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12 results on '"Sotoodehnia N."'

1. 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

2. Allele-specific NKX2-5 binding underlies multiple genetic associations with human electrocardiographic traits.

Author

Benaglio P, D'Antonio-Chronowska A, Ma W, Yang F, Young Greenwald WW, Donovan MKR, DeBoever C, Li H, Drees F, Singhal S, Matsui H, van Setten J, Sotoodehnia N, Gaulton KJ, Smith EN, D'Antonio M, Rosenfeld MG, and Frazer KA

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Child, Electrocardiography, Epigenomics, Female, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells pathology, Male, Middle Aged, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Phenotype, Protein Binding, Transcriptome, Young Adult, Atrial Fibrillation genetics, Atrial Fibrillation pathology, Homeobox Protein Nkx-2.5 genetics, Homeobox Protein Nkx-2.5 metabolism, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Regulatory Elements, Transcriptional
Abstract

The cardiac transcription factor (TF) gene NKX2-5 has been associated with electrocardiographic (EKG) traits through genome-wide association studies (GWASs), but the extent to which differential binding of NKX2-5 at common regulatory variants contributes to these traits has not yet been studied. We analyzed transcriptomic and epigenomic data from induced pluripotent stem cell-derived cardiomyocytes from seven related individuals, and identified ~2,000 single-nucleotide variants associated with allele-specific effects (ASE-SNVs) on NKX2-5 binding. NKX2-5 ASE-SNVs were enriched for altered TF motifs, for heart-specific expression quantitative trait loci and for EKG GWAS signals. Using fine-mapping combined with epigenomic data from induced pluripotent stem cell-derived cardiomyocytes, we prioritized candidate causal variants for EKG traits, many of which were NKX2-5 ASE-SNVs. Experimentally characterizing two NKX2-5 ASE-SNVs (rs3807989 and rs590041) showed that they modulate the expression of target genes via differential protein binding in cardiac cells, indicating that they are functional variants underlying EKG GWAS signals. Our results show that differential NKX2-5 binding at numerous regulatory variants across the genome contributes to EKG phenotypes.

Published
2019
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3. Multi-ethnic genome-wide association study for atrial fibrillation.

Author

Roselli C, Chaffin MD, Weng LC, Aeschbacher S, Ahlberg G, Albert CM, Almgren P, Alonso A, Anderson CD, Aragam KG, Arking DE, Barnard J, Bartz TM, Benjamin EJ, Bihlmeyer NA, Bis JC, Bloom HL, Boerwinkle E, Bottinger EB, Brody JA, Calkins H, Campbell A, Cappola TP, Carlquist J, Chasman DI, Chen LY, Chen YI, Choi EK, Choi SH, Christophersen IE, Chung MK, Cole JW, Conen D, Cook J, Crijns HJ, Cutler MJ, Damrauer SM, Daniels BR, Darbar D, Delgado G, Denny JC, Dichgans M, Dörr M, Dudink EA, Dudley SC, Esa N, Esko T, Eskola M, Fatkin D, Felix SB, Ford I, Franco OH, Geelhoed B, Grewal RP, Gudnason V, Guo X, Gupta N, Gustafsson S, Gutmann R, Hamsten A, Harris TB, Hayward C, Heckbert SR, Hernesniemi J, Hocking LJ, Hofman A, Horimoto ARVR, Huang J, Huang PL, Huffman J, Ingelsson E, Ipek EG, Ito K, Jimenez-Conde J, Johnson R, Jukema JW, Kääb S, Kähönen M, Kamatani Y, Kane JP, Kastrati A, Kathiresan S, Katschnig-Winter P, Kavousi M, Kessler T, Kietselaer BL, Kirchhof P, Kleber ME, Knight S, Krieger JE, Kubo M, Launer LJ, Laurikka J, Lehtimäki T, Leineweber K, Lemaitre RN, Li M, Lim HE, Lin HJ, Lin H, Lind L, Lindgren CM, Lokki ML, London B, Loos RJF, Low SK, Lu Y, Lyytikäinen LP, Macfarlane PW, Magnusson PK, Mahajan A, Malik R, Mansur AJ, Marcus GM, Margolin L, Margulies KB, März W, McManus DD, Melander O, Mohanty S, Montgomery JA, Morley MP, Morris AP, Müller-Nurasyid M, Natale A, Nazarian S, Neumann B, Newton-Cheh C, Niemeijer MN, Nikus K, Nilsson P, Noordam R, Oellers H, Olesen MS, Orho-Melander M, Padmanabhan S, Pak HN, Paré G, Pedersen NL, Pera J, Pereira A, Porteous D, Psaty BM, Pulit SL, Pullinger CR, Rader DJ, Refsgaard L, Ribasés M, Ridker PM, Rienstra M, Risch L, Roden DM, Rosand J, Rosenberg MA, Rost N, Rotter JI, Saba S, Sandhu RK, Schnabel RB, Schramm K, Schunkert H, Schurman C, Scott SA, Seppälä I, Shaffer C, Shah S, Shalaby AA, Shim J, Shoemaker MB, Siland JE, Sinisalo J, Sinner MF, Slowik A, Smith AV, Smith BH, Smith JG, Smith JD, Smith NL, Soliman EZ, Sotoodehnia N, Stricker BH, Sun A, Sun H, Svendsen JH, Tanaka T, Tanriverdi K, Taylor KD, Teder-Laving M, Teumer A, Thériault S, Trompet S, Tucker NR, Tveit A, Uitterlinden AG, Van Der Harst P, Van Gelder IC, Van Wagoner DR, Verweij N, Vlachopoulou E, Völker U, Wang B, Weeke PE, Weijs B, Weiss R, Weiss S, Wells QS, Wiggins KL, Wong JA, Woo D, Worrall BB, Yang PS, Yao J, Yoneda ZT, Zeller T, Zeng L, Lubitz SA, Lunetta KL, and Ellinor PT

Subjects
Atrial Fibrillation ethnology, Case-Control Studies, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Humans, Quantitative Trait Loci, Transcriptome, Atrial Fibrillation genetics, Ethnicity genetics
Abstract

Atrial fibrillation (AF) affects more than 33 million individuals worldwide 1 and has a complex heritability 2 . We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Published
2018
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4. Erratum: Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.

Author

Christophersen IE, Rienstra M, Roselli C, Yin X, Geelhoed B, Barnard J, Lin H, Arking DE, Smith AV, Albert CM, Chaffin M, Tucker NR, Li M, Klarin D, Bihlmeyer NA, Low SK, Weeke PE, Müller-Nurasyid M, Smith JG, Brody JA, Niemeijer MN, Dörr M, Trompet S, Huffman J, Gustafsson S, Schurmann C, Kleber ME, Lyytikäinen LP, Seppälä I, Malik R, R V R Horimoto A, Perez M, Sinisalo J, Aeschbacher S, Thériault S, Yao J, Radmanesh F, Weiss S, Teumer A, Choi SH, Weng LC, Clauss S, Deo R, Rader DJ, Shah SH, Sun A, Hopewell JC, Debette S, Chauhan G, Yang Q, Worrall BB, Paré G, Kamatani Y, Hagemeijer YP, Verweij N, Siland JE, Kubo M, Smith JD, Van Wagoner DR, Bis JC, Perz S, Psaty BM, Ridker PM, Magnani JW, Harris TB, Launer LJ, Shoemaker MB, Padmanabhan S, Haessler J, Bartz TM, Waldenberger M, Lichtner P, Arendt M, Krieger JE, Kähönen M, Risch L, Mansur AJ, Peters A, Smith BH, Lind L, Scott SA, Lu Y, Bottinger EB, Hernesniemi J, Lindgren CM, Wong JA, Huang J, Eskola M, Morris AP, Ford I, Reiner AP, Delgado G, Chen LY, Chen YI, Sandhu RK, Li M, Boerwinkle E, Eisele L, Lannfelt L, Rost N, Anderson CD, Taylor KD, Campbell A, Magnusson PK, Porteous D, Hocking LJ, Vlachopoulou E, Pedersen NL, Nikus K, Orho-Melander M, Hamsten A, Heeringa J, Denny JC, Kriebel J, Darbar D, Newton-Cheh C, Shaffer C, Macfarlane PW, Heilmann-Heimbach S, Almgren P, Huang PL, Sotoodehnia N, Soliman EZ, Uitterlinden AG, Hofman A, Franco OH, Völker U, Jöckel KH, Sinner MF, Lin HJ, Guo X, Dichgans M, Ingelsson E, Kooperberg C, Melander O, J F Loos R, Laurikka J, Conen D, Rosand J, van der Harst P, Lokki ML, Kathiresan S, Pereira A, Jukema JW, Hayward C, Rotter JI, März W, Lehtimäki T, Stricker BH, Chung MK, Felix SB, Gudnason V, Alonso A, Roden DM, Kääb S, Chasman DI, Heckbert SR, Benjamin EJ, Tanaka T, Lunetta KL, Lubitz SA, and Ellinor PT

Published
2017
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5. Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.

Author

Christophersen IE, Rienstra M, Roselli C, Yin X, Geelhoed B, Barnard J, Lin H, Arking DE, Smith AV, Albert CM, Chaffin M, Tucker NR, Li M, Klarin D, Bihlmeyer NA, Low SK, Weeke PE, Müller-Nurasyid M, Smith JG, Brody JA, Niemeijer MN, Dörr M, Trompet S, Huffman J, Gustafsson S, Schurmann C, Kleber ME, Lyytikäinen LP, Seppälä I, Malik R, Horimoto ARVR, Perez M, Sinisalo J, Aeschbacher S, Thériault S, Yao J, Radmanesh F, Weiss S, Teumer A, Choi SH, Weng LC, Clauss S, Deo R, Rader DJ, Shah SH, Sun A, Hopewell JC, Debette S, Chauhan G, Yang Q, Worrall BB, Paré G, Kamatani Y, Hagemeijer YP, Verweij N, Siland JE, Kubo M, Smith JD, Van Wagoner DR, Bis JC, Perz S, Psaty BM, Ridker PM, Magnani JW, Harris TB, Launer LJ, Shoemaker MB, Padmanabhan S, Haessler J, Bartz TM, Waldenberger M, Lichtner P, Arendt M, Krieger JE, Kähönen M, Risch L, Mansur AJ, Peters A, Smith BH, Lind L, Scott SA, Lu Y, Bottinger EB, Hernesniemi J, Lindgren CM, Wong JA, Huang J, Eskola M, Morris AP, Ford I, Reiner AP, Delgado G, Chen LY, Chen YI, Sandhu RK, Li M, Boerwinkle E, Eisele L, Lannfelt L, Rost N, Anderson CD, Taylor KD, Campbell A, Magnusson PK, Porteous D, Hocking LJ, Vlachopoulou E, Pedersen NL, Nikus K, Orho-Melander M, Hamsten A, Heeringa J, Denny JC, Kriebel J, Darbar D, Newton-Cheh C, Shaffer C, Macfarlane PW, Heilmann-Heimbach S, Almgren P, Huang PL, Sotoodehnia N, Soliman EZ, Uitterlinden AG, Hofman A, Franco OH, Völker U, Jöckel KH, Sinner MF, Lin HJ, Guo X, Dichgans M, Ingelsson E, Kooperberg C, Melander O, Loos RJF, Laurikka J, Conen D, Rosand J, van der Harst P, Lokki ML, Kathiresan S, Pereira A, Jukema JW, Hayward C, Rotter JI, März W, Lehtimäki T, Stricker BH, Chung MK, Felix SB, Gudnason V, Alonso A, Roden DM, Kääb S, Chasman DI, Heckbert SR, Benjamin EJ, Tanaka T, Lunetta KL, Lubitz SA, and Ellinor PT

Subjects
Black or African American genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Quantitative Trait Loci, White People genetics, Atrial Fibrillation genetics, Genetic Loci
Abstract

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

Published
2017
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6. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

Author

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 ÅT, 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 WH, Strait JB, Macfarlane PW, Brown M, Caulfield MJ, Samani NJ, Kronenberg F, Willeit J, Smith JG, Greiser KH, Meyer Zu Schwabedissen H, 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 RJ, 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 AA, 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 GC, Campbell H, Wild SH, El Mokhtari NE, Frey N, Asselbergs FW, Mateo Leach I, Navis G, van den Berg MP, van Veldhuisen DJ, Kellis M, Krijthe BP, Franco OH, Hofman A, Kors JA, Uitterlinden AG, Witteman JC, Kedenko L, Lamina C, Oostra BA, Abecasis GR, Lakatta EG, Mulas A, Orrú M, Schlessinger D, Uda M, Markus MR, 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 PI, and Newton-Cheh C

Subjects
Adult, Aged, Arrhythmias, Cardiac genetics, Arrhythmias, Cardiac metabolism, Death, Sudden, Cardiac etiology, Electrocardiography methods, Female, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Genotype, Heart Ventricles metabolism, Humans, Long QT Syndrome metabolism, Male, Middle Aged, Myocardium metabolism, Polymorphism, Single Nucleotide, Calcium Signaling genetics, Long QT Syndrome genetics
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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7. Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.

Author

den Hoed M, Eijgelsheim M, Esko T, Brundel BJ, Peal DS, Evans DM, Nolte IM, Segrè AV, Holm H, Handsaker RE, Westra HJ, Johnson T, Isaacs A, Yang J, Lundby A, Zhao JH, Kim YJ, Go MJ, Almgren P, Bochud M, Boucher G, Cornelis MC, Gudbjartsson D, Hadley D, van der Harst P, Hayward C, den Heijer M, Igl W, Jackson AU, Kutalik Z, Luan J, Kemp JP, Kristiansson K, Ladenvall C, Lorentzon M, Montasser ME, Njajou OT, O'Reilly PF, Padmanabhan S, St Pourcain B, Rankinen T, Salo P, Tanaka T, Timpson NJ, Vitart V, Waite L, Wheeler W, Zhang W, Draisma HH, Feitosa MF, Kerr KF, Lind PA, Mihailov E, Onland-Moret NC, Song C, Weedon MN, Xie W, Yengo L, Absher D, Albert CM, Alonso A, Arking DE, de Bakker PI, Balkau B, Barlassina C, Benaglio P, Bis JC, Bouatia-Naji N, Brage S, Chanock SJ, Chines PS, Chung M, Darbar D, Dina C, Dörr M, Elliott P, Felix SB, Fischer K, Fuchsberger C, de Geus EJ, Goyette P, Gudnason V, Harris TB, Hartikainen AL, Havulinna AS, Heckbert SR, Hicks AA, Hofman A, Holewijn S, Hoogstra-Berends F, Hottenga JJ, Jensen MK, Johansson A, Junttila J, Kääb S, Kanon B, Ketkar S, Khaw KT, Knowles JW, Kooner AS, Kors JA, Kumari M, Milani L, Laiho P, Lakatta EG, Langenberg C, Leusink M, Liu Y, Luben RN, Lunetta KL, Lynch SN, Markus MR, Marques-Vidal P, Mateo Leach I, McArdle WL, McCarroll SA, Medland SE, Miller KA, Montgomery GW, Morrison AC, Müller-Nurasyid M, Navarro P, Nelis M, O'Connell JR, O'Donnell CJ, Ong KK, Newman AB, Peters A, Polasek O, Pouta A, Pramstaller PP, Psaty BM, Rao DC, Ring SM, Rossin EJ, Rudan D, Sanna S, Scott RA, Sehmi JS, Sharp S, Shin JT, Singleton AB, Smith AV, Soranzo N, Spector TD, Stewart C, Stringham HM, Tarasov KV, Uitterlinden AG, Vandenput L, Hwang SJ, Whitfield JB, Wijmenga C, Wild SH, Willemsen G, Wilson JF, Witteman JC, Wong A, Wong Q, Jamshidi Y, Zitting P, Boer JM, Boomsma DI, Borecki IB, van Duijn CM, Ekelund U, Forouhi NG, Froguel P, Hingorani A, Ingelsson E, Kivimaki M, Kronmal RA, Kuh D, Lind L, Martin NG, Oostra BA, Pedersen NL, Quertermous T, Rotter JI, van der Schouw YT, Verschuren WM, Walker M, Albanes D, Arnar DO, Assimes TL, Bandinelli S, Boehnke M, de Boer RA, Bouchard C, Caulfield WL, Chambers JC, Curhan G, Cusi D, Eriksson J, Ferrucci L, van Gilst WH, Glorioso N, de Graaf J, Groop L, Gyllensten U, Hsueh WC, Hu FB, Huikuri HV, Hunter DJ, Iribarren C, Isomaa B, Jarvelin MR, Jula A, Kähönen M, Kiemeney LA, van der Klauw MM, Kooner JS, Kraft P, Iacoviello L, Lehtimäki T, Lokki ML, Mitchell BD, Navis G, Nieminen MS, Ohlsson C, Poulter NR, Qi L, Raitakari OT, Rimm EB, Rioux JD, Rizzi F, Rudan I, Salomaa V, Sever PS, Shields DC, Shuldiner AR, Sinisalo J, Stanton AV, Stolk RP, Strachan DP, Tardif JC, Thorsteinsdottir U, Tuomilehto J, van Veldhuisen DJ, Virtamo J, Viikari J, Vollenweider P, Waeber G, Widen E, Cho YS, Olsen JV, Visscher PM, Willer C, Franke L, Erdmann J, Thompson JR, Pfeufer A, Sotoodehnia N, Newton-Cheh C, Ellinor PT, Stricker BH, Metspalu A, Perola M, Beckmann JS, Smith GD, Stefansson K, Wareham NJ, Munroe PB, Sibon OC, Milan DJ, Snieder H, Samani NJ, and Loos RJ

Subjects
Animals, Arrhythmias, Cardiac physiopathology, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Heart Conduction System physiopathology, Humans, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Arrhythmias, Cardiac genetics, Heart Rate genetics
Abstract

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

Published
2013
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8. Meta-analysis identifies six new susceptibility loci for atrial fibrillation.

Author

Ellinor PT, Lunetta KL, Albert CM, Glazer NL, Ritchie MD, Smith AV, Arking DE, Müller-Nurasyid M, Krijthe BP, Lubitz SA, Bis JC, Chung MK, Dörr M, Ozaki K, Roberts JD, Smith JG, Pfeufer A, Sinner MF, Lohman K, Ding J, Smith NL, Smith JD, Rienstra M, Rice KM, Van Wagoner DR, Magnani JW, Wakili R, Clauss S, Rotter JI, Steinbeck G, Launer LJ, Davies RW, Borkovich M, Harris TB, Lin H, Völker U, Völzke H, Milan DJ, Hofman A, Boerwinkle E, Chen LY, Soliman EZ, Voight BF, Li G, Chakravarti A, Kubo M, Tedrow UB, Rose LM, Ridker PM, Conen D, Tsunoda T, Furukawa T, Sotoodehnia N, Xu S, Kamatani N, Levy D, Nakamura Y, Parvez B, Mahida S, Furie KL, Rosand J, Muhammad R, Psaty BM, Meitinger T, Perz S, Wichmann HE, Witteman JC, Kao WH, Kathiresan S, Roden DM, Uitterlinden AG, Rivadeneira F, McKnight B, Sjögren M, Newman AB, Liu Y, Gollob MH, Melander O, Tanaka T, Stricker BH, Felix SB, Alonso A, Darbar D, Barnard J, Chasman DI, Heckbert SR, Benjamin EJ, Gudnason V, and Kääb S

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Asian People genetics, Child, Child, Preschool, Female, Genetic Loci, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, White People genetics, Young Adult, Atrial Fibrillation genetics, Genetic Predisposition to Disease genetics
Abstract

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

Published
2012
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9. Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.

Author

Sotoodehnia N, Isaacs A, de Bakker PI, Dörr M, Newton-Cheh C, Nolte IM, van der Harst P, Müller M, Eijgelsheim M, Alonso A, Hicks AA, Padmanabhan S, Hayward C, Smith AV, Polasek O, Giovannone S, Fu J, Magnani JW, Marciante KD, Pfeufer A, Gharib SA, Teumer A, Li M, Bis JC, Rivadeneira F, Aspelund T, Köttgen A, Johnson T, Rice K, Sie MP, Wang YA, Klopp N, Fuchsberger C, Wild SH, Mateo Leach I, Estrada K, Völker U, Wright AF, Asselbergs FW, Qu J, Chakravarti A, Sinner MF, Kors JA, Petersmann A, Harris TB, Soliman EZ, Munroe PB, Psaty BM, Oostra BA, Cupples LA, Perz S, de Boer RA, Uitterlinden AG, Völzke H, Spector TD, Liu FY, Boerwinkle E, Dominiczak AF, Rotter JI, van Herpen G, Levy D, Wichmann HE, van Gilst WH, Witteman JC, Kroemer HK, Kao WH, Heckbert SR, Meitinger T, Hofman A, Campbell H, Folsom AR, van Veldhuisen DJ, Schwienbacher C, O'Donnell CJ, Volpato CB, Caulfield MJ, Connell JM, Launer L, Lu X, Franke L, Fehrmann RS, te Meerman G, Groen HJ, Weersma RK, van den Berg LH, Wijmenga C, Ophoff RA, Navis G, Rudan I, Snieder H, Wilson JF, Pramstaller PP, Siscovick DS, Wang TJ, Gudnason V, van Duijn CM, Felix SB, Fishman GI, Jamshidi Y, Stricker BH, Samani NJ, Kääb S, and Arking DE

Subjects
Animals, Animals, Newborn, Chromosomes, Human genetics, Computational Biology, Humans, Mice, Mice, Transgenic, Models, Animal, Myocytes, Cardiac metabolism, NAV1.8 Voltage-Gated Sodium Channel, Sodium Channels genetics, Electrocardiography, Genetic Loci genetics, Genome-Wide Association Study, Heart Conduction System physiology, Polymorphism, Single Nucleotide genetics
Abstract

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

Published
2010
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10. Genome-wide association study of PR interval.

Author

Pfeufer A, van Noord C, Marciante KD, Arking DE, Larson MG, Smith AV, Tarasov KV, Müller M, Sotoodehnia N, Sinner MF, Verwoert GC, Li M, Kao WH, Köttgen A, Coresh J, Bis JC, Psaty BM, Rice K, Rotter JI, Rivadeneira F, Hofman A, Kors JA, Stricker BH, Uitterlinden AG, van Duijn CM, Beckmann BM, Sauter W, Gieger C, Lubitz SA, Newton-Cheh C, Wang TJ, Magnani JW, Schnabel RB, Chung MK, Barnard J, Smith JD, Van Wagoner DR, Vasan RS, Aspelund T, Eiriksdottir G, Harris TB, Launer LJ, Najjar SS, Lakatta E, Schlessinger D, Uda M, Abecasis GR, Müller-Myhsok B, Ehret GB, Boerwinkle E, Chakravarti A, Soliman EZ, Lunetta KL, Perz S, Wichmann HE, Meitinger T, Levy D, Gudnason V, Ellinor PT, Sanna S, Kääb S, Witteman JC, Alonso A, Benjamin EJ, and Heckbert SR

Subjects
Aged, Atrial Fibrillation genetics, Atrial Fibrillation physiopathology, Cohort Studies, Female, Genetic Loci genetics, Genetic Predisposition to Disease, Humans, Male, Meta-Analysis as Topic, Electrocardiography, Genome-Wide Association Study, Heart Conduction System physiology
Abstract

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

Published
2010
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11. Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.

Author

Benjamin EJ, Rice KM, Arking DE, Pfeufer A, van Noord C, Smith AV, Schnabel RB, Bis JC, Boerwinkle E, Sinner MF, Dehghan A, Lubitz SA, D'Agostino RB Sr, Lumley T, Ehret GB, Heeringa J, Aspelund T, Newton-Cheh C, Larson MG, Marciante KD, Soliman EZ, Rivadeneira F, Wang TJ, Eiríksdottir G, Levy D, Psaty BM, Li M, Chamberlain AM, Hofman A, Vasan RS, Harris TB, Rotter JI, Kao WH, Agarwal SK, Stricker BH, Wang K, Launer LJ, Smith NL, Chakravarti A, Uitterlinden AG, Wolf PA, Sotoodehnia N, Köttgen A, van Duijn CM, Meitinger T, Mueller M, Perz S, Steinbeck G, Wichmann HE, Lunetta KL, Heckbert SR, Gudnason V, Alonso A, Kääb S, Ellinor PT, and Witteman JC

Subjects
Chromosomes, Human, Pair 16 genetics, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide genetics, Reproducibility of Results, Atrial Fibrillation genetics, Genetic Predisposition to Disease, Homeodomain Proteins genetics, Mutation genetics, White People genetics
Abstract

We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).

Published
2009
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12. Common variants at ten loci influence QT interval duration in the QTGEN Study.

Author

Newton-Cheh C, Eijgelsheim M, Rice KM, de Bakker PI, Yin X, Estrada K, Bis JC, Marciante K, Rivadeneira F, Noseworthy PA, Sotoodehnia N, Smith NL, Rotter JI, Kors JA, Witteman JC, Hofman A, Heckbert SR, O'Donnell CJ, Uitterlinden AG, Psaty BM, Lumley T, Larson MG, and Stricker BH

Subjects
Adaptor Proteins, Signal Transducing genetics, Adult, Aged, Arrhythmias, Cardiac chemically induced, Chromosome Mapping, Death, Sudden, Cardiac, ERG1 Potassium Channel, Electroencephalography, Ether-A-Go-Go Potassium Channels genetics, Genetic Predisposition to Disease genetics, Genome, Human, Humans, KCNQ1 Potassium Channel genetics, Meta-Analysis as Topic, Muscle Proteins genetics, NAV1.5 Voltage-Gated Sodium Channel, Potassium Channels, Voltage-Gated genetics, Risk Factors, Sodium Channels genetics, White People genetics, Arrhythmias, Cardiac genetics, Genetic Variation, Polymorphism, Single Nucleotide genetics
Abstract

QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 x 10(-8) with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4-6.5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.

Published
2009
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