal Medicine, Public Health, Epidemiology, Rehabilitation Medicine, Medical Informatics, Clinical Genetics, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Ethical, Legal, Social Issues in Genetics (ELSI), Stem Cell Aging Leukemia and Lymphoma (SALL), Arking, D, Pulit, S, Crotti, L, van der Harst, P, Munroe, P, Koopmann, T, Sotoodehnia, N, Rossin, E, Morley, M, Wang, X, Johnson, A, Lundby, A, Gudbjartsson, D, Noseworthy, P, Eijgelsheim, M, Bradford, Y, Tarasov, K, Dörr, M, Müller-Nurasyid, M, Lahtinen, A, Nolte, I, Smith, A, Bis, J, Isaacs, A, Newhouse, S, Evans, D, Post, W, Waggott, D, Lyytikäinen, L, Hicks, A, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, D, Chatel, S, Gustafsson, S, Kumari, M, Morris, R, Naluai, A, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, A, Torres, M, Knoflach, M, Hubacek, J, Slowikowski, K, Raychaudhuri, S, Kumar, R, Harris, T, Launer, L, Shuldiner, A, Alonso, A, Bader, J, Ehret, G, Huang, H, Kao, W, Strait, J, Macfarlane, P, Brown, M, Caulfield, M, Samani, N, Kronenberg, F, Willeit, J, Smith, J, Greiser, K, Meyer Zu Schwabedissen, H, Werdan, K, Carella, M, Zelante, L, Heckbert, S, Psaty, B, Rotter, J, Kolcic, I, Polašek, O, Wright, A, Griffin, M, Daly, M, Arnar, D, Hólm, H, Thorsteinsdottir, U, Denny, J, Roden, D, Zuvich, R, Emilsson, V, Plump, A, Larson, M, O'Donnell, C, Yin, X, Bobbo, M, D'Adamo, A, Iorio, A, Sinagra, G, Carracedo, A, Cummings, S, Nalls, M, Jula, A, Kontula, K, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K, Kälsch, H, Nöthen, M, den Hoed, M, Loos, R, Thelle, D, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, M, Waldenberger, M, de Boer, R, Franke, L, van der Vleuten, P, Beckmann, B, Martens, E, Bardai, A, Hofman, N, Wilde, A, Behr, E, Dalageorgou, C, Giudicessi, J, Medeiros-Domingo, A, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, R, Scherer, S, Brandimarto, J, Margulies, K, Moravec, C, Greco, M, Fuchsberger, C, O'Connell, J, Lee, W, Watt, G, Campbell, H, Wild, S, El Mokhtari, N, Frey, N, Asselbergs, F, Mateo Leach, I, Navis, G, van den Berg, M, van Veldhuisen, D, Kellis, M, Krijthe, B, Franco, O, Hofman, A, Kors, J, Uitterlinden, A, Witteman, J, Kedenko, L, Lamina, C, Oostra, B, Abecasis, G, Lakatta, E, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, M, Völker, U, Snieder, H, Spector, T, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, O, Viikari, J, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, A, Paulweber, B, Haerting, J, Dominiczak, A, Nyberg, F, Whincup, P, Hingorani, A, Schott, J, Bezzina, C, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, J, Rudan, I, Franke, A, Mühleisen, T, Pramstaller, P, Lehtimäki, T, Paterson, A, Parsa, A, Liu, Y, van Duijn, C, Siscovick, D, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, S, Sanna, S, Ritchie, M, Stricker, B, Stefansson, K, Boyer, L, Cappola, T, Olsen, J, Lage, K, Schwartz, P, Kääb, S, Chakravarti, A, Ackerman, M, Pfeufer, A, de Bakker, P, Newton-Cheh, C, Arking, Dan E., Pulit, Sara L., Crotti, Lia, Van Der Harst, Pim, Munroe, Patricia B., Koopmann, Tamara T., Sotoodehnia, Nona, Rossin, Elizabeth J., Morley, Michael, Wang, Xinchen, Johnson, Andrew D., Lundby, Alicia, Gudbjartsson, Daníel F., Noseworthy, Peter A., Eijgelsheim, Mark, Bradford, Yuki, Tarasov, Kirill V., Dörr, Marcu, Müller Nurasyid, Martina, Lahtinen, Annukka M., Nolte, Ilja M., Smith, Albert Vernon, Bis, Joshua C., Isaacs, Aaron, Newhouse, Stephen J., Evans, Daniel S., Post, Wendy S., Waggott, Daryl, Lyytikäinen, Leo Pekka, Hicks, Andrew A., Eisele, Lewin, Ellinghaus, David, Hayward, Caroline, Navarro, Pau, Ulivi, Sheila, Tanaka, Toshiko, Tester, David J., Chatel, Stéphanie, Gustafsson, Stefan, Kumari, Meena, Morris, Richard W., Naluai, Asa T., Padmanabhan, Sandosh, Kluttig, Alexander, Strohmer, Bernhard, Panayiotou, Andrie G., Torres, Maria, Knoflach, Michael, Hubacek, Jaroslav A., Slowikowski, Kamil, Raychaudhuri, Soumya, Kumar, Runjun D., Harris, Tamara B., Launer, Lenore J., Shuldiner, Alan R., Alonso, Alvaro, Bader, Joel S., Ehret, Georg, Huang, Hailiang, Kao, W. H. Linda, Strait, James B., Macfarlane, Peter W., Brown, Morri, Caulfield, Mark J., Samani, Nilesh J., Kronenberg, Florian, Willeit, Johann, Smith, J. Gustav, Greiser, Karin H., Zu Schwabedissen, Henriette Meyer, Werdan, Karl, Carella, Massimo, Zelante, Leopoldo, Heckbert, Susan R., Psaty, Bruce M., Rotter, Jerome I., Kolcic, Ivana, Polašek, Ozren, Wright, Alan F., Griffin, Maura, Daly, Mark J., Arnar, David O., Hólm, Hilma, Thorsteinsdottir, Unnur, Denny, Joshua C., Roden, Dan M., Zuvich, Rebecca L., Emilsson, Valur, Plump, Andrew S., Larson, Martin G., O'Donnell, Christopher J., Yin, Xiaoyan, Bobbo, Marco, D'Adamo, ADAMO PIO, Iorio, Annamaria, Sinagra, Gianfranco, Carracedo, Angel, Cummings, Steven R., Nalls, Michael A., Jula, Antti, Kontula, Kimmo K., Marjamaa, Annukka, Oikarinen, Lasse, Perola, Marku, Porthan, Kimmo, Erbel, Raimund, Hoffmann, Per, Jöckel, Karl Heinz, Kälsch, Hagen, Nöthen, Markus M., Den Hoed, Marcel, Loos, Ruth J. F., Thelle, Dag S., Gieger, Christian, Meitinger, Thoma, Perz, Siegfried, Peters, Annette, Prucha, Hanna, Sinner, Moritz F., Waldenberger, Melanie, De Boer, Rudolf A., Franke, Lude, Van Der Vleuten, Pieter A., Beckmann, Britt Maria, Martens, Eimo, Bardai, Abdennasser, Hofman, Nynke, Wilde, Arthur A. M., Behr, Elijah R., Dalageorgou, Chrysoula, Giudicessi, John R., Medeiros Domingo, Argelia, Barc, Julien, Kyndt, Florence, Probst, Vincent, Ghidoni, Alice, Insolia, Roberto, Hamilton, Robert M., Scherer, Stephen W., Brandimarto, Jeffrey, Margulies, Kenneth, Moravec, Christine E., Del Greco M, Fabiola, Fuchsberger, Christian, O'Connell, Jeffrey R., Lee, Wai K., Watt, Graham C. M., Campbell, Harry, Wild, Sarah H., El Mokhtari, Nour E., Frey, Norbert, Asselbergs, Folkert W., Leach, Irene Mateo, Navis, Gerjan, Van Den Berg, Maarten P., Van Veldhuisen, Dirk J., Kellis, Manoli, Krijthe, Bouwe P., Franco, Oscar H., Hofman, Albert, Kors, Jan A., Uitterlinden, André G., Witteman, Jacqueline C. M., Kedenko, Lyudmyla, Lamina, Claudia, Oostra, Ben A., Abecasis, Gonçalo R., Lakatta, Edward G., Mulas, Antonella, Orrú, Marco, Schlessinger, David, Uda, Manuela, Markus, Marcello R. P., Völker, Uwe, Snieder, Harold, Spector, Timothy D., Ärnlöv, Johan, Lind, Lar, Sundström, Johan, Syvänen, Ann Christine, Kivimaki, Mika, Kähönen, Mika, Mononen, Nina, Raitakari, Olli T., Viikari, Jorma S., Adamkova, Vera, Kiechl, Stefan, Brion, Maria, Nicolaides, Andrew N., Paulweber, Bernhard, Haerting, Johanne, Dominiczak, Anna F., Nyberg, Fredrik, Whincup, Peter H., Hingorani, Aroon D., Schott, Jean Jacque, Bezzina, Connie R., Ingelsson, Erik, Ferrucci, Luigi, Gasparini, Paolo, Wilson, James F., Rudan, Igor, Franke, Andre, Mühleisen, Thomas W., Pramstaller, Peter P., Lehtimäki, Terho J., Paterson, Andrew D., Parsa, Afshin, Liu, Yongmei, Van Duijn, Cornelia M., Siscovick, David S., Gudnason, Vilmundur, Jamshidi, Yalda, Salomaa, Veikko, Felix, Stephan B., Sanna, Serena, Ritchie, Marylyn D., Stricker, Bruno H., Stefansson, Kari, Boyer, Laurie A., Cappola, Thomas P., Olsen, Jesper V., Lage, Kasper, Schwartz, Peter J., Kääb, Stefan, Chakravarti, Aravinda, Ackerman, Michael J., Pfeufer, Arne, De Bakker, Paul I. W., Newton Cheh, Christopher, Cardiology, ACS - Amsterdam Cardiovascular Sciences, and Human Genetics

Subjects
Male, Candidate gene, Myocardium/metabolism, LOCI, Medizin, Heart electrophysiology, Genome-wide association study, Arrhythmias, Bioinformatics, Medical and Health Sciences, Heart Ventricle, Sudden cardiac death, Electrocardiography, PR INTERVAL, Arrhythmias, Cardiac/genetics, Death, Sudden, Cardiac/etiology, Genetics, ddc:616, Cardiac electrophysiology, Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Middle Aged, Myocardium, Polymorphism, Single Nucleotide, COMMON VARIANTS, Heart Ventricles/metabolism, Single Nucleotide, Long QT Syndrome/genetics, CHRONIC HEART-FAILURE, Death, Heart ventricle arrhythmia, genetic association study, gene, SNP, heart, Genome-Wide Association Study/methods, Long QT syndrome, QRS DURATION, Cardiac, Cardiac/etiology, Human, QT interval, congenital, hereditary, and neonatal diseases and abnormalities, Electrocardiography/methods, TRPM7, BIO/18 - GENETICA, Cardiac/genetics, Biology, Article, sudden cardiac death, QRS complex, CARDIAC REPOLARIZATION, medicine, Repolarization, cardiovascular diseases, GENOME-WIDE ASSOCIATION, Polymorphism, MED/01 - STATISTICA MEDICA, calcium, ta1184, Calcium signaling, Calcium Signaling/genetics, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, ta3121, Cardiovascular risk, medicine.disease, SARCOPLASMIC-RETICULUM, Sudden, MODEL, Genetic association, myocardial repolarization, Genetic variability, Gene expression, Clinical Medicine, genetic, Controlled study
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 similar to 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.

Published
2014

17. Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing.

Author

Nunn LM, Lopes LR, Syrris P, Murphy C, Plagnol V, Firman E, Dalageorgou C, Zorio E, Domingo D, Murday V, Findlay I, Duncan A, Carr-White G, Robert L, Bueser T, Langman C, Fynn SP, Goddard M, White A, Bundgaard H, Ferrero-Miliani L, Wheeldon N, Suvarna SK, O'Beirne A, Lowe MD, McKenna WJ, Elliott PM, and Lambiase PD

Subjects
Adolescent, Adult, Autopsy, Case-Control Studies, Child, Child, Preschool, Cohort Studies, Death, Sudden, Cardiac prevention & control, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Testing, Humans, Infant, Male, Middle Aged, Mutation, NAV1.5 Voltage-Gated Sodium Channel genetics, Pedigree, Sequence Analysis, DNA, United Kingdom, Young Adult, Brugada Syndrome diagnosis, Brugada Syndrome genetics, Exome genetics, Long QT Syndrome diagnosis, Long QT Syndrome genetics
Abstract

Aims: The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible., Methods and Results: To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency <0.02% in the NHLBI exome sequencing project and an internal set of control exomes were prioritized for analysis followed by <0.5% frequency threshold secondary analysis. First-degree relatives were offered clinical screening for inherited cardiac conditions. Seven probands (12%) carried very rare (<0.02%) or novel non-sense candidate mutations and 10 probands (17%) had previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands., Conclusion: Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Published
2016
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