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15 results on '"Roden, Dan M."'

3. Determinants of mosaic chromosomal alteration fitness

Author

Pershad, Yash, Mack, Taralynn, Poisner, Hannah, Jakubek, Yasminka A., Stilp, Adrienne M., Mitchell, Braxton D., Lewis, Joshua P., Boerwinkle, Eric, Loos, Ruth J. F., Chami, Nathalie, Wang, Zhe, Barnes, Kathleen, Pankratz, Nathan, Fornage, Myriam, Redline, Susan, Psaty, Bruce M., Bis, Joshua C., Shojaie, Ali, Silverman, Edwin K., Cho, Michael H., Yun, Jeong H., DeMeo, Dawn, Levy, Daniel, Johnson, Andrew D., Mathias, Rasika A., Taub, Margaret A., Arnett, Donna, North, Kari E., Raffield, Laura M., Carson, April P., Doyle, Margaret F., Rich, Stephen S., Rotter, Jerome I., Guo, Xiuqing, Cox, Nancy J., Roden, Dan M., Franceschini, Nora, Desai, Pinkal, Reiner, Alex P., Auer, Paul L., Scheet, Paul A., Jaiswal, Siddhartha, Weinstock, Joshua S., and Bick, Alexander G.

Published
2024
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4. Clinical associations with a polygenic predisposition to benign lower white blood cell counts

Author

Mosley, Jonathan D., Shelley, John P., Dickson, Alyson L., Zanussi, Jacy, Daniel, Laura L., Zheng, Neil S., Bastarache, Lisa, Wei, Wei-Qi, Shi, Mingjian, Jarvik, Gail P., Rosenthal, Elisabeth A., Khan, Atlas, Sherafati, Alborz, Kullo, Iftikhar J., Walunas, Theresa L., Glessner, Joseph, Hakonarson, Hakon, Cox, Nancy J., Roden, Dan M., Frangakis, Stephan G., Vanderwerff, Brett, Stein, C. Michael, Van Driest, Sara L., Borinstein, Scott C., Shu, Xiao-Ou, Zawistowski, Matthew, Chung, Cecilia P., and Kawai, Vivian K.

Published
2024
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5. Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets

Author

Haas, Kelsey M, McGregor, Michael J, Bouhaddou, Mehdi, Polacco, Benjamin J, Kim, Eun-Young, Nguyen, Thong T, Newton, Billy W, Urbanowski, Matthew, Kim, Heejin, Williams, Michael AP, Rezelj, Veronica V, Hardy, Alexandra, Fossati, Andrea, Stevenson, Erica J, Sukerman, Ellie, Kim, Tiffany, Penugonda, Sudhir, Moreno, Elena, Braberg, Hannes, Zhou, Yuan, Metreveli, Giorgi, Harjai, Bhavya, Tummino, Tia A, Melnyk, James E, Soucheray, Margaret, Batra, Jyoti, Pache, Lars, Martin-Sancho, Laura, Carlson-Stevermer, Jared, Jureka, Alexander S, Basler, Christopher F, Shokat, Kevan M, Shoichet, Brian K, Shriver, Leah P, Johnson, Jeffrey R, Shaw, Megan L, Chanda, Sumit K, Roden, Dan M, Carter, Tonia C, Kottyan, Leah C, Chisholm, Rex L, Pacheco, Jennifer A, Smith, Maureen E, Schrodi, Steven J, Albrecht, Randy A, Vignuzzi, Marco, Zuliani-Alvarez, Lorena, Swaney, Danielle L, Eckhardt, Manon, Wolinsky, Steven M, White, Kris M, Hultquist, Judd F, Kaake, Robyn M, García-Sastre, Adolfo, and Krogan, Nevan J

Subjects
Microbiology, Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Infectious Diseases, Prevention, Emerging Infectious Diseases, Vaccine Related, Influenza, Pneumonia & Influenza, Biodefense, Biotechnology, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Aetiology, Infection, Humans, Influenza A virus, Influenza, Human, Influenza A Virus, H5N1 Subtype, Influenza A Virus, H3N2 Subtype, Proteomics, Virus Replication, COVID-19, SARS-CoV-2, Antiviral Agents, Host-Pathogen Interactions
Abstract

Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

Published
2023

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 M, Fabiola, Foco, Luisa, Gögele, Martin, Hicks, Andrew A, Cook, James P, Lind, Lars, Lindgren, Cecilia M, Sundström, Johan, Nelson, Christopher P, Riaz, Muhammad B, Samani, Nilesh J, Sinagra, Gianfranco, Ulivi, Sheila, Kähönen, Mika, Mishra, Pashupati P, Mononen, Nina, Nikus, Kjell, Caulfield, Mark J, Dominiczak, Anna, Padmanabhan, Sandosh, Montasser, May E, O'Connell, Jeff R, Ryan, Kathleen, Shuldiner, Alan R, Aeschbacher, Stefanie, Conen, David, Risch, Lorenz, Thériault, Sébastien, Hutri-Kähönen, Nina, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Raitakari, Olli T, Barnes, Catriona LK, Campbell, Harry, Joshi, Peter K, Wilson, James F, Isaacs, Aaron, Kors, Jan A, van Duijn, Cornelia M, Huang, Paul L, Gudnason, Vilmundur, Harris, Tamara B, Launer, Lenore J, Smith, Albert V, Bottinger, Erwin P, Loos, Ruth JF, Nadkarni, Girish N, Preuss, Michael H, Correa, Adolfo, Mei, Hao, Wilson, James, Meitinger, Thomas, Müller-Nurasyid, Martina, Peters, Annette, Waldenberger, Melanie, Mangino, Massimo, Spector, Timothy D, Rienstra, Michiel, van de Vegte, Yordi J, van der Harst, Pim, Verweij, Niek, Kääb, Stefan, Schramm, Katharina, Sinner, Moritz F, Strauch, Konstantin, Cutler, Michael J, Fatkin, Diane, London, Barry, Olesen, Morten, and Roden, Dan M

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

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

Published
2020

10. Identifying genetically driven clinical phenotypes using linear mixed models.

Author

Mosley, Jonathan D, Witte, John S, Larkin, Emma K, Bastarache, Lisa, Shaffer, Christian M, Karnes, Jason H, Stein, C Michael, Phillips, Elizabeth, Hebbring, Scott J, Brilliant, Murray H, Mayer, John, Ye, Zhan, Roden, Dan M, and Denny, Joshua C

Subjects
Humans, Disease, Genetic Predisposition to Disease, HLA Antigens, Genotype, Phenotype, Polymorphism, Single Nucleotide, Models, Genetic, Adult, Aged, Aged, 80 and over, Middle Aged, European Continental Ancestry Group, Female, Male, Genetic Variation, Genome-Wide Association Study, Exome, and over, Models, Genetic, Polymorphism, Single Nucleotide
Abstract

We hypothesized that generalized linear mixed models (GLMMs), which estimate the additive genetic variance underlying phenotype variability, would facilitate rapid characterization of clinical phenotypes from an electronic health record. We evaluated 1,288 phenotypes in 29,349 subjects of European ancestry with single-nucleotide polymorphism (SNP) genotyping on the Illumina Exome Beadchip. We show that genetic liability estimates are primarily driven by SNPs identified by prior genome-wide association studies and SNPs within the human leukocyte antigen (HLA) region. We identify 44 (false discovery rate q

Published
2016

11. A study paradigm integrating prospective epidemiologic cohorts and electronic health records to identify disease biomarkers

Author

Mosley, Jonathan D., primary, Feng, QiPing, additional, Wells, Quinn S., additional, Van Driest, Sara L., additional, Shaffer, Christian M., additional, Edwards, Todd L., additional, Bastarache, Lisa, additional, Wei, Wei-Qi, additional, Davis, Lea K., additional, McCarty, Catherine A., additional, Thompson, Will, additional, Chute, Christopher G., additional, Jarvik, Gail P., additional, Gordon, Adam S., additional, Palmer, Melody R., additional, Crosslin, David R., additional, Larson, Eric B., additional, Carrell, David S., additional, Kullo, Iftikhar J., additional, Pacheco, Jennifer A., additional, Peissig, Peggy L., additional, Brilliant, Murray H., additional, Linneman, James G., additional, Namjou, Bahram, additional, Williams, Marc S., additional, Ritchie, Marylyn D., additional, Borthwick, Kenneth M., additional, Verma, Shefali S., additional, Karnes, Jason H., additional, Weiss, Scott T., additional, Wang, Thomas J., additional, Stein, C. Michael, additional, Denny, Josh C., additional, and Roden, Dan M., additional

Published
2018
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12. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

van Setten, Jessica, primary, Brody, Jennifer A., additional, Jamshidi, Yalda, additional, Swenson, Brenton R., additional, Butler, Anne M., additional, Campbell, Harry, additional, Del Greco, Fabiola M., additional, Evans, Daniel S., additional, Gibson, Quince, additional, Gudbjartsson, Daniel F., additional, Kerr, Kathleen F., additional, Krijthe, Bouwe P., additional, Lyytikäinen, Leo-Pekka, additional, Müller, Christian, additional, Müller-Nurasyid, Martina, additional, Nolte, Ilja M., additional, Padmanabhan, Sandosh, additional, Ritchie, Marylyn D., additional, Robino, Antonietta, additional, Smith, Albert V., additional, Steri, Maristella, additional, Tanaka, Toshiko, additional, Teumer, Alexander, additional, Trompet, Stella, additional, Ulivi, Sheila, additional, Verweij, Niek, additional, Yin, Xiaoyan, additional, Arnar, David O., additional, Asselbergs, Folkert W., additional, Bader, Joel S., additional, Barnard, John, additional, Bis, Josh, additional, Blankenberg, Stefan, additional, Boerwinkle, Eric, additional, Bradford, Yuki, additional, Buckley, Brendan M., additional, Chung, Mina K., additional, Crawford, Dana, additional, den Hoed, Marcel, additional, Denny, Josh C., additional, Dominiczak, Anna F., additional, Ehret, Georg B., additional, Eijgelsheim, Mark, additional, Ellinor, Patrick T., additional, Felix, Stephan B., additional, Franco, Oscar H., additional, Franke, Lude, additional, Harris, Tamara B., additional, Holm, Hilma, additional, Ilaria, Gandin, additional, Iorio, Annamaria, additional, Kähönen, Mika, additional, Kolcic, Ivana, additional, Kors, Jan A., additional, Lakatta, Edward G., additional, Launer, Lenore J., additional, Lin, Honghuang, additional, Lin, Henry J., additional, Loos, Ruth J. F., additional, Lubitz, Steven A., additional, Macfarlane, Peter W., additional, Magnani, Jared W., additional, Leach, Irene Mateo, additional, Meitinger, Thomas, additional, Mitchell, Braxton D., additional, Munzel, Thomas, additional, Papanicolaou, George J., additional, Peters, Annette, additional, Pfeufer, Arne, additional, Pramstaller, Peter P., additional, Raitakari, Olli T., additional, Rotter, Jerome I., additional, Rudan, Igor, additional, Samani, Nilesh J., additional, Schlessinger, David, additional, Silva Aldana, Claudia T., additional, Sinner, Moritz F., additional, Smith, Jonathan D., additional, Snieder, Harold, additional, Soliman, Elsayed Z., additional, Spector, Timothy D., additional, Stott, David J., additional, Strauch, Konstantin, additional, Tarasov, Kirill V., additional, Thorsteinsdottir, Unnur, additional, Uitterlinden, Andre G., additional, Van Wagoner, David R., additional, Völker, Uwe, additional, Völzke, Henry, additional, Waldenberger, Melanie, additional, Jan Westra, Harm, additional, Wild, Philipp S., additional, Zeller, Tanja, additional, Alonso, Alvaro, additional, Avery, Christy L., additional, Bandinelli, Stefania, additional, Benjamin, Emelia J., additional, Cucca, Francesco, additional, Dörr, Marcus, additional, Ferrucci, Luigi, additional, Gasparini, Paolo, additional, Gudnason, Vilmundur, additional, Hayward, Caroline, additional, Heckbert, Susan R., additional, Hicks, Andrew A., additional, Jukema, J. Wouter, additional, Kääb, Stefan, additional, Lehtimäki, Terho, additional, Liu, Yongmei, additional, Munroe, Patricia B., additional, Parsa, Afshin, additional, Polasek, Ozren, additional, Psaty, Bruce M., additional, Roden, Dan M., additional, Schnabel, Renate B., additional, Sinagra, Gianfranco, additional, Stefansson, Kari, additional, Stricker, Bruno H., additional, van der Harst, Pim, additional, van Duijn, Cornelia M., additional, Wilson, James F., additional, Gharib, Sina A., additional, de Bakker, Paul I. W., additional, Isaacs, Aaron, additional, Arking, Dan E., additional, and Sotoodehnia, Nona, additional

Published
2018
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13. KCNE1 induces fenestration in the Kv7.1/KCNE1 channel complex that allows for highly specific pharmacological targeting

Author

Wrobel, Eva, primary, Rothenberg, Ina, additional, Krisp, Christoph, additional, Hundt, Franziska, additional, Fraenzel, Benjamin, additional, Eckey, Karina, additional, Linders, Joannes T. M., additional, Gallacher, David J., additional, Towart, Rob, additional, Pott, Lutz, additional, Pusch, Michael, additional, Yang, Tao, additional, Roden, Dan M., additional, Kurata, Harley T., additional, Schulze-Bahr, Eric, additional, Strutz-Seebohm, Nathalie, additional, Wolters, Dirk, additional, and Seebohm, Guiscard, additional

Published
2016
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14. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author

Bruno H. Stricker, Antonietta Robino, Gandin Ilaria, Marylyn D. Ritchie, Mark Eijgelsheim, Hilma Holm, Marcus Dörr, Philipp S. Wild, Jessica van Setten, Stephan B. Felix, Maristella Steri, Jared W. Magnani, Brendan M. Buckley, Peter P. Pramstaller, Claudia T. Silva Aldana, Niek Verweij, Tim D. Spector, Ruth J. F. Loos, Dan M. Roden, Martina Müller-Nurasyid, Mina K. Chung, Sandosh Padmanabhan, Stefania Bandinelli, Harm-Jan Westra, James F. Wilson, Honghuang Lin, Braxton D. Mitchell, Patrick T. Ellinor, Patricia B. Munroe, Harold Snieder, Thomas Münzel, Sheila Ulivi, Andrew A. Hicks, Nona Sotoodehnia, Daniel S. Evans, Annamaria Iorio, Peter W. Macfarlane, Vilmundur Gudnason, Christy L. Avery, Caroline Hayward, Cornelia M. van Duijn, John Barnard, Alvaro Alonso, Dana C. Crawford, Uwe Völker, David R. Van Wagoner, Tamara B. Harris, Harry Campbell, Ozren Polasek, Daniel F. Gudbjartsson, Ilja M. Nolte, Bouwe P. Krijthe, Eric Boerwinkle, Moritz F. Sinner, Elsayed Z. Soliman, Mika Kähönen, Christian Müller, Renate B. Schnabel, Unnur Thorsteinsdottir, Leo-Pekka Lyytikäinen, George J. Papanicolaou, Ivana Kolcic, Stella Trompet, Jerome I. Rotter, Dan E. Arking, Kirill V. Tarasov, Igor Rudan, Bruce M. Psaty, Gianfranco Sinagra, Alexander Teumer, Yalda Jamshidi, David O. Arnar, Toshiko Tanaka, Melanie Waldenberger, Henry J. Lin, Luigi Ferrucci, Susan R. Heckbert, Jan A. Kors, Irene Mateo Leach, Joel S. Bader, Konstantin Strauch, Albert V. Smith, Paul I.W. de Bakker, Stefan Blankenberg, J. C. Bis, Edward G. Lakatta, Lenore J. Launer, Thomas Meitinger, Anna F. Dominiczak, Marcel den Hoed, Steven A. Lubitz, Stefan Kääb, David J. Stott, Francesco Cucca, Olli T. Raitakari, Afshin Parsa, Nilesh J. Samani, Josh C. Denny, Lude Franke, Oscar H. Franco, Yongmei Liu, Folkert W. Asselbergs, Henry Völzke, Terho Lehtimäki, Arne Pfeufer, Annette Peters, David Schlessinger, Xiaoyan Yin, Jennifer A. Brody, J. Wouter Jukema, Paolo Gasparini, Tanja Zeller, Aaron Isaacs, Anne M. Butler, Sina A. Gharib, Kathleen F. Kerr, Jonathan D. Smith, Pim van der Harst, André G. Uitterlinden, Quince Gibson, Yuki Bradford, Brenton R. Swenson, Emelia J. Benjamin, Georg Ehret, Kari Stefansson, Fabiola M. Del Greco, Biochemie, RS: CARIM - R1.01 - Blood proteins & engineering, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, RS: FHML MaCSBio, van Setten, Jessica, Brody, Jennifer A, Jamshidi, Yalda, Swenson, Brenton R, Butler, Anne M, Campbell, Harry, Del Greco, Fabiola M, Evans, Daniel S, Gibson, Quince, Gudbjartsson, Daniel F, Kerr, Kathleen F, Krijthe, Bouwe P, Lyytikäinen, Leo-Pekka, Müller, Christian, Müller-Nurasyid, Martina, Nolte, Ilja M, Padmanabhan, Sandosh, Ritchie, Marylyn D, Robino, Antonietta, Smith, Albert V, Steri, Maristella, Tanaka, Toshiko, Teumer, Alexander, Trompet, Stella, Ulivi, Sheila, Verweij, Niek, Yin, Xiaoyan, Arnar, David O, Asselbergs, Folkert W, Bader, Joel S, Barnard, John, Bis, Josh, Blankenberg, Stefan, Boerwinkle, Eric, Bradford, Yuki, Buckley, Brendan M, Chung, Mina K, Crawford, Dana, den Hoed, Marcel, Denny, Josh C, Dominiczak, Anna F, Ehret, Georg B, Eijgelsheim, Mark, Ellinor, Patrick T, Felix, Stephan B, Franco, Oscar H, Franke, Lude, Harris, Tamara B, Holm, Hilma, Gandin, Ilaria, Iorio, Annamaria, Kähönen, Mika, Kolcic, Ivana, Kors, Jan A, Lakatta, Edward G, Launer, Lenore J, Lin, Honghuang, Lin, Henry J, Loos, Ruth J F, Lubitz, Steven A, Macfarlane, Peter W, Magnani, Jared W, Leach, Irene Mateo, Meitinger, Thoma, Mitchell, Braxton D, Munzel, Thoma, Papanicolaou, George J, Peters, Annette, Pfeufer, Arne, Pramstaller, Peter P, Raitakari, Olli T, Rotter, Jerome I, Rudan, Igor, Samani, Nilesh J, Schlessinger, David, Silva Aldana, Claudia T, Sinner, Moritz F, Smith, Jonathan D, Snieder, Harold, Soliman, Elsayed Z, Spector, Timothy D, Stott, David J, Strauch, Konstantin, Tarasov, Kirill V, Thorsteinsdottir, Unnur, Uitterlinden, Andre G, Van Wagoner, David R, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Jan Westra, Harm, Wild, Philipp S, Zeller, Tanja, Alonso, Alvaro, Avery, Christy L, Bandinelli, Stefania, Benjamin, Emelia J, Cucca, Francesco, Dörr, Marcu, Ferrucci, Luigi, Gasparini, Paolo, Gudnason, Vilmundur, Hayward, Caroline, Heckbert, Susan R, Hicks, Andrew A, Jukema, J Wouter, Kääb, Stefan, Lehtimäki, Terho, Liu, Yongmei, Munroe, Patricia B, Parsa, Afshin, Polasek, Ozren, Psaty, Bruce M, Roden, Dan M, Schnabel, Renate B, Sinagra, Gianfranco, Stefansson, Kari, Stricker, Bruno H, van der Harst, Pim, van Duijn, Cornelia M, Wilson, James F, Gharib, Sina A, de Bakker, Paul I W, Isaacs, Aaron, Arking, Dan E, Sotoodehnia, Nona, Faculty of Medicine (UI), Læknadeild (HÍ), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Epidemiology, Medical Informatics, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
Male, QRS duration, Epidemiology, Genome-wide association study, Biochemistry, Linkage Disequilibrium, Electrocardiography, 0302 clinical medicine, Atrioventricular Conduction, lcsh:Science, COMMON VARIANTS, Heart Depolarization, Canal de iones, Cardiovascular system, Gene Locus, Blood, cardiovascular system, Qrs Interval, FIBRILLATION, Enfermedades cardiovasculares, Human, Missense Mutation, Heart block, Science, HEART-RATE, Single-nucleotide polymorphism, Missense/genetics, Physics and Astronomy(all), Factor de transcripción, European, General Biochemistry, Genetics and Molecular Biology, Article, PR interval genome, atrial electrical activity, atrioventricular electrical activity, 03 medical and health sciences, CARDIAC CONDUCTION, Cardiac conduction, Humans, Sistema cardiovascular, Common variants, Sangre, Cardiovascular genetics, medicine.disease, Heart-rate, Enfermedades, Electrophysiological Phenomena, 030104 developmental biology, Heart Block, Electric Activity, Mutation, lcsh:Q, Cell Junction, Cohorts, Meta-Analysis, 0301 basic medicine, Chemistry(all), Transcription Factor, General Physics and Astronomy, 030204 cardiovascular system & hematology, Fibrilación auricular, Electrophysiological Phenomena/genetics, RARE, Ion Channel, Heart Rate, Risk Factors, Atrial Fibrillation, EPIDEMIOLOGY, Bloqueo cardíaco, SNPS, Genetics, RISK, Multidisciplinary, Genome, Atrial fibrillation, Genetic Analysis, Atrioventricular Node/physiology, Atrial Function, Phenotype, Heart Disease, Rare, Atrioventricular Node, Female, medicine.symptom, QRS DURATION, Atrial Function/physiology, Medical Genetics, SNPs, Signal Transduction, Risk, Heart Diseases, Mutation, Missense, macromolecular substances, Biology, QRS complex, medicine, Disequilibrium, Linkage Disequilibrium/genetics, cardiovascular diseases, PR interval, Medicinsk genetik, Fibrillation, Biochemistry, Genetics and Molecular Biology(all), Risk Factor, African, General Chemistry, COHORTS, Pr Interval, Gene Linkage Disequilibrium, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein). Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations., Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development., Acknowledgements per cohort are listed in Supplementary Note 2. We thank the following studies for sharing their summary level results: QRS voltage (van der Harst et al., 2016)[12], heart rate (den Hoed et al., 2013)[35], RR interval (Eijgelsheim et al., 2010)[11], atrial fibrillation (Christophersen et al., 2017[15]), and CARe-COGENT AA PR Consortium (Butler et al., 2012)[33]. We acknowledge Dr. Vinicius Tragante for his help generating the author list.

Published
2018
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15. ParSE-seq: a calibrated multiplexed assay to facilitate the clinical classification of putative splice-altering variants.

Author

O'Neill MJ, Yang T, Laudeman J, Calandranis ME, Harvey ML, Solus JF, Roden DM, and Glazer AM

Subjects
Humans, Arrhythmias, Cardiac genetics, RNA Splice Sites genetics, CRISPR-Cas Systems genetics, Calibration, High-Throughput Nucleotide Sequencing methods, Genetic Variation, Introns genetics, HEK293 Cells, Induced Pluripotent Stem Cells metabolism, Myocytes, Cardiac metabolism, Myocytes, Cardiac cytology, RNA Splicing genetics, NAV1.5 Voltage-Gated Sodium Channel genetics, NAV1.5 Voltage-Gated Sodium Channel metabolism
Abstract

Interpreting the clinical significance of putative splice-altering variants outside canonical splice sites remains difficult without time-intensive experimental studies. To address this, we introduce Parallel Splice Effect Sequencing (ParSE-seq), a multiplexed assay to quantify variant effects on RNA splicing. We first apply this technique to study hundreds of variants in the arrhythmia-associated gene SCN5A. Variants are studied in 'minigene' plasmids with molecular barcodes to allow pooled variant effect quantification. We perform experiments in two cell types, including disease-relevant induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The assay strongly separates known control variants from ClinVar, enabling quantitative calibration of the ParSE-seq assay. Using these evidence strengths and experimental data, we reclassify 29 of 34 variants with conflicting interpretations and 11 of 42 variants of uncertain significance. In addition to intronic variants, we show that many synonymous and missense variants disrupted RNA splicing. Two splice-altering variants in the assay also disrupt splicing and sodium current when introduced into iPSC-CMs by CRISPR-Cas9 editing. ParSE-seq provides high-throughput experimental data for RNA-splicing to support precision medicine efforts and can be readily adopted to study other loss-of-function genotype-phenotype relationships., (© 2024. The Author(s).)

Published
2024
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