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1. 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

2. Large-scale single-nuclei profiling identifies role for ATRNL1 in atrial fibrillation.

Author

Hill, Matthew C., Simonson, Bridget, Roselli, Carolina, Xiao, Ling, Herndon, Caroline N., Chaffin, Mark, Mantineo, Helene, Atwa, Ondine, Bhasin, Harshit, Guedira, Yasmine, Bedi Jr., Kenneth C., Margulies, Kenneth B., Klattenhoff, Carla A., Tucker, Nathan R., and Ellinor, Patrick T.

Subjects
ACTION potentials, GENE expression, LEFT heart atrium, GENETIC overexpression, RNA sequencing, ARRHYTHMIA
Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia in humans, yet the molecular basis of AF remains incompletely understood. To determine the cell type-specific transcriptional changes underlying AF, we perform single-nucleus RNA-seq (snRNA-seq) on left atrial (LA) samples from patients with AF and controls. From more than 175,000 nuclei we find that only cardiomyocytes (CMs) and macrophages (MΦs) have a significant number of differentially expressed genes in patients with AF. Attractin Like 1 (ATRNL1) was overexpressed in CMs among patients with AF and localized to the intercalated disks. Further, in both knockdown and overexpression experiments we identify a potent role for ATRNL1 in cell stress response, and in the modulation of the cardiac action potential. Finally, we detect an unexpected expression pattern for a leading AF candidate gene, KCNN3. In sum, we uncover a role for ATRNL1 which may serve as potential therapeutic target for this common arrhythmia. Characterizing atrial fibrillation (AF) at the single cell level is challenging. Here, the authors perform snRNA-seq on 18 patients with AF to investigate the cell composition, and gene expression shifts associated with this common arrhythmia. [ABSTRACT FROM AUTHOR]

Published
2024
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3. COVID-19 and Cardiovascular Disease

Author

Chung, Mina K., Zidar, David A., Bristow, Michael R., Cameron, Scott J., Chan, Timothy, Harding, Clifford V., Kwon, Deborah H., Singh, Tamanna, Tilton, John C., Tsai, Emily J., Tucker, Nathan R., Barnard, John, and Loscalzo, Joseph

Subjects
Gene Expression, Virus Attachment, Review, Renin-Angiotensin System, angiotensin-converting enzyme 2, Risk Factors, magnetic resonance imaging, Humans, Myocytes, Cardiac, RNA, Messenger, thrombosis, Ventricular Remodeling, SARS-CoV-2, Myocardium, COVID-19, Virus Internalization, Platelet Activation, Neuropilin-1, Troponin, Return to Sport, inflammation, Cardiovascular Diseases, Immune System, Spike Glycoprotein, Coronavirus, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Cardiomyopathies, Biomarkers
Abstract

Supplemental Digital Content is available in the text., A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.

Published
2021

4. Transcriptional and Cellular Diversity of the Human Heart.

Author

Tucker, Nathan R., Chaffin, Mark, Fleming, Stephen J., Hall, Amelia W., Parsons, Victoria A., Bedi, Kenneth C., Akkad, Amer-Denis, Herndon, Caroline N., Arduini, Alessandro, Papangeli, Irinna, Roselli, Carolina, Aguet, François, Choi, Seung Hoan, Ardlie, Kristin G., Babadi, Mehrtash, Margulies, Kenneth B., Stegmann, Christian M., Ellinor, Patrick T., and Bedi, Kenneth C Jr

Subjects
*NUCLEOTIDE sequence, *HEART diseases, *HEART, *GENE expression, *EXTRACELLULAR matrix
Abstract

Background: The human heart requires a complex ensemble of specialized cell types to perform its essential function. A greater knowledge of the intricate cellular milieu of the heart is critical to increase our understanding of cardiac homeostasis and pathology. As recent advances in low-input RNA sequencing have allowed definitions of cellular transcriptomes at single-cell resolution at scale, we have applied these approaches to assess the cellular and transcriptional diversity of the nonfailing human heart.Methods: Microfluidic encapsulation and barcoding was used to perform single nuclear RNA sequencing with samples from 7 human donors, selected for their absence of overt cardiac disease. Individual nuclear transcriptomes were then clustered based on transcriptional profiles of highly variable genes. These clusters were used as the basis for between-chamber and between-sex differential gene expression analyses and intersection with genetic and pharmacologic data.Results: We sequenced the transcriptomes of 287 269 single cardiac nuclei, revealing 9 major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses include 2 distinct groups of resident macrophages, 4 endothelial subtypes, and 2 fibroblast subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs but also in subtypes involved in extracellular matrix remodeling and vascularization. Using genetic association data, we identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Intersection of our data set with genes on cardiac clinical testing panels and the druggable genome reveals striking patterns of cellular specificity.Conclusions: Using large-scale single nuclei RNA sequencing, we defined the transcriptional and cellular diversity in the normal human heart. Our identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Published
2020
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5. A Functional Variant Associated with Atrial Fibrillation Regulates PITX2c Expression through TFAP2a.

Author

Ye, Jiangchuan, Tucker, Nathan R., Weng, Lu-Chen, Clauss, Sebastian, Lubitz, Steven A., and Ellinor, Patrick T.

Subjects
*SINGLE nucleotide polymorphisms, *ATRIAL fibrillation, *PROTEIN expression, *HUMAN genetics, *HEART cells, *GENE expression
Abstract

The most significantly associated genetic locus for atrial fibrillation (AF) is in chromosomal region 4q25, where four independent association signals have been identified. Although model-system studies suggest that altered PITX2c expression might underlie the association, the link between specific variants and the direction of effect on gene expression remains unknown for all four signals. In the present study, we analyzed the AF-associated region most proximal to PITX2 at 4q25. First, we identified candidate regulatory variants that might confer AF risk through a combination of mammalian conservation, DNase hypersensitivity, and histone modification from ENCODE and the Roadmap Epigenomics Project, as well as through in vivo analysis of enhancer activity in embryonic zebrafish. Within candidate regions, we then identified a single associated SNP, rs2595104, which displayed dramatically reduced enhancer activity with the AF risk allele. CRISPR-Cas9-mediated deletion of the rs2595104 region and editing of the rs2595104 risk allele in human stem-cell-derived cardiomyocytes resulted in diminished PITX2c expression in comparison to that of the non-risk allele. This differential activity was mediated by activating enhancer binding protein 2 alpha (TFAP2a), which bound robustly to the non-risk allele at rs2595104, but not to the risk allele, in cardiomyocytes. In sum, we found that the AF-associated SNP rs2595104 altered PITX2c expression via interaction with TFAP2a. Such a pathway could ultimately contribute to AF susceptibility at the PITX2 locus associated with AF. [ABSTRACT FROM AUTHOR]

Published
2016
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6. Integrating Genetic, Transcriptional, and Functional Analyses to Identify 5 Novel Genes for Atrial Fibrillation.

Author

Sinner, Moritz F., Tucker, Nathan R., Lunetta, Kathryn L., Kouichi Ozaki, Smith, J. Gustav, Trompet, Stella, Bis, Joshua C., Honghuang Lin, Chung, Mina K., Nielsen, Jonas B., Lubitz, Steven A., Krijthe, Bouwe P., Magnani, Jared W., Jiangchuan Ye, Gollob, Michael H., Tatsuhiko Tsunoda, Müller-Nurasyid, Martina, Lichtner, Peter, Peters, Annette, and Dolmatova, Elena

Subjects
*ATRIAL fibrillation, *GENES, *SINGLE nucleotide polymorphisms, *LABORATORY zebrafish, *ACTION potentials, *GENETICS
Abstract

Background--Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood. Methods and Results--To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [Cl], 1.13-1.23; P=6.5xl0-16), GJA1 (rsl3216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2x10-8), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7xl0-11), and CAND2 (rs4642101; RR=1.10; 95% Cl, 1.06-1.14; P=9.8x10-9). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0x10-25) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9x10-9). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6x10-19), GJA1 (P=2.66x10-6), and TBX5 (P=1.36x10-5). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively). Conclusions--We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation. [ABSTRACT FROM AUTHOR]

Published
2014
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7. Overexpression of KCNN3 results in sudden cardiac death.

Author

Mahida, Saagar, Mills, Robert W., Tucker, Nathan R., Simonson, Bridget, Macri, Vincenzo, Lemoine, Marc D., Das, Saumya, Milan, David J., and Ellinor, Patrick T.

Subjects
HEART failure, GENE expression, DISEASE susceptibility, ATRIAL fibrillation, CALCIUM-dependent potassium channels, ARRHYTHMIA, ELECTROPHYSIOLOGY, LABORATORY mice, GENETICS
Abstract

Background A recent genome-wide association study identified a susceptibility locus for atrial fibrillation at the KCNN3 gene. Since the KCNN3 gene encodes for a small conductance calcium-activated potassium channel, we hypothesized that overexpression of the SK3 channel increases susceptibility to cardiac arrhythmias. Methods and results We characterized the cardiac electrophysiological phenotype of a mouse line with overexpression of the SK3 channel. We generated homozygote (SK3T/T) and heterozygote (SK3+/T) mice with overexpression of the channel and compared them with wild-type (WT) controls. We observed a high incidence of sudden death among SK3T/T mice (7 of 19 SK3T/T mice). Ambulatory monitoring demonstrated that sudden death was due to heart block and bradyarrhythmias. SK3T/T mice displayed normal body weight, temperature, and cardiac function on echocardiography; however, histological analysis demonstrated that these mice have abnormal atrioventricular node morphology. Optical mapping demonstrated that SK3T/T mice have slower ventricular conduction compared with WT controls (SK3T/T vs. WT; 0.45 ± 0.04 vs. 0.60 ± 0.09 mm/ms, P = 0.001). Programmed stimulation in 1-month-old SK3T/T mice demonstrated inducible atrial arrhythmias (50% of SK3T/T vs. 0% of WT mice) and also a shorter atrioventricular nodal refractory period (SK3T/T vs. WT; 43 ± 6 vs. 52 ± 9 ms, P = 0.02). Three-month-old SK3T/T mice on the other hand displayed a trend towards a more prolonged atrioventricular nodal refractory period (SK3T/T vs. WT; 61 ± 1 vs. 52 ± 6 ms, P = 0.06). Conclusion Overexpression of the SK3 channel causes an increased risk of sudden death associated with bradyarrhythmias and heart block, possibly due to atrioventricular nodal dysfunction. [ABSTRACT FROM AUTHOR]

Published
2014
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8. HSF1 Is Essential for the Resistance of Zebrafish Eye and Brain Tissues to Hypoxia/Reperfusion Injury.

Author

Tucker, Nathan R., Middleton, Ryan C., Le, Quynh P., and Shelden, Eric A.

Subjects
*HEAT shock proteins, *ZEBRA danio, *TISSUE analysis, *REPERFUSION injury, *TRANSCRIPTION factors, *GENE expression
Abstract

Ischemia and subsequent reperfusion (IR) produces injury to brain, eye and other tissues, contributing to the progression of important clinical pathologies. The response of cells to IR involves activation of several signaling pathways including those activating hypoxia and heat shock responsive transcription factors. However, specific roles of these responses in limiting cell damage and preventing cell death after IR have not been fully elucidated. Here, we have examined the role of heat shock factor 1 (HSF1) in the response of zebrafish embryos to hypoxia and subsequent return to normoxic conditions (HR) as a model for IR. Heat shock preconditioning elevated heat shock protein expression and protected zebrafish embryo eye and brain tissues against HR-induced apoptosis. These effects were inhibited by translational suppression of HSF1 expression. Reduced expression of HSF1 also increased cell death in brain and eye tissues of embryos subjected to hypoxia and reperfusion without prior heat shock. Surprisingly, reduced expression of HSF1 had only a modest effect on hypoxiainduced expression of Hsp70 and no effect on hypoxia-induced expression of Hsp27. These results establish the zebrafish embryo as a model for the study of ischemic injury in the brain and eye and reveal a critical role for HSF1 in the response of these tissues to HR. Our results also uncouple the role of HSF1 expression from that of Hsp27, a well characterized heat shock protein considered essential for cell survival after hypoxia. Alternative roles for HSF1 are considered. [ABSTRACT FROM AUTHOR]

Published
2011
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9. 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.

10. Highlights From the Family of Journals.

Author

Tucker, Nathan R., Dolmatova, Elena V., Honghuang Lin, Cooper, Rebecca R., Jiangchuan Ye, Hucker, William J., Jameson, Heather S., Parsons, Victoria A., Lu-Chen Weng, Mills, Robert W., Sinner, Moritz F., Imakaev, Maxim, Leyton-Mange, Jordan, Vlahakes, Gus, Benjamin, Emelia J., Lunetta, Kathryn L., Lubitz, Steven A., Mirny, Leonid, Milan, David J., and Ellinor, Patrick T.

Subjects
*GENE expression, *ATRIAL fibrillation, *TRANSCRIPTION factors, *PULMONARY veins, *MUSCLE cells, *GENETIC engineering
Abstract

The article offers information on identification of a functional genetic variant that alters PRRX1 gene expression in atrial myocytes and provides a link with atrial fibrillation (AF). It mentions the molecular mechanism of transcription factor PRRX1 which is expressed in the pulmonary veins. It also states the role of electrophysiological alterations in atrial myocytes in promoting AF.

Published
2017
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11. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author

Dennis O. Mook-Kanamori, Yalda Jamshidi, Peter K. Joshi, Seung Hoan Choi, Henry J. Lin, Rebecca D. Jackson, Alison D. Murray, May E. Montasser, Veikko Salomaa, Charles Kooperberg, Moritz F. Sinner, Gianfranco Sinagra, Luisa Foco, James G. Wilson, Johan Sundström, Kathleen A. Ryan, Eric A. Whitsel, Bruno H. Stricker, Sandosh Padmanabhan, Christopher Newton-Cheh, Ozren Polasek, Unnur Thorsteinsdottir, Niek Verweij, Pier D. Lambiase, Nathan R. Tucker, Stefan Kääb, Jun Ding, Stefan Weiss, Daniel F. Gudbjartsson, David Conen, Lars Lind, Ivana Kolcic, Lu-Chen Weng, J. Wouter Jukema, Kirill V. Tarasov, Xiuqing Guo, Stella Trompet, Patricia B. Munroe, Albert V. Smith, Elsayed Z. Soliman, Andrew Tinker, Antti Jula, J. Gustav Smith, Alexander P. Reiner, Sébastien Thériault, Kathryn L. Lunetta, Vilmundur Gudnason, Mika Kähönen, Massimo Mangino, Raymond Noordam, Joshua C. Bis, Alan R. Shuldiner, Tim D. Spector, Borbala Mifsud, Stefan van Duijvenboden, Jeffrey R. O'Connell, Emelia J. Benjamin, M. Benjamin Shoemaker, Stephan B. Felix, Peter W. Macfarlane, Lorenz Risch, Uwe Völker, Stephanie M. Gogarten, Maria Fernanda Lima-Costa, Julia Ramirez, Morten S. Olesen, Konstantin Strauch, Annette Peters, Aaron Isaacs, Steven A. Lubitz, Eric Boerwinkle, Carolina Roselli, James H. Cartwright, Nathalia M. Araujo, Ruth J. F. Loos, Diane Fatkin, Harry Campbell, Blair H. Smith, Thomas Meitinger, André G. Uitterlinden, Paul L. Huang, Tamara B. Harris, Kathleen F. Kerr, David J. Porteous, Martina Müller-Nurasyid, Francesco Cucca, Michiel Rienstra, Davíð O. Arnar, Amanda A. Seyerle, Caroline Hayward, M. Abdullah Said, Catriona L. K. Barnes, Kent D. Taylor, Nona Sotoodehnia, Nina Mononen, Dan M. Roden, Jonathan Marten, Terho Lehtimäki, Dan E. Arking, Anna F. Dominiczak, Jan A. Kors, Olli T. Raitakari, Igor Rudan, Yordi J. van de Vegte, Christopher P. Nelson, Erik Ingelsson, Ulrike Peters, Girish N. Nadkarni, Eduardo Tarazona-Santos, Edward G. Lakatta, Nina Hutri-Kähönen, Bruce M. Psaty, Patrick T. Ellinor, Christian Fuchsberger, Katharina Schramm, Amelia W. Hall, M. Yldau van der Ende, Alvaro Alonso, James F. Wilson, Sheila Ulivi, Rosa B. Thorolfsdottir, Stefanie Aeschbacher, Mary L. Biggs, Marten E. van den Berg, Nilesh J. Samani, Thibaud Boutin, Vilmantas Giedraitis, Honghuang Lin, Kjell Nikus, Helen R. Warren, Arie C. Maan, James J. Cranley, Adolfo Correa, Martin Gögele, Ian Ford, Katri Sääksjärvi, Georg Ehret, Michele Orini, Susan R. Heckbert, Cecilia M. Lindgren, Jie Yao, Maria Pina Concas, Pim van der Harst, Ioanna Ntalla, Jeffrey Haessler, Jerome I. Rotter, Pashupati P. Mishra, Michael J. Cutler, Erwin P. Bottinger, Cornelia M. van Duijn, Jennifer A. Brody, Paolo Gasparini, Lenore J. Launer, Andrew P. Morris, Renée de Mutsert, Aki S. Havulinna, James P. Cook, Hilma Holm, Patrick Sulem, Alessandro De Grandi, Cristian Pattaro, Gardar Sveinbjornsson, Antonio Luiz Pinho Ribeiro, Mark J. Caulfield, Gudmar Thorleifsson, Marcus Dörr, Muhammad B. Riaz, Peter P. Pramstaller, Yong Qian, Anubha Mahajan, Cathy C. Laurie, Kenneth Rice, Mark Chaffin, Kari Stefansson, Andrew A. Hicks, Solmaz Assa, Hao Mei, Leo-Pekka Lyytikäinen, Fabiola Del Greco M, Renan P. Souza, Michael Preuss, Adrienne M. Stilp, Barry London, Melanie Waldenberger, Christy L. Avery, Daniel Levy, Michael R. 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H., Hall, A. W., Sveinbjornsson, G., Tucker, N. R., Choi, S. H., Chaffin, M. D., Roselli, C., Barnes, M. R., Mifsud, B., Warren, H. R., Hayward, C., Marten, J., Cranley, J. J., Concas, M. P., Gasparini, P., Boutin, T., Kolcic, I., Polasek, O., Rudan, I., Araujo, N. M., Lima-Costa, M. F., Ribeiro, A. L. P., Souza, R. P., Tarazona-Santos, E., Giedraitis, V., Ingelsson, E., Mahajan, A., Morris, A. P., Del Greco M, F., Foco, L., Gogele, M., Hicks, A. A., Cook, J. P., Lind, L., Lindgren, C. M., Sundstrom, J., Nelson, C. P., Riaz, M. B., Samani, N. J., Sinagra, G., Ulivi, S., Kahonen, M., Mishra, P. P., Mononen, N., Nikus, K., Caulfield, M. J., Dominiczak, A., Padmanabhan, S., Montasser, M. E., O'Connell, J. R., Ryan, K., Shuldiner, A. R., Aeschbacher, S., Conen, D., Risch, L., Theriault, S., Hutri-Kahonen, N., Lehtimaki, T., Lyytikainen, L. -P., Raitakari, O. T., Barnes, C. L. K., Campbell, H., Joshi, P. K., Wilson, J. F., Isaacs, A., Kors, J. A., van Duijn, C. M., Huang, P. L., Gudnason, V., Harris, T. B., Launer, L. J., Smith, A. V., Bottinger, E. P., Loos, R. J. F., Nadkarni, G. N., Preuss, M. H., Correa, A., Mei, H., Wilson, J., Meitinger, T., Muller-Nurasyid, M., Peters, A., Waldenberger, M., Mangino, M., Spector, T. D., Rienstra, M., van de Vegte, Y. J., van der Harst, P., Verweij, N., Kaab, S., Schramm, K., Sinner, M. F., Strauch, K., Cutler, M. J., Fatkin, D., London, B., Olesen, M., Roden, D. M., Benjamin Shoemaker, M., Gustav Smith, J., Biggs, M. L., Bis, J. C., Brody, J. A., Psaty, B. M., Rice, K., Sotoodehnia, N., De Grandi, A., Fuchsberger, C., Pattaro, C., Pramstaller, P. P., Ford, I., Wouter Jukema, J., Macfarlane, P. W., Trompet, S., Dorr, M., Felix, S. B., Volker, U., Weiss, S., Havulinna, A. S., Jula, A., Saaksjarvi, K., Salomaa, V., Guo, X., Heckbert, S. R., Lin, H. J., Rotter, J. I., Taylor, K. D., Yao, J., de Mutsert, R., Maan, A. C., Mook-Kanamori, D. O., Noordam, R., Cucca, F., Ding, J., Lakatta, E. G., Qian, Y., Tarasov, K. V., Levy, D., Lin, H., Newton-Cheh, C. H., Lunetta, K. L., Murray, A. D., Porteous, D. J., Smith, B. H., Stricker, B. H., Uitterlinden, A., van den Berg, M. E., Haessler, J., Jackson, R. D., Kooperberg, C., Peters, U., Reiner, A. P., Whitsel, E. A., Alonso, A., Arking, D. E., Boerwinkle, E., Ehret, G. B., Soliman, E. Z., Avery, C. L., Gogarten, S. M., Kerr, K. F., Laurie, C. C., Seyerle, A. A., Stilp, A., Assa, S., Abdullah Said, M., Yldau van der Ende, M., Lambiase, P. D., Orini, M., Ramirez, J., Van Duijvenboden, S., Arnar, D. O., Gudbjartsson, D. F., Holm, H., Sulem, P., Thorleifsson, G., Thorolfsdottir, R. B., Thorsteinsdottir, U., Benjamin, E. J., Tinker, A., Stefansson, K., Ellinor, P. T., Jamshidi, Y., Lubitz, S. A., Munroe, P. B., Fysiologie, RS: FHML MaCSBio, RS: Carim - B01 Blood proteins & engineering, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, General Physics and Astronomy, Gene Expression, Genome-wide association study, 030204 cardiovascular system & hematology, Arrhythmias, Genome-wide association studies, CALCINEURIN, Electrocardiography, 0302 clinical medicine, Cardiovascular Disease, Multi-ancestry GWAS, ELEMENTS, Medicine, Cardiac and Cardiovascular Systems, Blóðrásarsjúkdómar, lcsh:Science, RISK, DECREASE, education.field_of_study, Multidisciplinary, Kardiologi, medicine.diagnostic_test, 1184 Genetics, developmental biology, physiology, Atrial fibrillation, 3142 Public health care science, environmental and occupational health, 3. Good health, Endophenotype, Arrhythmias, Cardiac, Cardiovascular Diseases, Endophenotypes, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Quantitative Trait Loci, cardiovascular system, Cardiology, medicine.symptom, Erfðarannsóknir, Cardiac, Medical Genetics, Human, Bradycardia, medicine.medical_specialty, Science, GENOME-WIDE ASSOCIATION, ATRIAL-FIBRILLATION, MUTATIONS, DURATION, CARDIOMYOPATHY, BRADYCARDIA, Population, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Internal medicine, Cardiac conduction, PR interval, education, Medicinsk genetik, business.industry, Cardiovascular genetics, General Chemistry, Arfgengi, medicine.disease, 030104 developmental biology, lcsh:Q, business
Abstract

Publisher's version (útgefin grein), 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., We provide all investigator and study-specific acknowledgements in Supplementary Note 1, and funding sources in Supplementary Note 2.

Published
2020
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