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1. Novel loci and biomedical consequences of iron homoeostasis variation

Author

Allara, Elias, Bell, Steven, Smith, Rebecca, Keene, Spencer J., Gill, Dipender, Gaziano, Liam, Morselli Gysi, Deisy, Wang, Feiyi, Tragante, Vinicius, Mason, Amy, Karthikeyan, Savita, Lumbers, R. Thomas, Bonglack, Emmanuela, Ouwehand, Willem, Roberts, David J., Dowsett, Joseph, Ostrowski, Sisse Rye, Larsen, Margit Hørup, Ullum, Henrik, Pedersen, Ole Birger, Brunak, Søren, Banasik, Karina, Erikstrup, Christian, Mitchell, Jonathan, Fuchsberger, Christian, Pattaro, Cristian, Pramstaller, Peter P., Girelli, Domenico, Arvas, Mikko, Toivonen, Jarkko, Molnos, Sophie, Peters, Annette, Polasek, Ozren, Rudan, Igor, Hayward, Caroline, McDonnell, Ciara, Pirastu, Nicola, Wilson, James F., van den Hurk, Katja, Quee, Franke, Ferrucci, Luigi, Bandinelli, Stefania, Tanaka, Toshiko, Girotto, Giorgia, Concas, Maria Pina, Pecori, Alessandro, Verweij, Niek, van der Harst, Pim, van de Vegte, Yordi J., Kiemeney, Lambertus A., Sweep, Fred C., Galesloot, Tessel E., Sulem, Patrick, Gudbjartsson, Daniel, Ferkingstad, Egil, Djousse, Luc, Cho, Kelly, Inouye, Michael, Burgess, Stephen, Benyamin, Beben, Oexle, Konrad, Swinkels, Dorine, Stefansson, Kari, Magnusson, Magnus, Ganna, Andrea, Gaziano, Michael, Ivey, Kerry, Danesh, John, Pereira, Alexandre, Wood, Angela M., Butterworth, Adam S., and Di Angelantonio, Emanuele

Published
2024
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4. Genetic insights into resting heart rate and its role in cardiovascular disease

Author

van de Vegte, Yordi J., Eppinga, Ruben N., van der Ende, M. Yldau, Hagemeijer, Yanick P., Mahendran, Yuvaraj, Salfati, Elias, Smith, Albert V., Tan, Vanessa Y., Arking, Dan E., Ntalla, Ioanna, Appel, Emil V., Schurmann, Claudia, Brody, Jennifer A., Rueedi, Rico, Polasek, Ozren, Sveinbjornsson, Gardar, Lecoeur, Cecile, Ladenvall, Claes, Zhao, Jing Hua, Isaacs, Aaron, Wang, Lihua, Luan, Jian’an, Hwang, Shih-Jen, Mononen, Nina, Auro, Kirsi, Jackson, Anne U., Bielak, Lawrence F., Zeng, Linyao, Shah, Nabi, Nethander, Maria, Campbell, Archie, Rankinen, Tuomo, Pechlivanis, Sonali, Qi, Lu, Zhao, Wei, Rizzi, Federica, Tanaka, Toshiko, Robino, Antonietta, Cocca, Massimiliano, Lange, Leslie, Müller-Nurasyid, Martina, Roselli, Carolina, Zhang, Weihua, Kleber, Marcus E., Guo, Xiuqing, Lin, Henry J., Pavani, Francesca, Galesloot, Tessel E., Noordam, Raymond, Milaneschi, Yuri, Schraut, Katharina E., den Hoed, Marcel, Degenhardt, Frauke, Trompet, Stella, van den Berg, Marten E., Pistis, Giorgio, Tham, Yih-Chung, Weiss, Stefan, Sim, Xueling S., Li, Hengtong L., van der Most, Peter J., Nolte, Ilja M., Lyytikäinen, Leo-Pekka, Said, M. Abdullah, Witte, Daniel R., Iribarren, Carlos, Launer, Lenore, Ring, Susan M., de Vries, Paul S., Sever, Peter, Linneberg, Allan, Bottinger, Erwin P., Padmanabhan, Sandosh, Psaty, Bruce M., Sotoodehnia, Nona, Kolcic, Ivana, Arnar, David O., Gudbjartsson, Daniel F., Holm, Hilma, Balkau, Beverley, Silva, Claudia T., Newton-Cheh, Christopher H., Nikus, Kjell, Salo, Perttu, Mohlke, Karen L., Peyser, Patricia A., Schunkert, Heribert, Lorentzon, Mattias, Lahti, Jari, Rao, Dabeeru C., Cornelis, Marilyn C., Faul, Jessica D., Smith, Jennifer A., Stolarz-Skrzypek, Katarzyna, Bandinelli, Stefania, Concas, Maria Pina, Sinagra, Gianfranco, Meitinger, Thomas, Waldenberger, Melanie, Sinner, Moritz F., Strauch, Konstantin, Delgado, Graciela E., Taylor, Kent D., Yao, Jie, Foco, Luisa, Melander, Olle, de Graaf, Jacqueline, de Mutsert, Renée, de Geus, Eco J. C., Johansson, Åsa, Joshi, Peter K., Lind, Lars, Franke, Andre, Macfarlane, Peter W., Tarasov, Kirill V., Tan, Nicholas, Felix, Stephan B., Tai, E-Shyong, Quek, Debra Q., Snieder, Harold, Ormel, Johan, Ingelsson, Martin, Lindgren, Cecilia, Morris, Andrew P., Raitakari, Olli T., Hansen, Torben, Assimes, Themistocles, Gudnason, Vilmundur, Timpson, Nicholas J., Morrison, Alanna C., Munroe, Patricia B., Strachan, David P., Grarup, Niels, Loos, Ruth J. F., Heckbert, Susan R., Vollenweider, Peter, Hayward, Caroline, Stefansson, Kari, Froguel, Philippe, Groop, Leif, Wareham, Nicholas J., van Duijn, Cornelia M., Feitosa, Mary F., O’Donnell, Christopher J., Kähönen, Mika, Perola, Markus, Boehnke, Michael, Kardia, Sharon L. R., Erdmann, Jeanette, Palmer, Colin N. A., Ohlsson, Claes, Porteous, David J., Eriksson, Johan G., Bouchard, Claude, Moebus, Susanne, Kraft, Peter, Weir, David R., Cusi, Daniele, Ferrucci, Luigi, Ulivi, Sheila, Girotto, Giorgia, Correa, Adolfo, Kääb, Stefan, Peters, Annette, Chambers, John C., Kooner, Jaspal S., März, Winfried, Rotter, Jerome I., Hicks, Andrew A., Smith, J. Gustav, Kiemeney, Lambertus A. L. M., Mook-Kanamori, Dennis O., Penninx, Brenda W. J. H., Gyllensten, Ulf, Wilson, James F., Burgess, Stephen, Sundström, Johan, Lieb, Wolfgang, Jukema, J. Wouter, Eijgelsheim, Mark, Lakatta, Edward L. M., Cheng, Ching-Yu, Dörr, Marcus, Wong, Tien-Yin, Sabanayagam, Charumathi, Oldehinkel, Albertine J., Riese, Harriette, Lehtimäki, Terho, Verweij, Niek, and van der Harst, Pim

Published
2023
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5. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Author

Ntalla, Ioanna, Weng, Lu-Chen, Cartwright, James H, Hall, Amelia Weber, Sveinbjornsson, Gardar, Tucker, Nathan R, Choi, Seung Hoan, Chaffin, Mark D, Roselli, Carolina, Barnes, Michael R, Mifsud, Borbala, Warren, Helen R, Hayward, Caroline, Marten, Jonathan, Cranley, James J, Concas, Maria Pina, Gasparini, Paolo, Boutin, Thibaud, Kolcic, Ivana, Polasek, Ozren, Rudan, Igor, Araujo, Nathalia M, Lima-Costa, Maria Fernanda, Ribeiro, Antonio Luiz P, Souza, Renan P, Tarazona-Santos, Eduardo, Giedraitis, Vilmantas, Ingelsson, Erik, Mahajan, Anubha, Morris, Andrew P, Del Greco M, Fabiola, Foco, Luisa, Gögele, Martin, Hicks, Andrew A, Cook, James P, Lind, Lars, Lindgren, Cecilia M, Sundström, Johan, Nelson, Christopher P, Riaz, Muhammad B, Samani, Nilesh J, Sinagra, Gianfranco, Ulivi, Sheila, Kähönen, Mika, Mishra, Pashupati P, Mononen, Nina, Nikus, Kjell, Caulfield, Mark J, Dominiczak, Anna, Padmanabhan, Sandosh, Montasser, May E, O'Connell, Jeff R, Ryan, Kathleen, Shuldiner, Alan R, Aeschbacher, Stefanie, Conen, David, Risch, Lorenz, Thériault, Sébastien, Hutri-Kähönen, Nina, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Raitakari, Olli T, Barnes, Catriona LK, Campbell, Harry, Joshi, Peter K, Wilson, James F, Isaacs, Aaron, Kors, Jan A, van Duijn, Cornelia M, Huang, Paul L, Gudnason, Vilmundur, Harris, Tamara B, Launer, Lenore J, Smith, Albert V, Bottinger, Erwin P, Loos, Ruth JF, Nadkarni, Girish N, Preuss, Michael H, Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Müller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D, Rienstra, Michiel, van de Vegte, Yordi J, van der Harst, Pim, Verweij, Niek, Kääb, Stefan, Schramm, Katharina, Sinner, Moritz F, Strauch, Konstantin, Cutler, Michael J, Fatkin, Diane, London, Barry, Olesen, Morten, and Roden, Dan M

Subjects
Humans, Cardiovascular Diseases, Genetic Predisposition to Disease, Electrocardiography, Gene Expression, Multifactorial Inheritance, Quantitative Trait Loci, Female, Male, Arrhythmias, Cardiac, Genetic Variation, Genome-Wide Association Study, Genetic Loci, Endophenotypes, Arrhythmias, Cardiac
Abstract

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

Published
2020

8. Proteomics couples electrical remodelling to inflammation in a murine model of heart failure with sinus node dysfunction

Author

Kahnert, Konstantin, primary, Soattin, Luca, additional, Mills, Robert W, additional, Wilson, Claire, additional, Maurya, Svetlana, additional, Sorrentino, Andrea, additional, Al-Othman, Sami, additional, Tikhomirov, Roman, additional, van de Vegte, Yordi J, additional, Hansen, Finn B, additional, Achter, Jonathan, additional, Hu, Wei, additional, Zi, Min, additional, Smith, Matthew, additional, van der Harst, Pim, additional, Olesen, Morten S, additional, Olsen, Kristine Boisen, additional, Banner, Jytte, additional, Jensen, Thomas H L, additional, Zhang, Henggui, additional, Boyett, Mark R, additional, D’Souza, Alicia, additional, and Lundby, Alicia, additional

Published
2024
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10. Proteomics couples electrical remodelling to inflammation in a murine model of heart failure with sinus node dysfunction

Author

Kahnert, Konstantin, Soattin, Luca, Mills, Robert W, Wilson, Claire, Maurya, Svetlana, Sorrentino, Andrea, Al-Othman, Sami, Tikhomirov, Roman, van de Vegte, Yordi J, Hansen, Finn B, Achter, Jonathan, Hu, Wei, Zi, Min, Smith, Matthew, van der Harst, Pim, Olesen, Morten S, Olsen, Kristine Boisen, Banner, Jytte, Jensen, Thomas H L, Zhang, Henggui, Boyett, Mark R, D'Souza, Alicia, Lundby, Alicia, Kahnert, Konstantin, Soattin, Luca, Mills, Robert W, Wilson, Claire, Maurya, Svetlana, Sorrentino, Andrea, Al-Othman, Sami, Tikhomirov, Roman, van de Vegte, Yordi J, Hansen, Finn B, Achter, Jonathan, Hu, Wei, Zi, Min, Smith, Matthew, van der Harst, Pim, Olesen, Morten S, Olsen, Kristine Boisen, Banner, Jytte, Jensen, Thomas H L, Zhang, Henggui, Boyett, Mark R, D'Souza, Alicia, and Lundby, Alicia

Abstract

AIMS: In patients with heart failure (HF), concomitant sinus node dysfunction (SND) is an important predictor of mortality, yet its molecular underpinnings are poorly understood. Using proteomics, this study aimed to dissect the protein and phosphorylation remodelling within the sinus node in an animal model of HF with concurrent SND.METHODS AND RESULTS: We acquired deep sinus node proteomes and phosphoproteomes in mice with heart failure and SND and report extensive remodelling. Intersecting the measured (phospho)proteome changes with human genomics pharmacovigilance data, highlighted downregulated proteins involved in electrical activity such as the pacemaker ion channel, Hcn4. We confirmed the importance of ion channel downregulation for sinus node physiology using computer modelling. Guided by the proteomics data, we hypothesized that an inflammatory response may drive the electrophysiological remodeling underlying SND in heart failure. In support of this, experimentally induced inflammation downregulated Hcn4 and slowed pacemaking in the isolated sinus node. From the proteomics data we identified proinflammatory cytokine-like protein galectin-3 as a potential target to mitigate the effect. Indeed, in vivo suppression of galectin-3 in the animal model of heart failure prevented SND.CONCLUSION: Collectively, we outline the protein and phosphorylation remodeling of SND in heart failure, we highlight a role for inflammation in electrophysiological remodelling of the sinus node, and we present galectin-3 signalling as a target to ameliorate SND in heart failure.

Published
2024

12. Proteomics couples electrical remodelling to inflammation in a murine model of heart failure with sinus node dysfunction

Author

Cardiologie, Genetica, Gezonde Vaten, Circulatory Health, Kahnert, Konstantin, Soattin, Luca, Mills, Robert W., Wilson, Claire, Maurya, Svetlana, Sorrentino, Andrea, Al-Othman, Sami, Tikhomirov, Roman, van de Vegte, Yordi J., Hansen, Finn B., Achter, Jonathan, Hu, Wei, Zi, Min, Smith, Matthew, van der Harst, Pim, Olesen, Morten S., Olsen, Kristine Boisen, Banner, Jytte, Jensen, Thomas H.L., Zhang, Henggui, Boyett, Mark R., D'Souza, Alicia, Lundby, Alicia, Cardiologie, Genetica, Gezonde Vaten, Circulatory Health, Kahnert, Konstantin, Soattin, Luca, Mills, Robert W., Wilson, Claire, Maurya, Svetlana, Sorrentino, Andrea, Al-Othman, Sami, Tikhomirov, Roman, van de Vegte, Yordi J., Hansen, Finn B., Achter, Jonathan, Hu, Wei, Zi, Min, Smith, Matthew, van der Harst, Pim, Olesen, Morten S., Olsen, Kristine Boisen, Banner, Jytte, Jensen, Thomas H.L., Zhang, Henggui, Boyett, Mark R., D'Souza, Alicia, and Lundby, Alicia

Published
2024

20. Genomic insights in ascending aortic size and distensibility

Author

Team Onderzoek, Arts Assistenten Cardiologie, Team Medisch, Circulatory Health, Benjamins, Jan Walter, Yeung, Ming Wai, van de Vegte, Yordi J, Said, M Abdullah, van der Linden, Thijs, Ties, Daan, Juarez-Orozco, Luis E, Verweij, Niek, van der Harst, Pim, Team Onderzoek, Arts Assistenten Cardiologie, Team Medisch, Circulatory Health, Benjamins, Jan Walter, Yeung, Ming Wai, van de Vegte, Yordi J, Said, M Abdullah, van der Linden, Thijs, Ties, Daan, Juarez-Orozco, Luis E, Verweij, Niek, and van der Harst, Pim

Published
2022

21. Twenty-Five Novel Loci for Carotid Intima-Media Thickness: A Genome-Wide Association Study in >45 000 Individuals and Meta-Analysis of >100 000 Individuals

Author

Team Onderzoek, Onderzoek Precision medicine, Circulatory Health, Team Medisch, Wai Yeung, Ming, Wang, Siqi, van de Vegte, Yordi J, Borisov, Oleg, van Setten, Jessica, Snieder, Harold, Verweij, Niek, Said, M Abdullah, van der Harst, Pim, Team Onderzoek, Onderzoek Precision medicine, Circulatory Health, Team Medisch, Wai Yeung, Ming, Wang, Siqi, van de Vegte, Yordi J, Borisov, Oleg, van Setten, Jessica, Snieder, Harold, Verweij, Niek, Said, M Abdullah, and van der Harst, Pim

Published
2022

25. Genome-Wide Association Study and Identification of a Protective Missense Variant on Lipoprotein(a) Concentration: Protective Missense Variant on Lipoprotein(a) Concentration-Brief Report

Author

Arts Assistenten Cardiologie, Team Medisch, Circulatory Health, Said, M Abdullah, Yeung, Ming Wai, van de Vegte, Yordi J, Benjamins, Jan Walter, Dullaart, Robin P F, Ruotsalainen, Sanni, Ripatti, Samuli, Natarajan, Pradeep, Juarez-Orozco, Luis Eduardo, Verweij, Niek, van der Harst, P, Arts Assistenten Cardiologie, Team Medisch, Circulatory Health, Said, M Abdullah, Yeung, Ming Wai, van de Vegte, Yordi J, Benjamins, Jan Walter, Dullaart, Robin P F, Ruotsalainen, Sanni, Ripatti, Samuli, Natarajan, Pradeep, Juarez-Orozco, Luis Eduardo, Verweij, Niek, and van der Harst, P

Published
2021

26. Search for a Functional Genetic Variant Mimicking the Effect of SGLT2 Inhibitor Treatment

Author

Team Medisch, Circulatory Health, Wang, Siqi, Said, M Abdullah, Groot, Hilde E, van der Most, Peter J, Thio, Chris H L, van de Vegte, Yordi J, Verweij, Niek, Snieder, Harold, van der Harst, Pim, Team Medisch, Circulatory Health, Wang, Siqi, Said, M Abdullah, Groot, Hilde E, van der Most, Peter J, Thio, Chris H L, van de Vegte, Yordi J, Verweij, Niek, Snieder, Harold, and van der Harst, Pim

Published
2021

27. Genome-Wide Association Study and Identification of a Protective Missense Variant on Lipoprotein(a) Concentration

Author

Said, M. Abdullah, primary, Yeung, Ming Wai, additional, van de Vegte, Yordi J., additional, Benjamins, Jan Walter, additional, Dullaart, Robin P.F., additional, Ruotsalainen, Sanni, additional, Ripatti, Samuli, additional, Natarajan, Pradeep, additional, Juarez-Orozco, Luis Eduardo, additional, Verweij, Niek, additional, and van der Harst, P., additional

Published
2021
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29. Lipidomics, Atrial Conduction, and Body Mass Index

Author

Del Greco M, Fabiola, Foco, Luisa, Teumer, Alexander, Verweij, Niek, Paglia, Giuseppe, Meraviglia, Viviana, Melotti, Roberto, Vukovic, Vladimir, Rauhe, Werner, Joshi, Peter K, Demirkan, Ayse, Felix, Stephan B, Pietzner, Maik, Said, M Abdullah, van de Vegte, Yordi J, van der Harst, Pim, Wright, Alan F, Hicks, Andrew A, Campbell, Harry, Dörr, Marcus, Snieder, Harold, Wilson, James F, Pramstaller, Peter P, Rossini, Alessandra, Pattaro, Cristian, Cardiovascular Centre (CVC), and Life Course Epidemiology (LCE)

Subjects
Adult, Male, Arteries, Mendelian Randomization Analysis, Middle Aged, Lipid Metabolism, Lipids, Body Mass Index, Electrocardiography, Cardiovascular Diseases, Risk Factors, Lipidomics, Humans, Female, Aged, Genome-Wide Association Study
Abstract

BACKGROUND: Lipids are increasingly involved in cardiovascular risk prediction as potential proarrhythmic influencers. However, knowledge is limited about the specific mechanisms connecting lipid alterations with atrial conduction. METHODS: To shed light on this issue, we conducted a broad assessment of 151 sphingo- and phospholipids, measured using mass spectrometry, for association with atrial conduction, measured by P wave duration (PWD) from standard electrocardiograms, in the MICROS study (Microisolates in South Tyrol) (n=839). Causal pathways involving lipidomics, body mass index (BMI), and PWD were assessed using 2-sample Mendelian randomization analyses based on published genome-wide association studies of lipidomics (n=4034) and BMI (n=734 481), and genetic association analysis of PWD in 5 population-based studies (n=24 236). RESULTS: We identified an association with relative phosphatidylcholine 38:3 (%PC 38:3) concentration, which was replicated in the ORCADES (Orkney Complex Disease Study; n=951), with a pooled association across studies of 2.59 (95% CI, 1.3-3.9; P=1.1×10-4) ms PWD per mol% increase. While being independent of cholesterol, triglycerides, and glucose levels, the %PC 38:3-PWD association was mediated by BMI. Results supported a causal effect of BMI on both PWD ( P=8.3×10-5) and %PC 38:3 ( P=0.014). CONCLUSIONS: Increased %PC 38:3 levels are consistently associated with longer PWD, partly because of the confounding effect of BMI. The causal effect of BMI on PWD reinforces evidence of BMI's involvement into atrial electrical activity.

Published
2019

34. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Author

Ntalla, Ioanna, primary, Weng, Lu-Chen, additional, Cartwright, James H., additional, Hall, Amelia Weber, additional, Sveinbjornsson, Gardar, additional, Tucker, Nathan R., additional, Choi, Seung Hoan, additional, Chaffin, Mark D., additional, Roselli, Carolina, additional, Barnes, Michael R., additional, Mifsud, Borbala, additional, Warren, Helen R., additional, Hayward, Caroline, additional, Marten, Jonathan, additional, Cranley, James J., additional, Concas, Maria Pina, additional, Gasparini, Paolo, additional, Boutin, Thibaud, additional, Kolcic, Ivana, additional, Polasek, Ozren, additional, Rudan, Igor, additional, Araujo, Nathalia M., additional, Lima-Costa, Maria Fernanda, additional, Ribeiro, Antonio Luiz P., additional, Souza, Renan P., additional, Tarazona-Santos, Eduardo, additional, Giedraitis, Vilmantas, additional, Ingelsson, Erik, additional, Mahajan, Anubha, additional, Morris, Andrew P., additional, Fabiola Del, Greco M., additional, Foco, Luisa, additional, Gögele, Martin, additional, Hicks, Andrew A., additional, Cook, James P., additional, Lind, Lars, additional, Lindgren, Cecilia M., additional, Sundström, Johan, additional, Nelson, Christopher P., additional, Riaz, Muhammad B., additional, Samani, Nilesh J., additional, Sinagra, Gianfranco, additional, Ulivi, Sheila, additional, Kähönen, Mika, additional, Mishra, Pashupati P., additional, Mononen, Nina, additional, Nikus, Kjell, additional, Caulfield, Mark J., additional, Dominiczak, Anna, additional, Padmanabhan, Sandosh, additional, Montasser, May E., additional, O’Connell, Jeff R., additional, Ryan, Kathleen, additional, Shuldiner, Alan R., additional, Aeschbacher, Stefanie, additional, Conen, David, additional, Risch, Lorenz, additional, Thériault, Sébastien, additional, Hutri-Kähönen, Nina, additional, Lehtimäki, Terho, additional, Lyytikäinen, Leo-Pekka, additional, Raitakari, Olli T., additional, Barnes, Catriona L. K., additional, Campbell, Harry, additional, Joshi, Peter K., additional, Wilson, James F., additional, Isaacs, Aaron, additional, Kors, Jan A., additional, van Duijn, Cornelia M., additional, Huang, Paul L., additional, Gudnason, Vilmundur, additional, Harris, Tamara B., additional, Launer, Lenore J., additional, Smith, Albert V., additional, Bottinger, Erwin P., additional, Loos, Ruth J. F., additional, Nadkarni, Girish N., additional, Preuss, Michael H., additional, Correa, Adolfo, additional, Mei, Hao, additional, Wilson, James, additional, Meitinger, Thomas, additional, Müller-Nurasyid, Martina, additional, Peters, Annette, additional, Waldenberger, Melanie, additional, Mangino, Massimo, additional, Spector, Timothy D., additional, Rienstra, Michiel, additional, van de Vegte, Yordi J., additional, van der Harst, Pim, additional, Verweij, Niek, additional, Kääb, Stefan, additional, Schramm, Katharina, additional, Sinner, Moritz F., additional, Strauch, Konstantin, additional, Cutler, Michael J., additional, Fatkin, Diane, additional, London, Barry, additional, Olesen, Morten, additional, Roden, Dan M., additional, Shoemaker, M. Benjamin, additional, Smith, J. Gustav, additional, Biggs, Mary L., additional, Bis, Joshua C., additional, Brody, Jennifer A., additional, Psaty, Bruce M., additional, Rice, Ken, additional, Sotoodehnia, Nona, additional, De Grandi, Alessandro, additional, Fuchsberger, Christian, additional, Pattaro, Cristian, additional, Pramstaller, Peter P., additional, Ford, Ian, additional, Jukema, J. Wouter, additional, Macfarlane, Peter W., additional, Trompet, Stella, additional, Dörr, Marcus, additional, Felix, Stephan B., additional, Völker, Uwe, additional, Weiss, Stefan, additional, Havulinna, Aki S., additional, Jula, Antti, additional, Sääksjärvi, Katri, additional, Salomaa, Veikko, additional, Guo, Xiuqing, additional, Heckbert, Susan R., additional, Lin, Henry J., additional, Rotter, Jerome I., additional, Taylor, Kent D., additional, Yao, Jie, additional, de Mutsert, Renée, additional, Maan, Arie C., additional, Mook-Kanamori, Dennis O., additional, Noordam, Raymond, additional, Cucca, Francesco, additional, Ding, Jun, additional, Lakatta, Edward G., additional, Qian, Yong, additional, Tarasov, Kirill V., additional, Levy, Daniel, additional, Lin, Honghuang, additional, Newton-Cheh, Christopher H., additional, Lunetta, Kathryn L., additional, Murray, Alison D., additional, Porteous, David J., additional, Smith, Blair H., additional, Stricker, Bruno H., additional, Uitterlinden, André, additional, van den Berg, Marten E., additional, Haessler, Jeffrey, additional, Jackson, Rebecca D., additional, Kooperberg, Charles, additional, Peters, Ulrike, additional, Reiner, Alexander P., additional, Whitsel, Eric A., additional, Alonso, Alvaro, additional, Arking, Dan E., additional, Boerwinkle, Eric, additional, Ehret, Georg B., additional, Soliman, Elsayed Z., additional, Avery, Christy L., additional, Gogarten, Stephanie M., additional, Kerr, Kathleen F., additional, Laurie, Cathy C., additional, Seyerle, Amanda A., additional, Stilp, Adrienne, additional, Assa, Solmaz, additional, Said, M. Abdullah, additional, van der Ende, M. Yldau, additional, Lambiase, Pier D., additional, Orini, Michele, additional, Ramirez, Julia, additional, Van Duijvenboden, Stefan, additional, Arnar, David O., additional, Gudbjartsson, Daniel F., additional, Holm, Hilma, additional, Sulem, Patrick, additional, Thorleifsson, Gudmar, additional, Thorolfsdottir, Rosa B., additional, Thorsteinsdottir, Unnur, additional, Benjamin, Emelia J., additional, Tinker, Andrew, additional, Stefansson, Kari, additional, Ellinor, Patrick T., additional, Jamshidi, Yalda, additional, Lubitz, Steven A., additional, and Munroe, Patricia B., additional

Published
2019
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37. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author

Ntalla, Ioanna, Weng, Lu-Chen, Cartwright, James H, Hall, Amelia Weber, Sveinbjornsson, Gardar, Tucker, Nathan R, Choi, Seung Hoan, Chaffin, Mark D, Roselli, Carolina, Barnes, Michael R, Mifsud, Borbala, Warren, Helen R, Hayward, Caroline, Marten, Jonathan, Cranley, James J, Concas, Maria Pina, Gasparini, Paolo, Boutin, Thibaud, Kolcic, Ivana, Polasek, Ozren, Rudan, Igor, Araujo, Nathalia M, Lima-Costa, Maria Fernanda, Ribeiro, Antonio Luiz P, Souza, Renan P, Tarazona-Santos, Eduardo, Giedraitis, Vilmantas, Ingelsson, Erik, Mahajan, Anubha, Morris, Andrew P, Del Greco M, Fabiola, Foco, Luisa, Gögele, Martin, Hicks, Andrew A, Cook, James P, Lind, Lars, Lindgren, Cecilia M, Sundström, Johan, Nelson, Christopher P, Riaz, Muhammad B, Samani, Nilesh J, Sinagra, Gianfranco, Ulivi, Sheila, Kähönen, Mika, Mishra, Pashupati P, Mononen, Nina, Nikus, Kjell, Caulfield, Mark J, Dominiczak, Anna, Padmanabhan, Sandosh, Montasser, May E, O'Connell, Jeff R, Ryan, Kathleen, Shuldiner, Alan R, Aeschbacher, Stefanie, Conen, David, Risch, Lorenz, Thériault, Sébastien, Hutri-Kähönen, Nina, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Raitakari, Olli T, Barnes, Catriona LK, Campbell, Harry, Joshi, Peter K, Wilson, James F, Isaacs, Aaron, Kors, Jan A, Van Duijn, Cornelia M, Huang, Paul L, Gudnason, Vilmundur, Harris, Tamara B, Launer, Lenore J, Smith, Albert V, Bottinger, Erwin P, Loos, Ruth JF, Nadkarni, Girish N, Preuss, Michael H, Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Müller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D, Rienstra, Michiel, Van De Vegte, Yordi J, Van Der Harst, Pim, Verweij, Niek, Kääb, Stefan, Schramm, Katharina, Sinner, Moritz F, Strauch, Konstantin, Cutler, Michael J, Fatkin, Diane, London, Barry, Olesen, Morten, Roden, Dan M, Benjamin Shoemaker, M, Gustav Smith, J, Biggs, Mary L, Bis, Joshua C, Brody, Jennifer A, Psaty, Bruce M, Rice, Kenneth, Sotoodehnia, Nona, De Grandi, Alessandro, Fuchsberger, Christian, Pattaro, Cristian, Pramstaller, Peter P, Ford, Ian, Wouter Jukema, J, Macfarlane, Peter W, Trompet, Stella, Dörr, Marcus, Felix, Stephan B, Völker, Uwe, Weiss, Stefan, Havulinna, Aki S, Jula, Antti, Sääksjärvi, Katri, Salomaa, Veikko, Guo, Xiuqing, Heckbert, Susan R, Lin, Henry J, Rotter, Jerome I, Taylor, Kent D, Yao, Jie, De Mutsert, Renée, Maan, Arie C, Mook-Kanamori, Dennis O, Noordam, Raymond, Cucca, Francesco, Ding, Jun, Lakatta, Edward G, Qian, Yong, Tarasov, Kirill V, Levy, Daniel, Lin, Honghuang, Newton-Cheh, Christopher H, Lunetta, Kathryn L, Murray, Alison D, Porteous, David J, Smith, Blair H, Stricker, Bruno H, Uitterlinden, André, Van Den Berg, Marten E, Haessler, Jeffrey, Jackson, Rebecca D, Kooperberg, Charles, Peters, Ulrike, Reiner, Alexander P, Whitsel, Eric A, Alonso, Alvaro, Arking, Dan E, Boerwinkle, Eric, Ehret, Georg B, Soliman, Elsayed Z, Avery, Christy L, Gogarten, Stephanie M, Kerr, Kathleen F, Laurie, Cathy C, Seyerle, Amanda A, Stilp, Adrienne, Assa, Solmaz, Abdullah Said, M, Yldau Van Der Ende, M, Lambiase, Pier D, Orini, Michele, Ramirez, Julia, Van Duijvenboden, Stefan, Arnar, David O, Gudbjartsson, Daniel F, Holm, Hilma, Sulem, Patrick, Thorleifsson, Gudmar, Thorolfsdottir, Rosa B, Thorsteinsdottir, Unnur, Benjamin, Emelia J, Tinker, Andrew, Stefansson, Kari, Ellinor, Patrick T, Jamshidi, Yalda, Lubitz, Steven A, and Munroe, Patricia B

Subjects
Male, Multifactorial Inheritance, Endophenotypes, Quantitative Trait Loci, Gene Expression, Genetic Variation, Arrhythmias, Cardiac, 3. Good health, Electrocardiography, Cardiovascular Diseases, Genetic Loci, Humans, Female, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

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