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38 results on '"Tucker, Nathan R."'

1. Single-Nuclear RNA Sequencing of Endomyocardial Biopsies Identifies Persistence of Donor-Recipient Chimerism With Distinct Signatures in Severe Cardiac Allograft Vasculopathy.

Author: Amancherla, Kaushik, Amancherla, Kaushik, Qin, Juan, Hulke, Michelle L, Pfeiffer, Ryan D, Agrawal, Vineet, Sheng, Quanhu, Xu, Yaomin, Schlendorf, Kelly H, Lindenfeld, JoAnn, Shah, Ravi V, Freedman, Jane E, Tucker, Nathan R, Moslehi, Javid, Amancherla, Kaushik, Amancherla, Kaushik, Qin, Juan, Hulke, Michelle L, Pfeiffer, Ryan D, Agrawal, Vineet, Sheng, Quanhu, Xu, Yaomin, Schlendorf, Kelly H, Lindenfeld, JoAnn, Shah, Ravi V, Freedman, Jane E, Tucker, Nathan R, and Moslehi, Javid
Published: 2023

2. Transcriptome variation in human tissues revealed by long-read sequencing

Author: Glinos, Dafni A., Garborcauskas, Garrett, Hoffman, Paul, Ehsan, Nava, Jiang, Lihua, Gokden, Alper, Dai, Xiaoguang, Aguet, Francois, Brown, Kathleen L., Garimella, Kiran, Bowers, Tera, Costello, Maura, Ardlie, Kristin, Jian, Ruiqi, Tucker, Nathan R., Ellinor, Patrick T., Harrington, Eoghan D., Tang, Hua, Snyder, Michael, Juul, Sissel, Mohammadi, Pejman, MacArthur, Daniel G., Lappalainen, Tuuli, Cummings, Beryl, Glinos, Dafni A., Garborcauskas, Garrett, Hoffman, Paul, Ehsan, Nava, Jiang, Lihua, Gokden, Alper, Dai, Xiaoguang, Aguet, Francois, Brown, Kathleen L., Garimella, Kiran, Bowers, Tera, Costello, Maura, Ardlie, Kristin, Jian, Ruiqi, Tucker, Nathan R., Ellinor, Patrick T., Harrington, Eoghan D., Tang, Hua, Snyder, Michael, Juul, Sissel, Mohammadi, Pejman, MacArthur, Daniel G., Lappalainen, Tuuli, and Cummings, Beryl
Abstract: Regulation of transcript structure generates transcript diversity and plays an important role in human disease(1-7). The advent oflong-read sequencing technologies offers the opportunity to study the role of genetic variation in transcript structure(8-)(16). In this Article, we present a large human long-read RNA-seq dataset using the Oxford Nanopore Technologies platform from 88 samples from Genotype-Tissue Expression (GTEx) tissues and cell lines, complementing the GTEx resource. We identified just over 70,000 novel transcripts for annotated genes, and validated the protein expression of 10% of novel transcripts. We developed a new computational package, LORALS, to analyse the genetic effects of rare and common variants on the transcriptome by allele-specific analysis of long reads. We characterized allele-specific expression and transcript structure events, providing new insights into the specific transcript alterations caused by common and rare genetic variants and highlighting the resolution gained from long-read data. We were able to perturb the transcript structure upon knockdown of PTBP1, an RNA binding protein that mediates splicing, thereby finding genetic regulatory effects that are modified by the cellular environment. Finally, we used this dataset to enhance variant interpretation and study rare variants leading to aberrant splicing patterns., QC 20221007
Published: 2022
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3. A Beary Good Genome: Haplotype-Resolved, Chromosome-Level Assembly of the Brown Bear (Ursus arctos).

Author: Armstrong, Ellie E, Fraser, Bonnie1, Armstrong, Ellie E, Perry, Blair W, Huang, Yongqing, Garimella, Kiran V, Jansen, Heiko T, Robbins, Charles T, Tucker, Nathan R, Kelley, Joanna L, Armstrong, Ellie E, Fraser, Bonnie1, Armstrong, Ellie E, Perry, Blair W, Huang, Yongqing, Garimella, Kiran V, Jansen, Heiko T, Robbins, Charles T, Tucker, Nathan R, and Kelley, Joanna L
Abstract: The brown bear (Ursus arctos) is the second largest and most widespread extant terrestrial carnivore on Earth and has recently emerged as a medical model for human metabolic diseases. Here, we report a fully phased chromosome-level assembly of a male North American brown bear built by combining Pacific Biosciences (PacBio) HiFi data and publicly available Hi-C data. The final genome size is 2.47 Gigabases (Gb) with a scaffold and contig N50 length of 70.08 and 43.94 Megabases (Mb), respectively. Benchmarking Universal Single-Copy Ortholog (BUSCO) analysis revealed that 94.5% of single copy orthologs from Mammalia were present in the genome (the highest of any ursid genome to date). Repetitive elements accounted for 44.48% of the genome and a total of 20,480 protein coding genes were identified. Based on whole genome alignment to the polar bear, the brown bear is highly syntenic with the polar bear, and our phylogenetic analysis of 7,246 single-copy orthologs supports the currently proposed species tree for Ursidae. This highly contiguous genome assembly will support future research on both the evolutionary history of the bear family and the physiological mechanisms behind hibernation, the latter of which has broad medical implications.
Published: 2022

4. SnRNA sequencing defines signaling by RBC-derived extracellular vesicles in the murine heart.

Author: Valkov, Nedyalka, Valkov, Nedyalka, Das, Avash, Tucker, Nathan R, Li, Guoping, Salvador, Ane M, Chaffin, Mark D, Pereira De Oliveira Junior, Getulio, Kur, Ivan, Gokulnath, Priyanka, Ziegler, Olivia, Yeri, Ashish, Lu, Shulin, Khamesra, Aushee, Xiao, Chunyang, Rodosthenous, Rodosthenis, Srinivasan, Srimeenakshi, Toxavidis, Vasilis, Tigges, John, Laurent, Louise C, Momma, Stefan, Kitchen, Robert, Ellinor, Patrick, Ghiran, Ionita, Das, Saumya, Valkov, Nedyalka, Valkov, Nedyalka, Das, Avash, Tucker, Nathan R, Li, Guoping, Salvador, Ane M, Chaffin, Mark D, Pereira De Oliveira Junior, Getulio, Kur, Ivan, Gokulnath, Priyanka, Ziegler, Olivia, Yeri, Ashish, Lu, Shulin, Khamesra, Aushee, Xiao, Chunyang, Rodosthenous, Rodosthenis, Srinivasan, Srimeenakshi, Toxavidis, Vasilis, Tigges, John, Laurent, Louise C, Momma, Stefan, Kitchen, Robert, Ellinor, Patrick, Ghiran, Ionita, and Das, Saumya
Abstract: Extracellular vesicles (EVs) mediate intercellular signaling by transferring their cargo to recipient cells, but the functional consequences of signaling are not fully appreciated. RBC-derived EVs are abundant in circulation and have been implicated in regulating immune responses. Here, we use a transgenic mouse model for fluorescence-based mapping of RBC-EV recipient cells to assess the role of this intercellular signaling mechanism in heart disease. Using fluorescent-based mapping, we detected an increase in RBC-EV-targeted cardiomyocytes in a murine model of ischemic heart failure. Single cell nuclear RNA sequencing of the heart revealed a complex landscape of cardiac cells targeted by RBC-EVs, with enrichment of genes implicated in cell proliferation and stress signaling pathways compared with non-targeted cells. Correspondingly, cardiomyocytes targeted by RBC-EVs more frequently express cellular markers of DNA synthesis, suggesting the functional significance of EV-mediated signaling. In conclusion, our mouse model for mapping of EV-recipient cells reveals a complex cellular network of RBC-EV-mediated intercellular communication in ischemic heart failure and suggests a functional role for this mode of intercellular signaling.
Published: 2021

5. SnRNA sequencing defines signaling by RBC-derived extracellular vesicles in the murine heart.

Author: Valkov, Nedyalka, Valkov, Nedyalka, Das, Avash, Tucker, Nathan R, Li, Guoping, Salvador, Ane M, Chaffin, Mark D, Pereira De Oliveira Junior, Getulio, Kur, Ivan, Gokulnath, Priyanka, Ziegler, Olivia, Yeri, Ashish, Lu, Shulin, Khamesra, Aushee, Xiao, Chunyang, Rodosthenous, Rodosthenis, Srinivasan, Srimeenakshi, Toxavidis, Vasilis, Tigges, John, Laurent, Louise C, Momma, Stefan, Kitchen, Robert, Ellinor, Patrick, Ghiran, Ionita, Das, Saumya, Valkov, Nedyalka, Valkov, Nedyalka, Das, Avash, Tucker, Nathan R, Li, Guoping, Salvador, Ane M, Chaffin, Mark D, Pereira De Oliveira Junior, Getulio, Kur, Ivan, Gokulnath, Priyanka, Ziegler, Olivia, Yeri, Ashish, Lu, Shulin, Khamesra, Aushee, Xiao, Chunyang, Rodosthenous, Rodosthenis, Srinivasan, Srimeenakshi, Toxavidis, Vasilis, Tigges, John, Laurent, Louise C, Momma, Stefan, Kitchen, Robert, Ellinor, Patrick, Ghiran, Ionita, and Das, Saumya
Abstract: Extracellular vesicles (EVs) mediate intercellular signaling by transferring their cargo to recipient cells, but the functional consequences of signaling are not fully appreciated. RBC-derived EVs are abundant in circulation and have been implicated in regulating immune responses. Here, we use a transgenic mouse model for fluorescence-based mapping of RBC-EV recipient cells to assess the role of this intercellular signaling mechanism in heart disease. Using fluorescent-based mapping, we detected an increase in RBC-EV-targeted cardiomyocytes in a murine model of ischemic heart failure. Single cell nuclear RNA sequencing of the heart revealed a complex landscape of cardiac cells targeted by RBC-EVs, with enrichment of genes implicated in cell proliferation and stress signaling pathways compared with non-targeted cells. Correspondingly, cardiomyocytes targeted by RBC-EVs more frequently express cellular markers of DNA synthesis, suggesting the functional significance of EV-mediated signaling. In conclusion, our mouse model for mapping of EV-recipient cells reveals a complex cellular network of RBC-EV-mediated intercellular communication in ischemic heart failure and suggests a functional role for this mode of intercellular signaling.
Published: 2021

6. Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics

Author: Muus, Christoph, Luecken, Malte D., Eraslan, Gokcen, Sikkema, Lisa, Waghray, Avinash, Heimberg, Graham, Kobayashi, Yoshihiko, Vaishnav, Eeshit Dhaval, Subramanian, Ayshwarya, Smillie, Christopher, Jagadeesh, Karthik A., Duong, Elizabeth Thu, Fiskin, Evgenij, Triglia, Elena Torlai, Ansari, Meshal, Cai, Peiwen, Lin, Brian, Buchanan, Justin, Chen, Sijia, Shu, Jian, Haber, Adam L., Chung, Hattie, Montoro, Daniel T., Adams, Taylor, Aliee, Hananeh, Allon, Samuel J., Andrusivova, Zaneta, Angelidis, Ilias, Ashenberg, Orr, Bassler, Kevin, Becavin, Christophe, Benhar, Inbal, Bergenstrahle, Joseph, Bergenstrahle, Ludvig, Bolt, Liam, Braun, Emelie, Bui, Linh T., Callori, Steven, Chaffin, Mark, Chichelnitskiy, Evgeny, Chiou, Joshua, Conlon, Thomas M., Cuoco, Michael S., Cuomo, Anna S. E., Deprez, Marie, Duclos, Grant, Fine, Denise, Fischer, David S., Ghazanfar, Shila, Gillich, Astrid, Giotti, Bruno, Gould, Joshua, Guo, Minzhe, Gutierrez, Austin J., Habermann, Arun C., Harvey, Tyler, He, Peng, Hou, Xiaomeng, Hu, Lijuan, Hu, Yan, Jaiswal, Alok, Ji, Lu, Jiang, Peiyong, Kapellos, Theodoros S., Kuo, Christin S., Larsson, Ludvig, Leney-Greene, Michael A., Lim, Kyungtae, Litvinukova, Monika, Ludwig, Leif S., Lukassen, Soeren, Luo, Wendy, Maatz, Henrike, Madissoon, Elo, Mamanova, Lira, Manakongtreecheep, Kasidet, Leroy, Sylvie, Mayr, Christoph H., Mbano, Ian M., McAdams, Alexi M., Nabhan, Ahmad N., Nyquist, Sarah K., Penland, Lolita, Poirion, Olivier B., Poli, Sergio, Qi, CanCan, Queen, Rachel, Reichart, Daniel, Rosas, Ivan, Schupp, Jonas C., Shea, Conor, Shi, Xingyi, Sinha, Rahul, Sit, Rene, Slowikowski, Kamil, Slyper, Michal, Smith, Neal P., Sountoulidis, Alex, Strunz, Maximilian, Sullivan, Travis B., Sun, Dawei, Talavera-Lopez, Carlos, Tan, Peng, Tantivit, Jessica, Travaglini, Kyle J., Tucker, Nathan R., Vernon, Katherine A., Wadsworth, Marc H., Waldman, Julia, Wang, Xiuting, Xu, Ke, Yan, Wenjun, Zhao, William, Ziegler, Carly G. K., Muus, Christoph, Luecken, Malte D., Eraslan, Gokcen, Sikkema, Lisa, Waghray, Avinash, Heimberg, Graham, Kobayashi, Yoshihiko, Vaishnav, Eeshit Dhaval, Subramanian, Ayshwarya, Smillie, Christopher, Jagadeesh, Karthik A., Duong, Elizabeth Thu, Fiskin, Evgenij, Triglia, Elena Torlai, Ansari, Meshal, Cai, Peiwen, Lin, Brian, Buchanan, Justin, Chen, Sijia, Shu, Jian, Haber, Adam L., Chung, Hattie, Montoro, Daniel T., Adams, Taylor, Aliee, Hananeh, Allon, Samuel J., Andrusivova, Zaneta, Angelidis, Ilias, Ashenberg, Orr, Bassler, Kevin, Becavin, Christophe, Benhar, Inbal, Bergenstrahle, Joseph, Bergenstrahle, Ludvig, Bolt, Liam, Braun, Emelie, Bui, Linh T., Callori, Steven, Chaffin, Mark, Chichelnitskiy, Evgeny, Chiou, Joshua, Conlon, Thomas M., Cuoco, Michael S., Cuomo, Anna S. E., Deprez, Marie, Duclos, Grant, Fine, Denise, Fischer, David S., Ghazanfar, Shila, Gillich, Astrid, Giotti, Bruno, Gould, Joshua, Guo, Minzhe, Gutierrez, Austin J., Habermann, Arun C., Harvey, Tyler, He, Peng, Hou, Xiaomeng, Hu, Lijuan, Hu, Yan, Jaiswal, Alok, Ji, Lu, Jiang, Peiyong, Kapellos, Theodoros S., Kuo, Christin S., Larsson, Ludvig, Leney-Greene, Michael A., Lim, Kyungtae, Litvinukova, Monika, Ludwig, Leif S., Lukassen, Soeren, Luo, Wendy, Maatz, Henrike, Madissoon, Elo, Mamanova, Lira, Manakongtreecheep, Kasidet, Leroy, Sylvie, Mayr, Christoph H., Mbano, Ian M., McAdams, Alexi M., Nabhan, Ahmad N., Nyquist, Sarah K., Penland, Lolita, Poirion, Olivier B., Poli, Sergio, Qi, CanCan, Queen, Rachel, Reichart, Daniel, Rosas, Ivan, Schupp, Jonas C., Shea, Conor, Shi, Xingyi, Sinha, Rahul, Sit, Rene, Slowikowski, Kamil, Slyper, Michal, Smith, Neal P., Sountoulidis, Alex, Strunz, Maximilian, Sullivan, Travis B., Sun, Dawei, Talavera-Lopez, Carlos, Tan, Peng, Tantivit, Jessica, Travaglini, Kyle J., Tucker, Nathan R., Vernon, Katherine A., Wadsworth, Marc H., Waldman, Julia, Wang, Xiuting, Xu, Ke, Yan, Wenjun, Zhao, William, and Ziegler, Carly G. K.
Abstract: Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2(+)TMPRSS2(+) cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention. An integrated analysis of over 100 single-cell and single-nucleus transcriptomics studies illustrates severe acute respiratory syndrome coronavirus 2 viral entry gene coexpression patterns across different human tissues, and shows association of age, smoking status and sex with viral entry gene expression in respiratory cell populations.
Published: 2021
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7. 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, Fabiola M., Foco, Luisa, Gogele, 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, Kahonen, 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, Theriault, Sebastien, Hutri-Kahonen, Nina, Lehtimaki, Terho, Lyytikainen, Leo-Pekka, Raitakari, Olli T., Barnes, Catriona L. K., 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 J. F., Nadkarni, Girish N., Preuss, Michael H., Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Mueller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D., Rienstra, Michiel, van de Vegte, Yordi J., van der Harst, Pim, Verweij, Niek, Kaab, Stefan, Schramm, Katharina, Sinner, Moritz F., Strauch, Konstantin, Cutler, Michael J., Fatkin, Diane, London, Barry, Olesen, Morten, Roden, Dan M., Shoemaker, M. Benjamin, Smith, J. Gustav, 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, Jukema, J. Wouter, Macfarlane, Peter W., Trompet, Stella, Doerr, Marcus, Felix, Stephan B., Voelker, Uwe, Weiss, Stefan, Havulinna, Aki S., Jula, Antti, Saaksjarvi, Katri, Salomaa, Veikko, Guo, Xiuqing, Heckbert, Susan R., Lin, Henry J., Rotter, Jerome, I, Taylor, Kent D., Yao, Jie, de Mutsert, Renee, 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, Andre, 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, Said, M. Abdullah, van der Ende, M. Yldau, 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., Munroe, Patricia B., 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, Fabiola M., Foco, Luisa, Gogele, 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, Kahonen, 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, Theriault, Sebastien, Hutri-Kahonen, Nina, Lehtimaki, Terho, Lyytikainen, Leo-Pekka, Raitakari, Olli T., Barnes, Catriona L. K., 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 J. F., Nadkarni, Girish N., Preuss, Michael H., Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Mueller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D., Rienstra, Michiel, van de Vegte, Yordi J., van der Harst, Pim, Verweij, Niek, Kaab, Stefan, Schramm, Katharina, Sinner, Moritz F., Strauch, Konstantin, Cutler, Michael J., Fatkin, Diane, London, Barry, Olesen, Morten, Roden, Dan M., Shoemaker, M. Benjamin, Smith, J. Gustav, 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, Jukema, J. Wouter, Macfarlane, Peter W., Trompet, Stella, Doerr, Marcus, Felix, Stephan B., Voelker, Uwe, Weiss, Stefan, Havulinna, Aki S., Jula, Antti, Saaksjarvi, Katri, Salomaa, Veikko, Guo, Xiuqing, Heckbert, Susan R., Lin, Henry J., Rotter, Jerome, I, Taylor, Kent D., Yao, Jie, de Mutsert, Renee, 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, Andre, 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, Said, M. Abdullah, van der Ende, M. Yldau, 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.
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. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
Published: 2020
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8. 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, Fabiola M., Foco, Luisa, Gogele, 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, Kahonen, 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, Theriault, Sebastien, Hutri-Kahonen, Nina, Lehtimaki, Terho, Lyytikainen, Leo-Pekka, Raitakari, Olli T., Barnes, Catriona L. K., 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 J. F., Nadkarni, Girish N., Preuss, Michael H., Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Mueller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D., Rienstra, Michiel, van de Vegte, Yordi J., van der Harst, Pim, Verweij, Niek, Kaab, Stefan, Schramm, Katharina, Sinner, Moritz F., Strauch, Konstantin, Cutler, Michael J., Fatkin, Diane, London, Barry, Olesen, Morten, Roden, Dan M., Shoemaker, M. Benjamin, Smith, J. Gustav, 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, Jukema, J. Wouter, Macfarlane, Peter W., Trompet, Stella, Doerr, Marcus, Felix, Stephan B., Voelker, Uwe, Weiss, Stefan, Havulinna, Aki S., Jula, Antti, Saaksjarvi, Katri, Salomaa, Veikko, Guo, Xiuqing, Heckbert, Susan R., Lin, Henry J., Rotter, Jerome, I, Taylor, Kent D., Yao, Jie, de Mutsert, Renee, 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, Andre, 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, Said, M. Abdullah, van der Ende, M. Yldau, 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., Munroe, Patricia B., 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, Fabiola M., Foco, Luisa, Gogele, 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, Kahonen, 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, Theriault, Sebastien, Hutri-Kahonen, Nina, Lehtimaki, Terho, Lyytikainen, Leo-Pekka, Raitakari, Olli T., Barnes, Catriona L. K., 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 J. F., Nadkarni, Girish N., Preuss, Michael H., Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Mueller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D., Rienstra, Michiel, van de Vegte, Yordi J., van der Harst, Pim, Verweij, Niek, Kaab, Stefan, Schramm, Katharina, Sinner, Moritz F., Strauch, Konstantin, Cutler, Michael J., Fatkin, Diane, London, Barry, Olesen, Morten, Roden, Dan M., Shoemaker, M. Benjamin, Smith, J. Gustav, 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, Jukema, J. Wouter, Macfarlane, Peter W., Trompet, Stella, Doerr, Marcus, Felix, Stephan B., Voelker, Uwe, Weiss, Stefan, Havulinna, Aki S., Jula, Antti, Saaksjarvi, Katri, Salomaa, Veikko, Guo, Xiuqing, Heckbert, Susan R., Lin, Henry J., Rotter, Jerome, I, Taylor, Kent D., Yao, Jie, de Mutsert, Renee, 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, Andre, 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, Said, M. Abdullah, van der Ende, M. Yldau, 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.
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. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
Published: 2020
Full Text: View/download PDF

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, Fabiola M., Foco, Luisa, Gogele, 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, Kahonen, 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, Theriault, Sebastien, Hutri-Kahonen, Nina, Lehtimaki, Terho, Lyytikainen, Leo-Pekka, Raitakari, Olli T., Barnes, Catriona L. K., 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 J. F., Nadkarni, Girish N., Preuss, Michael H., Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Mueller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D., Rienstra, Michiel, van de Vegte, Yordi J., van der Harst, Pim, Verweij, Niek, Kaab, Stefan, Schramm, Katharina, Sinner, Moritz F., Strauch, Konstantin, Cutler, Michael J., Fatkin, Diane, London, Barry, Olesen, Morten, Roden, Dan M., Shoemaker, M. Benjamin, Smith, J. Gustav, 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, Jukema, J. Wouter, Macfarlane, Peter W., Trompet, Stella, Doerr, Marcus, Felix, Stephan B., Voelker, Uwe, Weiss, Stefan, Havulinna, Aki S., Jula, Antti, Saaksjarvi, Katri, Salomaa, Veikko, Guo, Xiuqing, Heckbert, Susan R., Lin, Henry J., Rotter, Jerome, I, Taylor, Kent D., Yao, Jie, de Mutsert, Renee, 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, Andre, 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, Said, M. Abdullah, van der Ende, M. Yldau, 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., Munroe, Patricia B., 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, Fabiola M., Foco, Luisa, Gogele, 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, Kahonen, 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, Theriault, Sebastien, Hutri-Kahonen, Nina, Lehtimaki, Terho, Lyytikainen, Leo-Pekka, Raitakari, Olli T., Barnes, Catriona L. K., 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 J. F., Nadkarni, Girish N., Preuss, Michael H., Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Mueller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D., Rienstra, Michiel, van de Vegte, Yordi J., van der Harst, Pim, Verweij, Niek, Kaab, Stefan, Schramm, Katharina, Sinner, Moritz F., Strauch, Konstantin, Cutler, Michael J., Fatkin, Diane, London, Barry, Olesen, Morten, Roden, Dan M., Shoemaker, M. Benjamin, Smith, J. Gustav, 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, Jukema, J. Wouter, Macfarlane, Peter W., Trompet, Stella, Doerr, Marcus, Felix, Stephan B., Voelker, Uwe, Weiss, Stefan, Havulinna, Aki S., Jula, Antti, Saaksjarvi, Katri, Salomaa, Veikko, Guo, Xiuqing, Heckbert, Susan R., Lin, Henry J., Rotter, Jerome, I, Taylor, Kent D., Yao, Jie, de Mutsert, Renee, 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, Andre, 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, Said, M. Abdullah, van der Ende, M. Yldau, 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.
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. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
Published: 2020
Full Text: View/download PDF

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

Author: Ntalla, Ioanna, 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, Ntalla, Ioanna, 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
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

11. Epigenetic Analyses of Human Left Atrial Tissue Identifies Gene Networks Underlying Atrial Fibrillation

Author: Hall, Amelia Weber, Chaffin, Mark, Roselli, Carolina, Lin, Honghuang, Lubitz, Steven A, Bianchi, Valerio, Geeven, Geert, Bedi, Kenneth, Margulies, Kenneth B, de Laat, Wouter, Tucker, Nathan R, Ellinor, Patrick T, Hall, Amelia Weber, Chaffin, Mark, Roselli, Carolina, Lin, Honghuang, Lubitz, Steven A, Bianchi, Valerio, Geeven, Geert, Bedi, Kenneth, Margulies, Kenneth B, de Laat, Wouter, Tucker, Nathan R, and Ellinor, Patrick T
Abstract: BACKGROUND: Atrial fibrillation (AF) often arises from structural abnormalities in the left atria (LA). Annotation of the noncoding genome in human LA is limited, as are effects on gene expression and chromatin architecture. Many AF-associated genetic variants reside in noncoding regions; this knowledge gap impairs efforts to understand the molecular mechanisms of AF and cardiac conduction phenotypes.METHODS: We generated a model of the LA noncoding genome by profiling 7 histone post-translational modifications (active: H3K4me3, H3K4me2, H3K4me1, H3K27ac, H3K36me3; repressive: H3K27me3, H3K9me3), CTCF binding, and gene expression in samples from 5 individuals without structural heart disease or AF. We used MACS2 to identify peak regions (P<0.01), applied a Markov model to classify regulatory elements, and annotated this model with matched gene expression data. We intersected chromatin states with expression quantitative trait locus, DNA methylation, and HiC chromatin interaction data from LA and left ventricle. Finally, we integrated genome-wide association data for AF and electrocardiographic traits to link disease-related variants to genes.RESULTS: Our model identified 21 epigenetic states, encompassing regulatory motifs, such as promoters, enhancers, and repressed regions. Genes were regulated by proximal chromatin states; repressive states were associated with a significant reduction in gene expression (P<2×10-16). Chromatin states were differentially methylated, promoters were less methylated than repressed regions (P<2×10-16). We identified over 15 000 LA-specific enhancers, defined by homeobox family motifs, and annotated several cardiovascular disease susceptibility loci. Intersecting AF and PR genome-wide association studies loci with long-range chromatin conformation data identified a gene interaction network dominated by NKX2-5, TBX3, ZFHX3, and SYNPO2L.CONCLUSIONS: Profiling the noncoding genome provides new insights into
Published: 2020

12. Epigenetic and Transcriptional Networks Underlying Atrial Fibrillation

Author: van Ouwerkerk, Antoinette F, Hall, Amelia W, Kadow, Zachary A, Lazarevic, Sonja, Reyat, Jasmeet S, Tucker, Nathan R, Nadadur, Rangarajan D, Bosada, Fernanda M, Bianchi, Valerio, Ellinor, Patrick T, Fabritz, Larissa, Martin, James F, de Laat, Wouter, Kirchhof, Paulus, Moskowitz, Ivan P, Christoffels, Vincent M, van Ouwerkerk, Antoinette F, Hall, Amelia W, Kadow, Zachary A, Lazarevic, Sonja, Reyat, Jasmeet S, Tucker, Nathan R, Nadadur, Rangarajan D, Bosada, Fernanda M, Bianchi, Valerio, Ellinor, Patrick T, Fabritz, Larissa, Martin, James F, de Laat, Wouter, Kirchhof, Paulus, Moskowitz, Ivan P, and Christoffels, Vincent M
Abstract: Genome-wide association studies have uncovered over a 100 genetic loci associated with atrial fibrillation (AF), the most common arrhythmia. Many of the top AF-associated loci harbor key cardiac transcription factors, including PITX2, TBX5, PRRX1, and ZFHX3. Moreover, the vast majority of the AF-associated variants lie within noncoding regions of the genome where causal variants affect gene expression by altering the activity of transcription factors and the epigenetic state of chromatin. In this review, we discuss a transcriptional regulatory network model for AF defined by effector genes in Genome-wide association studies loci. We describe the current state of the field regarding the identification and function of AF-relevant gene regulatory networks, including variant regulatory elements, dose-sensitive transcription factor functionality, target genes, and epigenetic states. We illustrate how altered transcriptional networks may impact cardiomyocyte function and ionic currents that impact AF risk. Last, we identify the need for improved tools to identify and functionally test transcriptional components to define the links between genetic variation, epigenetic gene regulation, and atrial function.
Published: 2020

13. 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, Fabiola M., Foco, Luisa, Gogele, 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, Kahonen, 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, Theriault, Sebastien, Hutri-Kahonen, Nina, Lehtimaki, Terho, Lyytikainen, Leo-Pekka, Raitakari, Olli T., Barnes, Catriona L. K., 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 J. F., Nadkarni, Girish N., Preuss, Michael H., Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Mueller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D., Rienstra, Michiel, van de Vegte, Yordi J., van der Harst, Pim, Verweij, Niek, Kaab, Stefan, Schramm, Katharina, Sinner, Moritz F., Strauch, Konstantin, Cutler, Michael J., Fatkin, Diane, London, Barry, Olesen, Morten, Roden, Dan M., Shoemaker, M. Benjamin, Smith, J. Gustav, 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, Jukema, J. Wouter, Macfarlane, Peter W., Trompet, Stella, Doerr, Marcus, Felix, Stephan B., Voelker, Uwe, Weiss, Stefan, Havulinna, Aki S., Jula, Antti, Saaksjarvi, Katri, Salomaa, Veikko, Guo, Xiuqing, Heckbert, Susan R., Lin, Henry J., Rotter, Jerome, I, Taylor, Kent D., Yao, Jie, de Mutsert, Renee, 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, Andre, 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, Said, M. Abdullah, van der Ende, M. Yldau, 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., Munroe, Patricia B., 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, Fabiola M., Foco, Luisa, Gogele, 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, Kahonen, 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, Theriault, Sebastien, Hutri-Kahonen, Nina, Lehtimaki, Terho, Lyytikainen, Leo-Pekka, Raitakari, Olli T., Barnes, Catriona L. K., 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 J. F., Nadkarni, Girish N., Preuss, Michael H., Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Mueller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D., Rienstra, Michiel, van de Vegte, Yordi J., van der Harst, Pim, Verweij, Niek, Kaab, Stefan, Schramm, Katharina, Sinner, Moritz F., Strauch, Konstantin, Cutler, Michael J., Fatkin, Diane, London, Barry, Olesen, Morten, Roden, Dan M., Shoemaker, M. Benjamin, Smith, J. Gustav, 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, Jukema, J. Wouter, Macfarlane, Peter W., Trompet, Stella, Doerr, Marcus, Felix, Stephan B., Voelker, Uwe, Weiss, Stefan, Havulinna, Aki S., Jula, Antti, Saaksjarvi, Katri, Salomaa, Veikko, Guo, Xiuqing, Heckbert, Susan R., Lin, Henry J., Rotter, Jerome, I, Taylor, Kent D., Yao, Jie, de Mutsert, Renee, 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, Andre, 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, Said, M. Abdullah, van der Ende, M. Yldau, 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.
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. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
Published: 2020
Full Text: View/download PDF

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

Author: Ntalla, Ioanna, 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, Ntalla, Ioanna, 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
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

15. 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, Fabiola M., Foco, Luisa, Gogele, 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, Kahonen, 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, Theriault, Sebastien, Hutri-Kahonen, Nina, Lehtimaki, Terho, Lyytikainen, Leo-Pekka, Raitakari, Olli T., Barnes, Catriona L. K., 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 J. F., Nadkarni, Girish N., Preuss, Michael H., Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Mueller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D., Rienstra, Michiel, van de Vegte, Yordi J., van der Harst, Pim, Verweij, Niek, Kaab, Stefan, Schramm, Katharina, Sinner, Moritz F., Strauch, Konstantin, Cutler, Michael J., Fatkin, Diane, London, Barry, Olesen, Morten, Roden, Dan M., Shoemaker, M. Benjamin, Smith, J. Gustav, 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, Jukema, J. Wouter, Macfarlane, Peter W., Trompet, Stella, Doerr, Marcus, Felix, Stephan B., Voelker, Uwe, Weiss, Stefan, Havulinna, Aki S., Jula, Antti, Saaksjarvi, Katri, Salomaa, Veikko, Guo, Xiuqing, Heckbert, Susan R., Lin, Henry J., Rotter, Jerome, I, Taylor, Kent D., Yao, Jie, de Mutsert, Renee, 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, Andre, 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, Said, M. Abdullah, van der Ende, M. Yldau, 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., Munroe, Patricia B., 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, Fabiola M., Foco, Luisa, Gogele, 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, Kahonen, 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, Theriault, Sebastien, Hutri-Kahonen, Nina, Lehtimaki, Terho, Lyytikainen, Leo-Pekka, Raitakari, Olli T., Barnes, Catriona L. K., 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 J. F., Nadkarni, Girish N., Preuss, Michael H., Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Mueller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D., Rienstra, Michiel, van de Vegte, Yordi J., van der Harst, Pim, Verweij, Niek, Kaab, Stefan, Schramm, Katharina, Sinner, Moritz F., Strauch, Konstantin, Cutler, Michael J., Fatkin, Diane, London, Barry, Olesen, Morten, Roden, Dan M., Shoemaker, M. Benjamin, Smith, J. Gustav, 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, Jukema, J. Wouter, Macfarlane, Peter W., Trompet, Stella, Doerr, Marcus, Felix, Stephan B., Voelker, Uwe, Weiss, Stefan, Havulinna, Aki S., Jula, Antti, Saaksjarvi, Katri, Salomaa, Veikko, Guo, Xiuqing, Heckbert, Susan R., Lin, Henry J., Rotter, Jerome, I, Taylor, Kent D., Yao, Jie, de Mutsert, Renee, 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, Andre, 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, Said, M. Abdullah, van der Ende, M. Yldau, 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.
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. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
Published: 2020
Full Text: View/download PDF

16. Epigenetic Analyses of Human Left Atrial Tissue Identifies Gene Networks Underlying Atrial Fibrillation

Author: Hall, Amelia Weber, Chaffin, Mark, Roselli, Carolina, Lin, Honghuang, Lubitz, Steven A, Bianchi, Valerio, Geeven, Geert, Bedi, Kenneth, Margulies, Kenneth B, de Laat, Wouter, Tucker, Nathan R, Ellinor, Patrick T, Hall, Amelia Weber, Chaffin, Mark, Roselli, Carolina, Lin, Honghuang, Lubitz, Steven A, Bianchi, Valerio, Geeven, Geert, Bedi, Kenneth, Margulies, Kenneth B, de Laat, Wouter, Tucker, Nathan R, and Ellinor, Patrick T
Abstract: BACKGROUND: Atrial fibrillation (AF) often arises from structural abnormalities in the left atria (LA). Annotation of the noncoding genome in human LA is limited, as are effects on gene expression and chromatin architecture. Many AF-associated genetic variants reside in noncoding regions; this knowledge gap impairs efforts to understand the molecular mechanisms of AF and cardiac conduction phenotypes.METHODS: We generated a model of the LA noncoding genome by profiling 7 histone post-translational modifications (active: H3K4me3, H3K4me2, H3K4me1, H3K27ac, H3K36me3; repressive: H3K27me3, H3K9me3), CTCF binding, and gene expression in samples from 5 individuals without structural heart disease or AF. We used MACS2 to identify peak regions (P<0.01), applied a Markov model to classify regulatory elements, and annotated this model with matched gene expression data. We intersected chromatin states with expression quantitative trait locus, DNA methylation, and HiC chromatin interaction data from LA and left ventricle. Finally, we integrated genome-wide association data for AF and electrocardiographic traits to link disease-related variants to genes.RESULTS: Our model identified 21 epigenetic states, encompassing regulatory motifs, such as promoters, enhancers, and repressed regions. Genes were regulated by proximal chromatin states; repressive states were associated with a significant reduction in gene expression (P<2×10-16). Chromatin states were differentially methylated, promoters were less methylated than repressed regions (P<2×10-16). We identified over 15 000 LA-specific enhancers, defined by homeobox family motifs, and annotated several cardiovascular disease susceptibility loci. Intersecting AF and PR genome-wide association studies loci with long-range chromatin conformation data identified a gene interaction network dominated by NKX2-5, TBX3, ZFHX3, and SYNPO2L.CONCLUSIONS: Profiling the noncoding genome provides new insights into
Published: 2020

17. Epigenetic and Transcriptional Networks Underlying Atrial Fibrillation

Author: van Ouwerkerk, Antoinette F, Hall, Amelia W, Kadow, Zachary A, Lazarevic, Sonja, Reyat, Jasmeet S, Tucker, Nathan R, Nadadur, Rangarajan D, Bosada, Fernanda M, Bianchi, Valerio, Ellinor, Patrick T, Fabritz, Larissa, Martin, James F, de Laat, Wouter, Kirchhof, Paulus, Moskowitz, Ivan P, Christoffels, Vincent M, van Ouwerkerk, Antoinette F, Hall, Amelia W, Kadow, Zachary A, Lazarevic, Sonja, Reyat, Jasmeet S, Tucker, Nathan R, Nadadur, Rangarajan D, Bosada, Fernanda M, Bianchi, Valerio, Ellinor, Patrick T, Fabritz, Larissa, Martin, James F, de Laat, Wouter, Kirchhof, Paulus, Moskowitz, Ivan P, and Christoffels, Vincent M
Abstract: Genome-wide association studies have uncovered over a 100 genetic loci associated with atrial fibrillation (AF), the most common arrhythmia. Many of the top AF-associated loci harbor key cardiac transcription factors, including PITX2, TBX5, PRRX1, and ZFHX3. Moreover, the vast majority of the AF-associated variants lie within noncoding regions of the genome where causal variants affect gene expression by altering the activity of transcription factors and the epigenetic state of chromatin. In this review, we discuss a transcriptional regulatory network model for AF defined by effector genes in Genome-wide association studies loci. We describe the current state of the field regarding the identification and function of AF-relevant gene regulatory networks, including variant regulatory elements, dose-sensitive transcription factor functionality, target genes, and epigenetic states. We illustrate how altered transcriptional networks may impact cardiomyocyte function and ionic currents that impact AF risk. Last, we identify the need for improved tools to identify and functionally test transcriptional components to define the links between genetic variation, epigenetic gene regulation, and atrial function.
Published: 2020

18. 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 L.K., 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 J.F., 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., Munroe, Patricia B., 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 L.K., 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 J.F., 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.
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

19. 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, Fabiola M., Foco, Luisa, Gogele, 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, Kahonen, 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, Theriault, Sebastien, Hutri-Kahonen, Nina, Lehtimaki, Terho, Lyytikainen, Leo-Pekka, Raitakari, Olli T., Barnes, Catriona L. K., 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 J. F., Nadkarni, Girish N., Preuss, Michael H., Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Mueller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D., Rienstra, Michiel, van de Vegte, Yordi J., van der Harst, Pim, Verweij, Niek, Kaab, Stefan, Schramm, Katharina, Sinner, Moritz F., Strauch, Konstantin, Cutler, Michael J., Fatkin, Diane, London, Barry, Olesen, Morten, Roden, Dan M., Shoemaker, M. Benjamin, Smith, J. Gustav, 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, Jukema, J. Wouter, Macfarlane, Peter W., Trompet, Stella, Doerr, Marcus, Felix, Stephan B., Voelker, Uwe, Weiss, Stefan, Havulinna, Aki S., Jula, Antti, Saaksjarvi, Katri, Salomaa, Veikko, Guo, Xiuqing, Heckbert, Susan R., Lin, Henry J., Rotter, Jerome, I, Taylor, Kent D., Yao, Jie, de Mutsert, Renee, 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, Andre, 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, Said, M. Abdullah, van der Ende, M. Yldau, 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., Munroe, Patricia B., 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, Fabiola M., Foco, Luisa, Gogele, 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, Kahonen, 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, Theriault, Sebastien, Hutri-Kahonen, Nina, Lehtimaki, Terho, Lyytikainen, Leo-Pekka, Raitakari, Olli T., Barnes, Catriona L. K., 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 J. F., Nadkarni, Girish N., Preuss, Michael H., Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Mueller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D., Rienstra, Michiel, van de Vegte, Yordi J., van der Harst, Pim, Verweij, Niek, Kaab, Stefan, Schramm, Katharina, Sinner, Moritz F., Strauch, Konstantin, Cutler, Michael J., Fatkin, Diane, London, Barry, Olesen, Morten, Roden, Dan M., Shoemaker, M. Benjamin, Smith, J. Gustav, 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, Jukema, J. Wouter, Macfarlane, Peter W., Trompet, Stella, Doerr, Marcus, Felix, Stephan B., Voelker, Uwe, Weiss, Stefan, Havulinna, Aki S., Jula, Antti, Saaksjarvi, Katri, Salomaa, Veikko, Guo, Xiuqing, Heckbert, Susan R., Lin, Henry J., Rotter, Jerome, I, Taylor, Kent D., Yao, Jie, de Mutsert, Renee, 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, Andre, 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, Said, M. Abdullah, van der Ende, M. Yldau, 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.
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. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
Published: 2020
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20. 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 L.K., 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 J.F., 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., Munroe, Patricia B., 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 L.K., 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 J.F., 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.
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

21. Epigenetic Analyses of Human Left Atrial Tissue Identifies Gene Networks Underlying Atrial Fibrillation

Author: CMM Groep Burgering, Genetica, Cancer, Hubrecht Institute with UMC, Hall, Amelia Weber, Chaffin, Mark, Roselli, Carolina, Lin, Honghuang, Lubitz, Steven A, Bianchi, Valerio, Geeven, Geert, Bedi, Kenneth, Margulies, Kenneth B, de Laat, Wouter, Tucker, Nathan R, Ellinor, Patrick T, CMM Groep Burgering, Genetica, Cancer, Hubrecht Institute with UMC, Hall, Amelia Weber, Chaffin, Mark, Roselli, Carolina, Lin, Honghuang, Lubitz, Steven A, Bianchi, Valerio, Geeven, Geert, Bedi, Kenneth, Margulies, Kenneth B, de Laat, Wouter, Tucker, Nathan R, and Ellinor, Patrick T
Published: 2020

22. Epigenetic and Transcriptional Networks Underlying Atrial Fibrillation

Author: Genetica, Cancer, Hubrecht Institute with UMC, van Ouwerkerk, Antoinette F, Hall, Amelia W, Kadow, Zachary A, Lazarevic, Sonja, Reyat, Jasmeet S, Tucker, Nathan R, Nadadur, Rangarajan D, Bosada, Fernanda M, Bianchi, Valerio, Ellinor, Patrick T, Fabritz, Larissa, Martin, James F, de Laat, Wouter, Kirchhof, Paulus, Moskowitz, Ivan P, Christoffels, Vincent M, Genetica, Cancer, Hubrecht Institute with UMC, van Ouwerkerk, Antoinette F, Hall, Amelia W, Kadow, Zachary A, Lazarevic, Sonja, Reyat, Jasmeet S, Tucker, Nathan R, Nadadur, Rangarajan D, Bosada, Fernanda M, Bianchi, Valerio, Ellinor, Patrick T, Fabritz, Larissa, Martin, James F, de Laat, Wouter, Kirchhof, Paulus, Moskowitz, Ivan P, and Christoffels, Vincent M
Published: 2020

23. Multi-ethnic genome-wide association study for atrial fibrillation

Author: Roselli, Carolina, Chaffin, Mark D., Weng, Lu-Chen, Aeschbacher, Stefanie, Ahlberg, Gustav, Albert, Christine M., Almgren, Peter, Alonso, Alvaro, Anderson, Christopher D., Aragam, Krishna G., Arking, Dan E., Barnard, John, Bartz, Traci M., Benjamin, Emelia J., Bihlmeyer, Nathan A., Bis, Joshua C., Bloom, Heather L., Boerwinkle, Eric, Bottinger, Erwin B., Brody, Jennifer A., Calkins, Hugh, Campbell, Archie, Cappola, Thomas P., Carlquist, John, Chasman, Daniel I., Chen, Lin Y., Chen, Yii-Der Ida, Choi, Eue-Keun, Choi, Seung Hoan, Christophersen, Ingrid E., Chung, Mina K., Cole, John W., Conen, David, Cook, James, Crijns, Harry J., Cutler, Michael J., Damrauer, Scott M., Daniels, Brian R., Darbar, Dawood, Delgado, Graciela, Denny, Joshua C., Dichgans, Martin, Doerr, Marcus, Dudink, Elton A., Dudley, Samuel C., Esa, Nada, Esko, Tonu, Eskola, Markku, Fatkin, Diane, Felix, Stephan B., Ford, Ian, Franco, Oscar H., Geelhoed, Bastiaan, Grewal, Raji P., Gudnason, Vilmundur, Guo, Xiuqing, Gupta, Namrata, Gustafsson, Stefan, Gutmann, Rebecca, Hamsten, Anders, Harris, Tamara B., Hayward, Caroline, Heckbert, Susan R., Hernesniemi, Jussi, Hocking, Lynne J., Hofman, Albert, Horimoto, Andrea R. V. R., Huang, Jie, Huang, Paul L., Huffman, Jennifer, Ingelsson, Erik, Ipek, Esra Gucuk, Ito, Kaoru, Jimenez-Conde, Jordi, Johnson, Renee, Jukema, J. Wouter, Kaeaeb, Stefan, Kahonen, Mika, Kamatani, Yoichiro, Kane, John P., Kastrati, Adnan, Kathiresan, Sekar, Katschnig-Winter, Petra, Kavousi, Maryam, Kessler, Thorsten, Kietselaer, Bas L., Kirchhof, Paulus, Kleber, Marcus E., Knight, Stacey, Krieger, Jose E., Kubo, Michiaki, Launer, Lenore J., Laurikka, Jari, Lehtimaki, Terho, Leineweber, Kirsten, Lemaitre, Rozenn N., Li, Man, Lim, Hong Euy, Lin, Henry J., Lin, Honghuang, Lind, Lars, Lindgren, Cecilia M., Lokki, Marja-Liisa, London, Barry, Loos, Ruth J. F., Low, Siew-Kee, Lu, Yingchang, Lyytikainen, Leo-Pekka, Macfarlane, Peter W., Magnusson, Patrik K., Mahajan, Anubha, Malik, Rainer, Mansur, Alfredo J., Marcus, Gregory M., Margolin, Lauren, Margulies, Kenneth B., Maerz, Winfried, McManus, David D., Melander, Olle, Mohanty, Sanghamitra, Montgomery, Jay A., Morley, Michael P., Morris, Andrew P., Mueller-Nurasyid, Martina, Natale, Andrea, Nazarian, Saman, Neumann, Benjamin, Newton-Cheh, Christopher, Niemeijer, Maartje N., Nikus, Kjell, Nilsson, Peter, Noordam, Raymond, Oellers, Heidi, Olesen, Morten S., Orho-Melander, Marju, Padmanabhan, Sandosh, Pak, Hui-Nam, Pare, Guillaume, Pedersen, Nancy L., Pera, Joanna, Pereira, Alexandre, Porteous, David, Psaty, Bruce M., Pulit, Sara L., Pullinger, Clive R., Rader, Daniel J., Refsgaard, Lena, Ribases, Marta, Ridker, Paul M., Rienstra, Michiel, Risch, Lorenz, Roden, Dan M., Rosand, Jonathan, Rosenberg, Michael A., Rost, Natalia, Rotter, Jerome I., Saba, Samir, Sandhu, Roopinder K., Schnabel, Renate B., Schramm, Katharina, Schunkert, Heribert, Schurman, Claudia, Scott, Stuart A., Seppala, Ilkka, Shaffer, Christian, Shah, Svati, Shalaby, Alaa A., Shim, Jaemin, Shoemaker, M. Benjamin, Siland, Joylene E., Sinisalo, Juha, Sinner, Moritz F., Slowik, Agnieszka, Smith, Albert V., Smith, Blair H., Smith, J. Gustav, Smith, Jonathan D., Smith, Nicholas L., Soliman, Elsayed Z., Sotoodehnia, Nona, Stricker, Bruno H., Sun, Albert, Sun, Han, Svendsen, Jesper H., Tanaka, Toshihiro, Tanriverdi, Kahraman, Taylor, Kent D., Teder-Laving, Maris, Teumer, Alexander, Theriault, Sebastien, Trompet, Stella, Tucker, Nathan R., Tveit, Arnljot, Uitterlinden, Andre G., Van Der Harst, Pim, Van Gelder, Isabelle C., Van Wagoner, David R., Verweij, Niek, Vlachopoulou, Efthymia, Voelker, Uwe, Wang, Biqi, Weeke, Peter E., Weijs, Bob, Weiss, Raul, Weiss, Stefan, Wells, Quinn S., Wiggins, Kerri L., Wong, Jorge A., Woo, Daniel, Worrall, Bradford B., Yang, Pil-Sung, Yao, Jie, Yoneda, Zachary T., Zeller, Tanja, Zeng, Lingyao, Lubitz, Steven A., Lunetta, Kathryn L., Ellinor, Patrick T., Roselli, Carolina, Chaffin, Mark D., Weng, Lu-Chen, Aeschbacher, Stefanie, Ahlberg, Gustav, Albert, Christine M., Almgren, Peter, Alonso, Alvaro, Anderson, Christopher D., Aragam, Krishna G., Arking, Dan E., Barnard, John, Bartz, Traci M., Benjamin, Emelia J., Bihlmeyer, Nathan A., Bis, Joshua C., Bloom, Heather L., Boerwinkle, Eric, Bottinger, Erwin B., Brody, Jennifer A., Calkins, Hugh, Campbell, Archie, Cappola, Thomas P., Carlquist, John, Chasman, Daniel I., Chen, Lin Y., Chen, Yii-Der Ida, Choi, Eue-Keun, Choi, Seung Hoan, Christophersen, Ingrid E., Chung, Mina K., Cole, John W., Conen, David, Cook, James, Crijns, Harry J., Cutler, Michael J., Damrauer, Scott M., Daniels, Brian R., Darbar, Dawood, Delgado, Graciela, Denny, Joshua C., Dichgans, Martin, Doerr, Marcus, Dudink, Elton A., Dudley, Samuel C., Esa, Nada, Esko, Tonu, Eskola, Markku, Fatkin, Diane, Felix, Stephan B., Ford, Ian, Franco, Oscar H., Geelhoed, Bastiaan, Grewal, Raji P., Gudnason, Vilmundur, Guo, Xiuqing, Gupta, Namrata, Gustafsson, Stefan, Gutmann, Rebecca, Hamsten, Anders, Harris, Tamara B., Hayward, Caroline, Heckbert, Susan R., Hernesniemi, Jussi, Hocking, Lynne J., Hofman, Albert, Horimoto, Andrea R. V. R., Huang, Jie, Huang, Paul L., Huffman, Jennifer, Ingelsson, Erik, Ipek, Esra Gucuk, Ito, Kaoru, Jimenez-Conde, Jordi, Johnson, Renee, Jukema, J. Wouter, Kaeaeb, Stefan, Kahonen, Mika, Kamatani, Yoichiro, Kane, John P., Kastrati, Adnan, Kathiresan, Sekar, Katschnig-Winter, Petra, Kavousi, Maryam, Kessler, Thorsten, Kietselaer, Bas L., Kirchhof, Paulus, Kleber, Marcus E., Knight, Stacey, Krieger, Jose E., Kubo, Michiaki, Launer, Lenore J., Laurikka, Jari, Lehtimaki, Terho, Leineweber, Kirsten, Lemaitre, Rozenn N., Li, Man, Lim, Hong Euy, Lin, Henry J., Lin, Honghuang, Lind, Lars, Lindgren, Cecilia M., Lokki, Marja-Liisa, London, Barry, Loos, Ruth J. F., Low, Siew-Kee, Lu, Yingchang, Lyytikainen, Leo-Pekka, Macfarlane, Peter W., Magnusson, Patrik K., Mahajan, Anubha, Malik, Rainer, Mansur, Alfredo J., Marcus, Gregory M., Margolin, Lauren, Margulies, Kenneth B., Maerz, Winfried, McManus, David D., Melander, Olle, Mohanty, Sanghamitra, Montgomery, Jay A., Morley, Michael P., Morris, Andrew P., Mueller-Nurasyid, Martina, Natale, Andrea, Nazarian, Saman, Neumann, Benjamin, Newton-Cheh, Christopher, Niemeijer, Maartje N., Nikus, Kjell, Nilsson, Peter, Noordam, Raymond, Oellers, Heidi, Olesen, Morten S., Orho-Melander, Marju, Padmanabhan, Sandosh, Pak, Hui-Nam, Pare, Guillaume, Pedersen, Nancy L., Pera, Joanna, Pereira, Alexandre, Porteous, David, Psaty, Bruce M., Pulit, Sara L., Pullinger, Clive R., Rader, Daniel J., Refsgaard, Lena, Ribases, Marta, Ridker, Paul M., Rienstra, Michiel, Risch, Lorenz, Roden, Dan M., Rosand, Jonathan, Rosenberg, Michael A., Rost, Natalia, Rotter, Jerome I., Saba, Samir, Sandhu, Roopinder K., Schnabel, Renate B., Schramm, Katharina, Schunkert, Heribert, Schurman, Claudia, Scott, Stuart A., Seppala, Ilkka, Shaffer, Christian, Shah, Svati, Shalaby, Alaa A., Shim, Jaemin, Shoemaker, M. Benjamin, Siland, Joylene E., Sinisalo, Juha, Sinner, Moritz F., Slowik, Agnieszka, Smith, Albert V., Smith, Blair H., Smith, J. Gustav, Smith, Jonathan D., Smith, Nicholas L., Soliman, Elsayed Z., Sotoodehnia, Nona, Stricker, Bruno H., Sun, Albert, Sun, Han, Svendsen, Jesper H., Tanaka, Toshihiro, Tanriverdi, Kahraman, Taylor, Kent D., Teder-Laving, Maris, Teumer, Alexander, Theriault, Sebastien, Trompet, Stella, Tucker, Nathan R., Tveit, Arnljot, Uitterlinden, Andre G., Van Der Harst, Pim, Van Gelder, Isabelle C., Van Wagoner, David R., Verweij, Niek, Vlachopoulou, Efthymia, Voelker, Uwe, Wang, Biqi, Weeke, Peter E., Weijs, Bob, Weiss, Raul, Weiss, Stefan, Wells, Quinn S., Wiggins, Kerri L., Wong, Jorge A., Woo, Daniel, Worrall, Bradford B., Yang, Pil-Sung, Yao, Jie, Yoneda, Zachary T., Zeller, Tanja, Zeng, Lingyao, Lubitz, Steven A., Lunetta, Kathryn L., and Ellinor, Patrick T.
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
Full Text: View/download PDF

24. Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

Author: Lin, Honghuang, van Setten, Jessica, Smith, Albert V, Bihlmeyer, Nathan A, Warren, Helen R, Brody, Jennifer A, Radmanesh, Farid, Hall, Leanne, Grarup, Niels, Müller-Nurasyid, Martina, Boutin, Thibaud, Verweij, Niek, Lin, Henry J, Li-Gao, Ruifang, van den Berg, Marten E, Marten, Jonathan, Weiss, Stefan, Prins, Bram P, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Mei, Hao, Harris, Tamara B, Launer, Lenore J, Li, Man, Alonso, Alvaro, Soliman, Elsayed Z, Connell, John M, Huang, Paul L, Weng, Lu-Chen, Jameson, Heather S, Hucker, William, Hanley, Alan, Tucker, Nathan R, Chen, Yii-Der Ida, Bis, Joshua C, Rice, Kenneth M, Sitlani, Colleen M, Kors, Jan A, Xie, Zhijun, Wen, Chengping, Magnani, Jared W, Nelson, Christopher P, Kanters, Jørgen K, Sinner, Moritz F, Strauch, Konstantin, Peters, Annette, Waldenberger, Melanie, Meitinger, Thomas, Bork-Jensen, Jette, Pedersen, Oluf, Linneberg, Allan, Rudan, Igor, de Boer, Rudolf A, van der Meer, Peter, Yao, Jie, Guo, Xiuqing, Taylor, Kent D, Sotoodehnia, Nona, Rotter, Jerome I, Mook-Kanamori, Dennis O, Trompet, Stella, Rivadeneira, Fernando, Uitterlinden, André, Eijgelsheim, Mark, Padmanabhan, Sandosh, Smith, Blair H, Völzke, Henry, Felix, Stephan B, Homuth, Georg, Völker, Uwe, Mangino, Massimo, Spector, Timothy D, Bots, Michiel L, Perez, Marco, Kähönen, Mika, Raitakari, Olli T, Gudnason, Vilmundur, Arking, Dan E, Munroe, Patricia B, Psaty, Bruce M, van Duijn, Cornelia M, Benjamin, Emelia J, Rosand, Jonathan, Samani, Nilesh J, Hansen, Torben, Kääb, Stefan, Polasek, Ozren, van der Harst, Pim, Heckbert, Susan R, Jukema, J Wouter, Stricker, Bruno H, Hayward, Caroline, Dörr, Marcus, Jamshidi, Yalda, Asselbergs, Folkert W, Kooperberg, Charles, Lehtimäki, Terho, Wilson, James G, Ellinor, Patrick T, Lubitz, Steven A, Isaacs, Aaron, Lin, Honghuang, van Setten, Jessica, Smith, Albert V, Bihlmeyer, Nathan A, Warren, Helen R, Brody, Jennifer A, Radmanesh, Farid, Hall, Leanne, Grarup, Niels, Müller-Nurasyid, Martina, Boutin, Thibaud, Verweij, Niek, Lin, Henry J, Li-Gao, Ruifang, van den Berg, Marten E, Marten, Jonathan, Weiss, Stefan, Prins, Bram P, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Mei, Hao, Harris, Tamara B, Launer, Lenore J, Li, Man, Alonso, Alvaro, Soliman, Elsayed Z, Connell, John M, Huang, Paul L, Weng, Lu-Chen, Jameson, Heather S, Hucker, William, Hanley, Alan, Tucker, Nathan R, Chen, Yii-Der Ida, Bis, Joshua C, Rice, Kenneth M, Sitlani, Colleen M, Kors, Jan A, Xie, Zhijun, Wen, Chengping, Magnani, Jared W, Nelson, Christopher P, Kanters, Jørgen K, Sinner, Moritz F, Strauch, Konstantin, Peters, Annette, Waldenberger, Melanie, Meitinger, Thomas, Bork-Jensen, Jette, Pedersen, Oluf, Linneberg, Allan, Rudan, Igor, de Boer, Rudolf A, van der Meer, Peter, Yao, Jie, Guo, Xiuqing, Taylor, Kent D, Sotoodehnia, Nona, Rotter, Jerome I, Mook-Kanamori, Dennis O, Trompet, Stella, Rivadeneira, Fernando, Uitterlinden, André, Eijgelsheim, Mark, Padmanabhan, Sandosh, Smith, Blair H, Völzke, Henry, Felix, Stephan B, Homuth, Georg, Völker, Uwe, Mangino, Massimo, Spector, Timothy D, Bots, Michiel L, Perez, Marco, Kähönen, Mika, Raitakari, Olli T, Gudnason, Vilmundur, Arking, Dan E, Munroe, Patricia B, Psaty, Bruce M, van Duijn, Cornelia M, Benjamin, Emelia J, Rosand, Jonathan, Samani, Nilesh J, Hansen, Torben, Kääb, Stefan, Polasek, Ozren, van der Harst, Pim, Heckbert, Susan R, Jukema, J Wouter, Stricker, Bruno H, Hayward, Caroline, Dörr, Marcus, Jamshidi, Yalda, Asselbergs, Folkert W, Kooperberg, Charles, Lehtimäki, Terho, Wilson, James G, Ellinor, Patrick T, Lubitz, Steven A, and Isaacs, Aaron
Published: 2018

25. Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

Author: Lin, Honghuang, van Setten, Jessica, Smith, Albert V, Bihlmeyer, Nathan A, Warren, Helen R, Brody, Jennifer A, Radmanesh, Farid, Hall, Leanne, Grarup, Niels, Müller-Nurasyid, Martina, Boutin, Thibaud, Verweij, Niek, Lin, Henry J, Li-Gao, Ruifang, van den Berg, Marten E, Marten, Jonathan, Weiss, Stefan, Prins, Bram P, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Mei, Hao, Harris, Tamara B, Launer, Lenore J, Li, Man, Alonso, Alvaro, Soliman, Elsayed Z, Connell, John M, Huang, Paul L, Weng, Lu-Chen, Jameson, Heather S, Hucker, William, Hanley, Alan, Tucker, Nathan R, Chen, Yii-Der Ida, Bis, Joshua C, Rice, Kenneth M, Sitlani, Colleen M, Kors, Jan A, Xie, Zhijun, Wen, Chengping, Magnani, Jared W, Nelson, Christopher P, Kanters, Jørgen K, Sinner, Moritz F, Strauch, Konstantin, Peters, Annette, Waldenberger, Melanie, Meitinger, Thomas, Bork-Jensen, Jette, Pedersen, Oluf, Linneberg, Allan, Rudan, Igor, de Boer, Rudolf A, van der Meer, Peter, Yao, Jie, Guo, Xiuqing, Taylor, Kent D, Sotoodehnia, Nona, Rotter, Jerome I, Mook-Kanamori, Dennis O, Trompet, Stella, Rivadeneira, Fernando, Uitterlinden, André, Eijgelsheim, Mark, Padmanabhan, Sandosh, Smith, Blair H, Völzke, Henry, Felix, Stephan B, Homuth, Georg, Völker, Uwe, Mangino, Massimo, Spector, Timothy D, Bots, Michiel L, Perez, Marco, Kähönen, Mika, Raitakari, Olli T, Gudnason, Vilmundur, Arking, Dan E, Munroe, Patricia B, Psaty, Bruce M, van Duijn, Cornelia M, Benjamin, Emelia J, Rosand, Jonathan, Samani, Nilesh J, Hansen, Torben, Kääb, Stefan, Polasek, Ozren, van der Harst, Pim, Heckbert, Susan R, Jukema, J Wouter, Stricker, Bruno H, Hayward, Caroline, Dörr, Marcus, Jamshidi, Yalda, Asselbergs, Folkert W, Kooperberg, Charles, Lehtimäki, Terho, Wilson, James G, Ellinor, Patrick T, Lubitz, Steven A, Isaacs, Aaron, Lin, Honghuang, van Setten, Jessica, Smith, Albert V, Bihlmeyer, Nathan A, Warren, Helen R, Brody, Jennifer A, Radmanesh, Farid, Hall, Leanne, Grarup, Niels, Müller-Nurasyid, Martina, Boutin, Thibaud, Verweij, Niek, Lin, Henry J, Li-Gao, Ruifang, van den Berg, Marten E, Marten, Jonathan, Weiss, Stefan, Prins, Bram P, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Mei, Hao, Harris, Tamara B, Launer, Lenore J, Li, Man, Alonso, Alvaro, Soliman, Elsayed Z, Connell, John M, Huang, Paul L, Weng, Lu-Chen, Jameson, Heather S, Hucker, William, Hanley, Alan, Tucker, Nathan R, Chen, Yii-Der Ida, Bis, Joshua C, Rice, Kenneth M, Sitlani, Colleen M, Kors, Jan A, Xie, Zhijun, Wen, Chengping, Magnani, Jared W, Nelson, Christopher P, Kanters, Jørgen K, Sinner, Moritz F, Strauch, Konstantin, Peters, Annette, Waldenberger, Melanie, Meitinger, Thomas, Bork-Jensen, Jette, Pedersen, Oluf, Linneberg, Allan, Rudan, Igor, de Boer, Rudolf A, van der Meer, Peter, Yao, Jie, Guo, Xiuqing, Taylor, Kent D, Sotoodehnia, Nona, Rotter, Jerome I, Mook-Kanamori, Dennis O, Trompet, Stella, Rivadeneira, Fernando, Uitterlinden, André, Eijgelsheim, Mark, Padmanabhan, Sandosh, Smith, Blair H, Völzke, Henry, Felix, Stephan B, Homuth, Georg, Völker, Uwe, Mangino, Massimo, Spector, Timothy D, Bots, Michiel L, Perez, Marco, Kähönen, Mika, Raitakari, Olli T, Gudnason, Vilmundur, Arking, Dan E, Munroe, Patricia B, Psaty, Bruce M, van Duijn, Cornelia M, Benjamin, Emelia J, Rosand, Jonathan, Samani, Nilesh J, Hansen, Torben, Kääb, Stefan, Polasek, Ozren, van der Harst, Pim, Heckbert, Susan R, Jukema, J Wouter, Stricker, Bruno H, Hayward, Caroline, Dörr, Marcus, Jamshidi, Yalda, Asselbergs, Folkert W, Kooperberg, Charles, Lehtimäki, Terho, Wilson, James G, Ellinor, Patrick T, Lubitz, Steven A, and Isaacs, Aaron
Published: 2018

26. Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

Author: Lin, Honghuang, van Setten, Jessica, Smith, Albert V, Bihlmeyer, Nathan A, Warren, Helen R, Brody, Jennifer A, Radmanesh, Farid, Hall, Leanne, Grarup, Niels, Müller-Nurasyid, Martina, Boutin, Thibaud, Verweij, Niek, Lin, Henry J, Li-Gao, Ruifang, van den Berg, Marten E, Marten, Jonathan, Weiss, Stefan, Prins, Bram P, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Mei, Hao, Harris, Tamara B, Launer, Lenore J, Li, Man, Alonso, Alvaro, Soliman, Elsayed Z, Connell, John M, Huang, Paul L, Weng, Lu-Chen, Jameson, Heather S, Hucker, William, Hanley, Alan, Tucker, Nathan R, Chen, Yii-Der Ida, Bis, Joshua C, Rice, Kenneth M, Sitlani, Colleen M, Kors, Jan A, Xie, Zhijun, Wen, Chengping, Magnani, Jared W, Nelson, Christopher P, Kanters, Jørgen K, Sinner, Moritz F, Strauch, Konstantin, Peters, Annette, Waldenberger, Melanie, Meitinger, Thomas, Bork-Jensen, Jette, Pedersen, Oluf, Linneberg, Allan, Rudan, Igor, de Boer, Rudolf A, van der Meer, Peter, Yao, Jie, Guo, Xiuqing, Taylor, Kent D, Sotoodehnia, Nona, Rotter, Jerome I, Mook-Kanamori, Dennis O, Trompet, Stella, Rivadeneira, Fernando, Uitterlinden, André, Eijgelsheim, Mark, Padmanabhan, Sandosh, Smith, Blair H, Völzke, Henry, Felix, Stephan B, Homuth, Georg, Völker, Uwe, Mangino, Massimo, Spector, Timothy D, Bots, Michiel L, Perez, Marco, Kähönen, Mika, Raitakari, Olli T, Gudnason, Vilmundur, Arking, Dan E, Munroe, Patricia B, Psaty, Bruce M, van Duijn, Cornelia M, Benjamin, Emelia J, Rosand, Jonathan, Samani, Nilesh J, Hansen, Torben, Kääb, Stefan, Polasek, Ozren, van der Harst, Pim, Heckbert, Susan R, Jukema, J Wouter, Stricker, Bruno H, Hayward, Caroline, Dörr, Marcus, Jamshidi, Yalda, Asselbergs, Folkert W, Kooperberg, Charles, Lehtimäki, Terho, Wilson, James G, Ellinor, Patrick T, Lubitz, Steven A, Isaacs, Aaron, Lin, Honghuang, van Setten, Jessica, Smith, Albert V, Bihlmeyer, Nathan A, Warren, Helen R, Brody, Jennifer A, Radmanesh, Farid, Hall, Leanne, Grarup, Niels, Müller-Nurasyid, Martina, Boutin, Thibaud, Verweij, Niek, Lin, Henry J, Li-Gao, Ruifang, van den Berg, Marten E, Marten, Jonathan, Weiss, Stefan, Prins, Bram P, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Mei, Hao, Harris, Tamara B, Launer, Lenore J, Li, Man, Alonso, Alvaro, Soliman, Elsayed Z, Connell, John M, Huang, Paul L, Weng, Lu-Chen, Jameson, Heather S, Hucker, William, Hanley, Alan, Tucker, Nathan R, Chen, Yii-Der Ida, Bis, Joshua C, Rice, Kenneth M, Sitlani, Colleen M, Kors, Jan A, Xie, Zhijun, Wen, Chengping, Magnani, Jared W, Nelson, Christopher P, Kanters, Jørgen K, Sinner, Moritz F, Strauch, Konstantin, Peters, Annette, Waldenberger, Melanie, Meitinger, Thomas, Bork-Jensen, Jette, Pedersen, Oluf, Linneberg, Allan, Rudan, Igor, de Boer, Rudolf A, van der Meer, Peter, Yao, Jie, Guo, Xiuqing, Taylor, Kent D, Sotoodehnia, Nona, Rotter, Jerome I, Mook-Kanamori, Dennis O, Trompet, Stella, Rivadeneira, Fernando, Uitterlinden, André, Eijgelsheim, Mark, Padmanabhan, Sandosh, Smith, Blair H, Völzke, Henry, Felix, Stephan B, Homuth, Georg, Völker, Uwe, Mangino, Massimo, Spector, Timothy D, Bots, Michiel L, Perez, Marco, Kähönen, Mika, Raitakari, Olli T, Gudnason, Vilmundur, Arking, Dan E, Munroe, Patricia B, Psaty, Bruce M, van Duijn, Cornelia M, Benjamin, Emelia J, Rosand, Jonathan, Samani, Nilesh J, Hansen, Torben, Kääb, Stefan, Polasek, Ozren, van der Harst, Pim, Heckbert, Susan R, Jukema, J Wouter, Stricker, Bruno H, Hayward, Caroline, Dörr, Marcus, Jamshidi, Yalda, Asselbergs, Folkert W, Kooperberg, Charles, Lehtimäki, Terho, Wilson, James G, Ellinor, Patrick T, Lubitz, Steven A, and Isaacs, Aaron
Published: 2018

27. Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

Author: Onderzoek Precision medicine, Cardiovasculaire Epi Team 5, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Team Medisch, Lin, Honghuang, van Setten, Jessica, Smith, Albert V, Bihlmeyer, Nathan A, Warren, Helen R, Brody, Jennifer A, Radmanesh, Farid, Hall, Leanne, Grarup, Niels, Müller-Nurasyid, Martina, Boutin, Thibaud, Verweij, Niek, Lin, Henry J, Li-Gao, Ruifang, van den Berg, Marten E, Marten, Jonathan, Weiss, Stefan, Prins, Bram P, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Mei, Hao, Harris, Tamara B, Launer, Lenore J, Li, Man, Alonso, Alvaro, Soliman, Elsayed Z, Connell, John M, Huang, Paul L, Weng, Lu-Chen, Jameson, Heather S, Hucker, William, Hanley, Alan, Tucker, Nathan R, Chen, Yii-Der Ida, Bis, Joshua C, Rice, Kenneth M, Sitlani, Colleen M, Kors, Jan A, Xie, Zhijun, Wen, Chengping, Magnani, Jared W, Nelson, Christopher P, Kanters, Jørgen K, Sinner, Moritz F, Strauch, Konstantin, Peters, Annette, Waldenberger, Melanie, Meitinger, Thomas, Bork-Jensen, Jette, Pedersen, Oluf, Linneberg, Allan, Rudan, Igor, de Boer, Rudolf A, van der Meer, Peter, Yao, Jie, Guo, Xiuqing, Taylor, Kent D, Sotoodehnia, Nona, Rotter, Jerome I, Mook-Kanamori, Dennis O, Trompet, Stella, Rivadeneira, Fernando, Uitterlinden, André, Eijgelsheim, Mark, Padmanabhan, Sandosh, Smith, Blair H, Völzke, Henry, Felix, Stephan B, Homuth, Georg, Völker, Uwe, Mangino, Massimo, Spector, Timothy D, Bots, Michiel L, Perez, Marco, Kähönen, Mika, Raitakari, Olli T, Gudnason, Vilmundur, Arking, Dan E, Munroe, Patricia B, Psaty, Bruce M, van Duijn, Cornelia M, Benjamin, Emelia J, Rosand, Jonathan, Samani, Nilesh J, Hansen, Torben, Kääb, Stefan, Polasek, Ozren, van der Harst, Pim, Heckbert, Susan R, Jukema, J Wouter, Stricker, Bruno H, Hayward, Caroline, Dörr, Marcus, Jamshidi, Yalda, Asselbergs, Folkert W, Kooperberg, Charles, Lehtimäki, Terho, Wilson, James G, Ellinor, Patrick T, Lubitz, Steven A, Isaacs, Aaron, Onderzoek Precision medicine, Cardiovasculaire Epi Team 5, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Team Medisch, Lin, Honghuang, van Setten, Jessica, Smith, Albert V, Bihlmeyer, Nathan A, Warren, Helen R, Brody, Jennifer A, Radmanesh, Farid, Hall, Leanne, Grarup, Niels, Müller-Nurasyid, Martina, Boutin, Thibaud, Verweij, Niek, Lin, Henry J, Li-Gao, Ruifang, van den Berg, Marten E, Marten, Jonathan, Weiss, Stefan, Prins, Bram P, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Mei, Hao, Harris, Tamara B, Launer, Lenore J, Li, Man, Alonso, Alvaro, Soliman, Elsayed Z, Connell, John M, Huang, Paul L, Weng, Lu-Chen, Jameson, Heather S, Hucker, William, Hanley, Alan, Tucker, Nathan R, Chen, Yii-Der Ida, Bis, Joshua C, Rice, Kenneth M, Sitlani, Colleen M, Kors, Jan A, Xie, Zhijun, Wen, Chengping, Magnani, Jared W, Nelson, Christopher P, Kanters, Jørgen K, Sinner, Moritz F, Strauch, Konstantin, Peters, Annette, Waldenberger, Melanie, Meitinger, Thomas, Bork-Jensen, Jette, Pedersen, Oluf, Linneberg, Allan, Rudan, Igor, de Boer, Rudolf A, van der Meer, Peter, Yao, Jie, Guo, Xiuqing, Taylor, Kent D, Sotoodehnia, Nona, Rotter, Jerome I, Mook-Kanamori, Dennis O, Trompet, Stella, Rivadeneira, Fernando, Uitterlinden, André, Eijgelsheim, Mark, Padmanabhan, Sandosh, Smith, Blair H, Völzke, Henry, Felix, Stephan B, Homuth, Georg, Völker, Uwe, Mangino, Massimo, Spector, Timothy D, Bots, Michiel L, Perez, Marco, Kähönen, Mika, Raitakari, Olli T, Gudnason, Vilmundur, Arking, Dan E, Munroe, Patricia B, Psaty, Bruce M, van Duijn, Cornelia M, Benjamin, Emelia J, Rosand, Jonathan, Samani, Nilesh J, Hansen, Torben, Kääb, Stefan, Polasek, Ozren, van der Harst, Pim, Heckbert, Susan R, Jukema, J Wouter, Stricker, Bruno H, Hayward, Caroline, Dörr, Marcus, Jamshidi, Yalda, Asselbergs, Folkert W, Kooperberg, Charles, Lehtimäki, Terho, Wilson, James G, Ellinor, Patrick T, Lubitz, Steven A, and Isaacs, Aaron
Published: 2018

28. Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

Author: Lin, Honghuang, van Setten, Jessica, Smith, Albert V, Bihlmeyer, Nathan A, Warren, Helen R, Brody, Jennifer A, Radmanesh, Farid, Hall, Leanne, Grarup, Niels, Müller-Nurasyid, Martina, Boutin, Thibaud, Verweij, Niek, Lin, Henry J, Li-Gao, Ruifang, van den Berg, Marten E, Marten, Jonathan, Weiss, Stefan, Prins, Bram P, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Mei, Hao, Harris, Tamara B, Launer, Lenore J, Li, Man, Alonso, Alvaro, Soliman, Elsayed Z, Connell, John M, Huang, Paul L, Weng, Lu-Chen, Jameson, Heather S, Hucker, William, Hanley, Alan, Tucker, Nathan R, Chen, Yii-Der Ida, Bis, Joshua C, Rice, Kenneth M, Sitlani, Colleen M, Kors, Jan A, Xie, Zhijun, Wen, Chengping, Magnani, Jared W, Nelson, Christopher P, Kanters, Jørgen K., Sinner, Moritz F, Strauch, Konstantin, Peters, Annette, Waldenberger, Melanie, Meitinger, Thomas, Bork-Jensen, Jette, Pedersen, Oluf, Linneberg, Allan, Rudan, Igor, de Boer, Rudolf A, van der Meer, Peter, Yao, Jie, Guo, Xiuqing, Taylor, Kent D, Sotoodehnia, Nona, Rotter, Jerome I, Mook-Kanamori, Dennis O, Trompet, Stella, Rivadeneira, Fernando, Uitterlinden, André, Eijgelsheim, Mark, Padmanabhan, Sandosh, Smith, Blair H, Völzke, Henry, Felix, Stephan B, Homuth, Georg, Völker, Uwe, Mangino, Massimo, Spector, Timothy D, Bots, Michiel L, Perez, Marco, Kähönen, Mika, Raitakari, Olli T, Gudnason, Vilmundur, Arking, Dan E, Munroe, Patricia B, Psaty, Bruce M, van Duijn, Cornelia M, Benjamin, Emelia J, Rosand, Jonathan, Samani, Nilesh J, Hansen, Torben, Kääb, Stefan, Polasek, Ozren, van der Harst, Pim, Heckbert, Susan R, Jukema, J Wouter, Stricker, Bruno H, Hayward, Caroline, Dörr, Marcus, Jamshidi, Yalda, Asselbergs, Folkert W, Kooperberg, Charles, Lehtimäki, Terho, Wilson, James G, Ellinor, Patrick T, Lubitz, Steven A, Isaacs, Aaron, Lin, Honghuang, van Setten, Jessica, Smith, Albert V, Bihlmeyer, Nathan A, Warren, Helen R, Brody, Jennifer A, Radmanesh, Farid, Hall, Leanne, Grarup, Niels, Müller-Nurasyid, Martina, Boutin, Thibaud, Verweij, Niek, Lin, Henry J, Li-Gao, Ruifang, van den Berg, Marten E, Marten, Jonathan, Weiss, Stefan, Prins, Bram P, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Mei, Hao, Harris, Tamara B, Launer, Lenore J, Li, Man, Alonso, Alvaro, Soliman, Elsayed Z, Connell, John M, Huang, Paul L, Weng, Lu-Chen, Jameson, Heather S, Hucker, William, Hanley, Alan, Tucker, Nathan R, Chen, Yii-Der Ida, Bis, Joshua C, Rice, Kenneth M, Sitlani, Colleen M, Kors, Jan A, Xie, Zhijun, Wen, Chengping, Magnani, Jared W, Nelson, Christopher P, Kanters, Jørgen K., Sinner, Moritz F, Strauch, Konstantin, Peters, Annette, Waldenberger, Melanie, Meitinger, Thomas, Bork-Jensen, Jette, Pedersen, Oluf, Linneberg, Allan, Rudan, Igor, de Boer, Rudolf A, van der Meer, Peter, Yao, Jie, Guo, Xiuqing, Taylor, Kent D, Sotoodehnia, Nona, Rotter, Jerome I, Mook-Kanamori, Dennis O, Trompet, Stella, Rivadeneira, Fernando, Uitterlinden, André, Eijgelsheim, Mark, Padmanabhan, Sandosh, Smith, Blair H, Völzke, Henry, Felix, Stephan B, Homuth, Georg, Völker, Uwe, Mangino, Massimo, Spector, Timothy D, Bots, Michiel L, Perez, Marco, Kähönen, Mika, Raitakari, Olli T, Gudnason, Vilmundur, Arking, Dan E, Munroe, Patricia B, Psaty, Bruce M, van Duijn, Cornelia M, Benjamin, Emelia J, Rosand, Jonathan, Samani, Nilesh J, Hansen, Torben, Kääb, Stefan, Polasek, Ozren, van der Harst, Pim, Heckbert, Susan R, Jukema, J Wouter, Stricker, Bruno H, Hayward, Caroline, Dörr, Marcus, Jamshidi, Yalda, Asselbergs, Folkert W, Kooperberg, Charles, Lehtimäki, Terho, Wilson, James G, Ellinor, Patrick T, Lubitz, Steven A, and Isaacs, Aaron
Abstract: BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2×10-6), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9×10-11) and SCN5A (P=1.1×10-7) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus.CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.
Published: 2018

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

Author: Christophersen, Ingrid E., Rienstra, Michiel, Roselli, Carolina, Yin, Xiaoyan, Geelhoed, Bastiaan, Barnard, John, Lin, Honghuang, Arking, Dan E., Smith, Albert V., Albert, Christine M., Chaffin, Mark, Tucker, Nathan R., Li, Molong, Klarin, Derek, Bihlmeyer, Nathan A., Low, Siew-Kee, Weeke, Peter E., Mueller-Nurasyid, Martina, Smith, J. Gustav, Brody, Jennifer A., Niemeijer, Maartje N., Doerr, Marcus, Trompet, Stella, Huffman, Jennifer, Gustafsson, Stefan, Schurmann, Claudia, Kleber, Marcus E., Lyytikainen, Leo-Pekka, Seppala, Ilkka, Malik, Rainer, Horimoto, Andrea R. V. R., Perez, Marco, Sinisalo, Juha, Aeschbacher, Stefanie, Theriault, Sebastien, Yao, Jie, Radmanesh, Farid, Weiss, Stefan, Teumer, Alexander, Choi, Seung Hoan, Weng, Lu-Chen, Clauss, Sebastian, Deo, Rajat, Rader, Daniel J., Shah, Svati H., Sun, Albert, Hopewell, Jemma C., Debette, Stephanie, Chauhan, Ganesh, Yang, Qiong, Worrall, Bradford B., Pare, Guillaume, Kamatani, Yoichiro, Hagemeijer, Yanick P., Verweij, Niek, Siland, Joylene E., Kubo, Michiaki, Smith, Jonathan D., Van Wagoner, David R., Bis, Joshua C., Perz, Siegfried, Psaty, Bruce M., Ridker, Paul M., Magnani, Jared W., Harris, Tamara B., Launer, Lenore J., Shoemaker, M. Benjamin, Padmanabhan, Sandosh, Haessler, Jeffrey, Bartz, Traci M., Waldenberger, Melanie, Lichtner, Peter, Arendt, Marina, Krieger, Jose E., Kahonen, Mika, Risch, Lorenz, Mansur, Alfredo J., Peters, Annette, Smith, Blair H., Lind, Lars, Scott, Stuart A., Lu, Yingchang, Bottinger, Erwin B., Hernesniemi, Jussi, Lindgren, Cecilia M., Wong, Jorge A., Huang, Jie, Eskola, Markku, Morris, Andrew P., Ford, Ian, Reiner, Alex P., Delgado, Graciela, Chen, Lin Y., Chen, Yii-Der Ida, Sandhu, Roopinder K., Li, Man, Boerwinkle, Eric, Eisele, Lewin, Lannfelt, Lars, Rost, Natalia, Anderson, Christopher D., Taylor, Kent D., Campbell, Archie, Magnusson, Patrik K., Porteous, David, Hocking, Lynne J., Vlachopoulou, Efthymia, Pedersen, Nancy L., Nikus, Kjell, Orho-Melander, Marju, Hamsten, Anders, Heeringa, Jan, Denny, Joshua C., Kriebel, Jennifer, Darbar, Dawood, Newton-Cheh, Christopher, Shaffer, Christian, Macfarlane, Peter W., Heilmann-Heimbach, Stefanie, Almgren, Peter, Huang, Paul L., Sotoodehnia, Nona, Soliman, Elsayed Z., Uitterlinden, Andre G., Hofman, Albert, Franco, Oscar H., Voelker, Uwe, Joeckel, Karl-Heinz, Sinner, Moritz F., Lin, Henry J., Guo, Xiuqing, Dichgans, Martin, Ingelsson, Erik, Kooperberg, Charles, Melander, Olle, Loos, Ruth J. F., Laurikka, Jari, Conen, David, Rosand, Jonathan, van der Harst, Pim, Lokki, Marja-Liisa, Kathiresan, Sekar, Pereira, Alexandre, Jukema, J. Wouter, Hayward, Caroline, Rotter, Jerome I., Maerz, Winfried, Lehtimaki, Terho, Stricker, Bruno H., Chung, Mina K., Felix, Stephan B., Gudnason, Vilmundur, Alonso, Alvaro, Roden, Dan M., Kaeaeb, Stefan, Chasman, Daniel I., Heckbert, Susan R., Benjamin, Emelia J., Tanaka, Toshihiro, Lunetta, Kathryn L., Lubitz, Steven A., Ellinor, Patrick T., Christophersen, Ingrid E., Rienstra, Michiel, Roselli, Carolina, Yin, Xiaoyan, Geelhoed, Bastiaan, Barnard, John, Lin, Honghuang, Arking, Dan E., Smith, Albert V., Albert, Christine M., Chaffin, Mark, Tucker, Nathan R., Li, Molong, Klarin, Derek, Bihlmeyer, Nathan A., Low, Siew-Kee, Weeke, Peter E., Mueller-Nurasyid, Martina, Smith, J. Gustav, Brody, Jennifer A., Niemeijer, Maartje N., Doerr, Marcus, Trompet, Stella, Huffman, Jennifer, Gustafsson, Stefan, Schurmann, Claudia, Kleber, Marcus E., Lyytikainen, Leo-Pekka, Seppala, Ilkka, Malik, Rainer, Horimoto, Andrea R. V. R., Perez, Marco, Sinisalo, Juha, Aeschbacher, Stefanie, Theriault, Sebastien, Yao, Jie, Radmanesh, Farid, Weiss, Stefan, Teumer, Alexander, Choi, Seung Hoan, Weng, Lu-Chen, Clauss, Sebastian, Deo, Rajat, Rader, Daniel J., Shah, Svati H., Sun, Albert, Hopewell, Jemma C., Debette, Stephanie, Chauhan, Ganesh, Yang, Qiong, Worrall, Bradford B., Pare, Guillaume, Kamatani, Yoichiro, Hagemeijer, Yanick P., Verweij, Niek, Siland, Joylene E., Kubo, Michiaki, Smith, Jonathan D., Van Wagoner, David R., Bis, Joshua C., Perz, Siegfried, Psaty, Bruce M., Ridker, Paul M., Magnani, Jared W., Harris, Tamara B., Launer, Lenore J., Shoemaker, M. Benjamin, Padmanabhan, Sandosh, Haessler, Jeffrey, Bartz, Traci M., Waldenberger, Melanie, Lichtner, Peter, Arendt, Marina, Krieger, Jose E., Kahonen, Mika, Risch, Lorenz, Mansur, Alfredo J., Peters, Annette, Smith, Blair H., Lind, Lars, Scott, Stuart A., Lu, Yingchang, Bottinger, Erwin B., Hernesniemi, Jussi, Lindgren, Cecilia M., Wong, Jorge A., Huang, Jie, Eskola, Markku, Morris, Andrew P., Ford, Ian, Reiner, Alex P., Delgado, Graciela, Chen, Lin Y., Chen, Yii-Der Ida, Sandhu, Roopinder K., Li, Man, Boerwinkle, Eric, Eisele, Lewin, Lannfelt, Lars, Rost, Natalia, Anderson, Christopher D., Taylor, Kent D., Campbell, Archie, Magnusson, Patrik K., Porteous, David, Hocking, Lynne J., Vlachopoulou, Efthymia, Pedersen, Nancy L., Nikus, Kjell, Orho-Melander, Marju, Hamsten, Anders, Heeringa, Jan, Denny, Joshua C., Kriebel, Jennifer, Darbar, Dawood, Newton-Cheh, Christopher, Shaffer, Christian, Macfarlane, Peter W., Heilmann-Heimbach, Stefanie, Almgren, Peter, Huang, Paul L., Sotoodehnia, Nona, Soliman, Elsayed Z., Uitterlinden, Andre G., Hofman, Albert, Franco, Oscar H., Voelker, Uwe, Joeckel, Karl-Heinz, Sinner, Moritz F., Lin, Henry J., Guo, Xiuqing, Dichgans, Martin, Ingelsson, Erik, Kooperberg, Charles, Melander, Olle, Loos, Ruth J. F., Laurikka, Jari, Conen, David, Rosand, Jonathan, van der Harst, Pim, Lokki, Marja-Liisa, Kathiresan, Sekar, Pereira, Alexandre, Jukema, J. Wouter, Hayward, Caroline, Rotter, Jerome I., Maerz, Winfried, Lehtimaki, Terho, Stricker, Bruno H., Chung, Mina K., Felix, Stephan B., Gudnason, Vilmundur, Alonso, Alvaro, Roden, Dan M., Kaeaeb, Stefan, Chasman, Daniel I., Heckbert, Susan R., Benjamin, Emelia J., Tanaka, Toshihiro, Lunetta, Kathryn L., Lubitz, Steven A., and Ellinor, Patrick T.
Abstract: Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death(1,2). Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups(3-7). 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(8).
Published: 2017
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30. Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures

Author: Wang, Xinchen, Tucker, Nathan R., Rizki, Gizem, Mills, Robert, Krijger, Peter Hugo Lodewijk, de Wit, Elzo, Subramanian, Vidya, Bartell, Eric, Nguyen, Xinh Xinh, Ye, Jiangchuan, Leyton-Mange, Jordan, Dolmatova, Elena V., Harst, Pim Van Der, Laat, Wouter De, Ellinor, Patrick T., Newton-Cheh, Christopher, Milan, David J., Kellis, Manolis, Boyer, Laurie A., Wang, Xinchen, Tucker, Nathan R., Rizki, Gizem, Mills, Robert, Krijger, Peter Hugo Lodewijk, de Wit, Elzo, Subramanian, Vidya, Bartell, Eric, Nguyen, Xinh Xinh, Ye, Jiangchuan, Leyton-Mange, Jordan, Dolmatova, Elena V., Harst, Pim Van Der, Laat, Wouter De, Ellinor, Patrick T., Newton-Cheh, Christopher, Milan, David J., Kellis, Manolis, and Boyer, Laurie A.
Published: 2016

31. Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures

Author: Wang, Xinchen, Tucker, Nathan R, Rizki, Gizem, Mills, Robert, Krijger, Peter Hl, de Wit, Elzo, Subramanian, Vidya, Bartell, Eric, Nguyen, Xinh-Xinh, Ye, Jiangchuan, Leyton-Mange, Jordan, Dolmatova, Elena V, van der Harst, Pim, de Laat, Wouter, Ellinor, Patrick T, Newton-Cheh, Christopher, Milan, David J, Kellis, Manolis, Boyer, Laurie A, Wang, Xinchen, Tucker, Nathan R, Rizki, Gizem, Mills, Robert, Krijger, Peter Hl, de Wit, Elzo, Subramanian, Vidya, Bartell, Eric, Nguyen, Xinh-Xinh, Ye, Jiangchuan, Leyton-Mange, Jordan, Dolmatova, Elena V, van der Harst, Pim, de Laat, Wouter, Ellinor, Patrick T, Newton-Cheh, Christopher, Milan, David J, Kellis, Manolis, and Boyer, Laurie A
Abstract: Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these 'sub-threshold' signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mouse. Our work provides a general approach for improving the detection of novel loci associated with complex human traits.
Published: 2016

32. Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures

Author: Wang, Xinchen, Tucker, Nathan R., Rizki, Gizem, Mills, Robert, Krijger, Peter Hugo Lodewijk, de Wit, Elzo, Subramanian, Vidya, Bartell, Eric, Nguyen, Xinh Xinh, Ye, Jiangchuan, Leyton-Mange, Jordan, Dolmatova, Elena V., Harst, Pim Van Der, Laat, Wouter De, Ellinor, Patrick T., Newton-Cheh, Christopher, Milan, David J., Kellis, Manolis, Boyer, Laurie A., Wang, Xinchen, Tucker, Nathan R., Rizki, Gizem, Mills, Robert, Krijger, Peter Hugo Lodewijk, de Wit, Elzo, Subramanian, Vidya, Bartell, Eric, Nguyen, Xinh Xinh, Ye, Jiangchuan, Leyton-Mange, Jordan, Dolmatova, Elena V., Harst, Pim Van Der, Laat, Wouter De, Ellinor, Patrick T., Newton-Cheh, Christopher, Milan, David J., Kellis, Manolis, and Boyer, Laurie A.
Published: 2016

33. Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures

Author: Divisie Biomedische Genetica, Hubrecht Institute with UMC, Cancer, Wang, Xinchen, Tucker, Nathan R., Rizki, Gizem, Mills, Robert, Krijger, Peter Hugo Lodewijk, de Wit, Elzo, Subramanian, Vidya, Bartell, Eric, Nguyen, Xinh Xinh, Ye, Jiangchuan, Leyton-Mange, Jordan, Dolmatova, Elena V., Harst, Pim Van Der, Laat, Wouter De, Ellinor, Patrick T., Newton-Cheh, Christopher, Milan, David J., Kellis, Manolis, Boyer, Laurie A., Divisie Biomedische Genetica, Hubrecht Institute with UMC, Cancer, Wang, Xinchen, Tucker, Nathan R., Rizki, Gizem, Mills, Robert, Krijger, Peter Hugo Lodewijk, de Wit, Elzo, Subramanian, Vidya, Bartell, Eric, Nguyen, Xinh Xinh, Ye, Jiangchuan, Leyton-Mange, Jordan, Dolmatova, Elena V., Harst, Pim Van Der, Laat, Wouter De, Ellinor, Patrick T., Newton-Cheh, Christopher, Milan, David J., Kellis, Manolis, and Boyer, Laurie A.
Published: 2016

34. Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures

Author: Wang, Xinchen, Tucker, Nathan R, Rizki, Gizem, Mills, Robert, Krijger, Peter Hl, de Wit, Elzo, Subramanian, Vidya, Bartell, Eric, Nguyen, Xinh-Xinh, Ye, Jiangchuan, Leyton-Mange, Jordan, Dolmatova, Elena V, van der Harst, Pim, de Laat, Wouter, Ellinor, Patrick T, Newton-Cheh, Christopher, Milan, David J, Kellis, Manolis, Boyer, Laurie A, Wang, Xinchen, Tucker, Nathan R, Rizki, Gizem, Mills, Robert, Krijger, Peter Hl, de Wit, Elzo, Subramanian, Vidya, Bartell, Eric, Nguyen, Xinh-Xinh, Ye, Jiangchuan, Leyton-Mange, Jordan, Dolmatova, Elena V, van der Harst, Pim, de Laat, Wouter, Ellinor, Patrick T, Newton-Cheh, Christopher, Milan, David J, Kellis, Manolis, and Boyer, Laurie A
Abstract: Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these 'sub-threshold' signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mouse. Our work provides a general approach for improving the detection of novel loci associated with complex human traits.
Published: 2016

35. Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures

Author: Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Wang, Xinchen, Rizki, Gizem, Subramanian, Vidya, Bartell, Eric R., Kellis, Manolis, Boyer, Laurie, Mills, Robert, de Wit, Elzo, Nguyen, Xinh-Xinh, Ye, Jiangchuan, Leyton-Mange, Jordan, van der Harst, Pim, de Laat, Wouter, Newton-Cheh, Christopher, Tucker, Nathan R., Krijger, Peter H. L., Dolmatova, Elena V., Ellinor, Patrick T., Milan, David J., Boyer, Laurie Ann, Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Wang, Xinchen, Rizki, Gizem, Subramanian, Vidya, Bartell, Eric R., Kellis, Manolis, Boyer, Laurie, Mills, Robert, de Wit, Elzo, Nguyen, Xinh-Xinh, Ye, Jiangchuan, Leyton-Mange, Jordan, van der Harst, Pim, de Laat, Wouter, Newton-Cheh, Christopher, Tucker, Nathan R., Krijger, Peter H. L., Dolmatova, Elena V., Ellinor, Patrick T., Milan, David J., and Boyer, Laurie Ann
Abstract: Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these 'sub-threshold' signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mouse. Our work provides a general approach for improving the detection of novel loci associated with complex human traits.
Published: 2016

36. Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation

Author: Sinner, Moritz F, Tucker, Nathan R, Lunetta, Kathryn L, Ozaki, Kouichi, Smith, J Gustav, Trompet, Stella, Bis, Joshua C, Lin, Honghuang, Chung, Mina K, Nielsen, Jonas B, Lubitz, Steven A, Krijthe, Bouwe P, Magnani, Jared W, Ye, Jiangchuan, Gollob, Michael H, Tsunoda, Tatsuhiko, Müller-Nurasyid, Martina, Lichtner, Peter, Peters, Annette, Dolmatova, Elena, Kubo, Michiaki, Smith, Jonathan D, Psaty, Bruce M, Smith, Nicholas L, Jukema, J Wouter, Chasman, Daniel I, Albert, Christine M, Ebana, Yusuke, Furukawa, Tetsushi, Macfarlane, Peter W, Harris, Tamara B, Darbar, Dawood, Dörr, Marcus, Holst, Anders G, Svendsen, Jesper H, Hofman, Albert, Uitterlinden, Andre G, Gudnason, Vilmundur, Isobe, Mitsuaki, Malik, Rainer, Dichgans, Martin, Rosand, Jonathan, Van Wagoner, David R, Benjamin, Emelia J, Milan, David J, Melander, Olle, Heckbert, Susan R, Ford, Ian, Liu, Yongmei, Olesen, Morten S, Sinner, Moritz F, Tucker, Nathan R, Lunetta, Kathryn L, Ozaki, Kouichi, Smith, J Gustav, Trompet, Stella, Bis, Joshua C, Lin, Honghuang, Chung, Mina K, Nielsen, Jonas B, Lubitz, Steven A, Krijthe, Bouwe P, Magnani, Jared W, Ye, Jiangchuan, Gollob, Michael H, Tsunoda, Tatsuhiko, Müller-Nurasyid, Martina, Lichtner, Peter, Peters, Annette, Dolmatova, Elena, Kubo, Michiaki, Smith, Jonathan D, Psaty, Bruce M, Smith, Nicholas L, Jukema, J Wouter, Chasman, Daniel I, Albert, Christine M, Ebana, Yusuke, Furukawa, Tetsushi, Macfarlane, Peter W, Harris, Tamara B, Darbar, Dawood, Dörr, Marcus, Holst, Anders G, Svendsen, Jesper H, Hofman, Albert, Uitterlinden, Andre G, Gudnason, Vilmundur, Isobe, Mitsuaki, Malik, Rainer, Dichgans, Martin, Rosand, Jonathan, Van Wagoner, David R, Benjamin, Emelia J, Milan, David J, Melander, Olle, Heckbert, Susan R, Ford, Ian, Liu, Yongmei, and Olesen, Morten S
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 [CI], 1.13-1.23; P=6.5×10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10(-19)), GJA1 (P=2.66×10(-6)), and TBX5 (P=1.36×10(-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.
Published: 2014

37. Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation

Author: Sinner, Moritz F, Tucker, Nathan R, Lunetta, Kathryn L, Ozaki, Kouichi, Smith, J Gustav, Trompet, Stella, Bis, Joshua C, Lin, Honghuang, Chung, Mina K, Nielsen, Jonas B, Lubitz, Steven A, Krijthe, Bouwe P, Magnani, Jared W, Ye, Jiangchuan, Gollob, Michael H, Tsunoda, Tatsuhiko, Müller-Nurasyid, Martina, Lichtner, Peter, Peters, Annette, Dolmatova, Elena, Kubo, Michiaki, Smith, Jonathan D, Psaty, Bruce M, Smith, Nicholas L, Jukema, J Wouter, Chasman, Daniel I, Albert, Christine M, Ebana, Yusuke, Furukawa, Tetsushi, Macfarlane, Peter W, Harris, Tamara B, Darbar, Dawood, Dörr, Marcus, Holst, Anders G, Svendsen, Jesper H, Hofman, Albert, Uitterlinden, Andre G, Gudnason, Vilmundur, Isobe, Mitsuaki, Malik, Rainer, Dichgans, Martin, Rosand, Jonathan, Van Wagoner, David R, Benjamin, Emelia J, Milan, David J, Melander, Olle, Heckbert, Susan R, Ford, Ian, Liu, Yongmei, Olesen, Morten S, Sinner, Moritz F, Tucker, Nathan R, Lunetta, Kathryn L, Ozaki, Kouichi, Smith, J Gustav, Trompet, Stella, Bis, Joshua C, Lin, Honghuang, Chung, Mina K, Nielsen, Jonas B, Lubitz, Steven A, Krijthe, Bouwe P, Magnani, Jared W, Ye, Jiangchuan, Gollob, Michael H, Tsunoda, Tatsuhiko, Müller-Nurasyid, Martina, Lichtner, Peter, Peters, Annette, Dolmatova, Elena, Kubo, Michiaki, Smith, Jonathan D, Psaty, Bruce M, Smith, Nicholas L, Jukema, J Wouter, Chasman, Daniel I, Albert, Christine M, Ebana, Yusuke, Furukawa, Tetsushi, Macfarlane, Peter W, Harris, Tamara B, Darbar, Dawood, Dörr, Marcus, Holst, Anders G, Svendsen, Jesper H, Hofman, Albert, Uitterlinden, Andre G, Gudnason, Vilmundur, Isobe, Mitsuaki, Malik, Rainer, Dichgans, Martin, Rosand, Jonathan, Van Wagoner, David R, Benjamin, Emelia J, Milan, David J, Melander, Olle, Heckbert, Susan R, Ford, Ian, Liu, Yongmei, and Olesen, Morten S
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 [CI], 1.13-1.23; P=6.5×10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10(-19)), GJA1 (P=2.66×10(-6)), and TBX5 (P=1.36×10(-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.
Published: 2014

38. Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels

Author: O' Brien, Sian, Holmes, Andrew P., Johnson, Daniel M., Kabir, S. Nashitha, O' Shea, Christopher, O' Reilly, Molly, Avezzu, Adelisa, Reyat, Jasmeet S., Hall, Amelia W., Apicella, Clara, Ellinor, Patrick T., Niederer, Steven, Tucker, Nathan R., Fabritz, Larissa, Kirchhof, Paulus, Pavlovic, Davor, O' Brien, Sian, Holmes, Andrew P., Johnson, Daniel M., Kabir, S. Nashitha, O' Shea, Christopher, O' Reilly, Molly, Avezzu, Adelisa, Reyat, Jasmeet S., Hall, Amelia W., Apicella, Clara, Ellinor, Patrick T., Niederer, Steven, Tucker, Nathan R., Fabritz, Larissa, Kirchhof, Paulus, and Pavlovic, Davor
Abstract: Atrial fibrillation (AF) affects over 1% of the population and is a leading cause of stroke and heart failure in the elderly. A feared side effect of sodium channel blocker therapy, ventricular pro-arrhythmia, appears to be relatively rare in patients with AF. The biophysical reasons for this relative safety of sodium blockers are not known. Our data demonstrates intrinsic differences between atrial and ventricular cardiac voltage-gated sodium currents (INa), leading to reduced maximum upstroke velocity of action potential and slower conduction, in left atria compared to ventricle. Reduced atrial INa is only detected at physiological membrane potentials and is driven by alterations in sodium channel biophysical properties and not by NaV1.5 protein expression. Flecainide displayed greater inhibition of atrial INa, greater reduction of maximum upstroke velocity of action potential, and slowed conduction in atrial cells and tissue. Our work highlights differences in biophysical properties of sodium channels in left atria and ventricles and their response to flecainide. These differences can explain the relative safety of sodium channel blocker therapy in patients with atrial fibrillation.

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