52 Genetic Loci Influencing Myocardial Mass

Abstract Background Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflec...

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Veröffentlicht in:	Journal of the American College of Cardiology 2016-09, Vol.68 (13), p.1435-1448
Hauptverfasser:	van der Harst, Pim, MD, PhD, Verweij, Niek, PhD, Vogler, Georg, PhD, Franke, Lude, PhD, Maurano, Matthew T., PhD, Mateo Leach, Irene, PhD, Eijgelsheim, Mark, MD, PhD, Sotoodehnia, Nona, MD, MPH, Hayward, Caroline, PhD, Sorice, Rossella, PhD, Lyytikäinen, Leo-Pekka, MD, Polašek, Ozren, MD, PhD, Tanaka, Toshiko, PhD, Dörr, Marcus, MD, Magnani, Jared W., MD, MSc, Del Greco M., Fabiola, PhD, Zhang, Weihua, PhD, Tragante, Vinicius, PhD, Abecasis, Gonçalo R., PhD, Adriaens, Michiel E., PhD, Barnett, Phil, PhD, Bis, Joshua C., PhD, Bodmer, Rolf, PhD, Campbell, Harry, MD, Chakravarti, Aravinda, PhD, Delitala, Alessandro, PhD, Devereux, Richard B., MD, Doevendans, Pieter A., MD, PhD, Ferrucci, Luigi, MD, PhD, Gieger, Christian, PhD, Harris, Tamara B., PhD, Haugen, Eric, Heinig, Matthias, PhD, Hernandez, Dena G., MSc, Hillege, Hans L., MD, PhD, Hirschhorn, Joel N., MD, PhD, Hofman, Albert, MD, PhD, Hubner, Norbert, MD, Hwang, Shih-Jen, PhD, Kähönen, Mika, MD, PhD, Kolcic, Ivana, MD, PhD, Kooner, Ishminder K., MD, PhD, Kooner, Jaspal S., MBBS, MD, Lakatta, Edward G., MD, Lage, Kasper, PhD, Launer, Lenore J., PhD, Levy, Daniel, MD, Macfarlane, Peter W., DSc, May, Dalit, MD, Meitinger, Thomas, MD, MSc, Metspalu, Andres, PhD, Nappo, Stefania, MSc, Neph, Shane, BS, Nutile, Teresa, PhD, Okin, Peter M., MD, Olsen, Jesper V., PhD, Oostra, Ben A., PhD, Penninger, Josef M., MD, Pennacchio, Len A., PhD, Pers, Tune H., PhD, Peters, Annette, PhD, Pinto, Yigal M., MD, PhD, Pramstaller, Peter P., MD, Prins, Bram P., MSc, Raychaudhuri, Soumya, MD, PhD, Rice, Ken M., PhD, Schmidt, Carsten O., PhD, Silljé, Herman H.W., PhD, Sinagra, Gianfranco, MD, Sinner, Moritz F., MD, MPH, Soliman, Elsayed Z., MD, MSc, Spector, Timothy D., MBBS, MD, MSc, Strauch, Konstantin, PhD, Tan, Sian-Tsung, MD, Tarasov, Kirill V., MD, PhD, Trinh, Bosco, BSc, Uitterlinden, Andre G., PhD, van Duijn, Cornelia M., PhD, Viikari, Jorma S., MD, PhD, Völker, Uwe, PhD, Westra, Harm-Jan, PhD, Yang, Jian, PhD, Munroe, Patricia B., PhD, Snieder, Harold, PhD, Wright, Alan F., MBChB, PhD, Boyer, Laurie A., PhD, Alonso, Alvaro, MD, PhD, Jukema, J. Wouter, MD, PhD, Kääb, Stefan, MD, PhD, Felix, Stephan B., MD, Heckbert, Susan R., MD, PhD, de Boer, Rudolf A., MD, PhD, Newton-Cheh, Christopher, MD, MPH, Hicks, Andrew A., PhD, Chambers, John C., MBBS, PhD, Jamshidi, Yalda, PhD, Visel, Axel, PhD, Christoffels, Vincent M., PhD, Samani, Nilesh J., MD, de Bakker, Paul I.W., PhD
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Binding sites Cardiology Cardiomegaly - genetics Cardiomyopathy Cardiovascular Deoxyribonucleic acid DNA Drosophila melanogaster electrocardiogram Experiments Gene expression Gene loci genetic association study Genetic Loci Genome-Wide Association Study Genomes Heart failure Humans Internal Medicine left ventricular hypertrophy Mortality Mus musculus QRS Quality control Statistical analysis Stem cells Studies
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container_title	Journal of the American College of Cardiology
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creator	van der Harst, Pim, MD, PhD Verweij, Niek, PhD Vogler, Georg, PhD Franke, Lude, PhD Maurano, Matthew T., PhD Mateo Leach, Irene, PhD Eijgelsheim, Mark, MD, PhD Sotoodehnia, Nona, MD, MPH Hayward, Caroline, PhD Sorice, Rossella, PhD Lyytikäinen, Leo-Pekka, MD Polašek, Ozren, MD, PhD Tanaka, Toshiko, PhD Dörr, Marcus, MD Magnani, Jared W., MD, MSc Del Greco M., Fabiola, PhD Zhang, Weihua, PhD Tragante, Vinicius, PhD Abecasis, Gonçalo R., PhD Adriaens, Michiel E., PhD Barnett, Phil, PhD Bis, Joshua C., PhD Bodmer, Rolf, PhD Campbell, Harry, MD Chakravarti, Aravinda, PhD Delitala, Alessandro, PhD Devereux, Richard B., MD Doevendans, Pieter A., MD, PhD Ferrucci, Luigi, MD, PhD Gieger, Christian, PhD Harris, Tamara B., PhD Haugen, Eric Heinig, Matthias, PhD Hernandez, Dena G., MSc Hillege, Hans L., MD, PhD Hirschhorn, Joel N., MD, PhD Hofman, Albert, MD, PhD Hubner, Norbert, MD Hwang, Shih-Jen, PhD Kähönen, Mika, MD, PhD Kolcic, Ivana, MD, PhD Kooner, Ishminder K., MD, PhD Kooner, Jaspal S., MBBS, MD Lakatta, Edward G., MD Lage, Kasper, PhD Launer, Lenore J., PhD Levy, Daniel, MD Macfarlane, Peter W., DSc May, Dalit, MD Meitinger, Thomas, MD, MSc Metspalu, Andres, PhD Nappo, Stefania, MSc Neph, Shane, BS Nutile, Teresa, PhD Okin, Peter M., MD Olsen, Jesper V., PhD Oostra, Ben A., PhD Penninger, Josef M., MD Pennacchio, Len A., PhD Pers, Tune H., PhD Peters, Annette, PhD Pinto, Yigal M., MD, PhD Pramstaller, Peter P., MD Prins, Bram P., MSc Raychaudhuri, Soumya, MD, PhD Rice, Ken M., PhD Schmidt, Carsten O., PhD Silljé, Herman H.W., PhD Sinagra, Gianfranco, MD Sinner, Moritz F., MD, MPH Soliman, Elsayed Z., MD, MSc Spector, Timothy D., MBBS, MD, MSc Strauch, Konstantin, PhD Tan, Sian-Tsung, MD Tarasov, Kirill V., MD, PhD Trinh, Bosco, BSc Uitterlinden, Andre G., PhD van Duijn, Cornelia M., PhD Viikari, Jorma S., MD, PhD Völker, Uwe, PhD Westra, Harm-Jan, PhD Yang, Jian, PhD Munroe, Patricia B., PhD Snieder, Harold, PhD Wright, Alan F., MBChB, PhD Boyer, Laurie A., PhD Alonso, Alvaro, MD, PhD Jukema, J. Wouter, MD, PhD Kääb, Stefan, MD, PhD Felix, Stephan B., MD Heckbert, Susan R., MD, PhD de Boer, Rudolf A., MD, PhD Newton-Cheh, Christopher, MD, MPH Hicks, Andrew A., PhD Chambers, John C., MBBS, PhD Jamshidi, Yalda, PhD Visel, Axel, PhD Christoffels, Vincent M., PhD Samani, Nilesh J., MD de Bakker, Paul I.W., PhD
description	Abstract Background Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. Objectives This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. Methods We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. Results We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10−8 . These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus . We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. Conclusions Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.
doi_str_mv	10.1016/j.jacc.2016.07.729
format	Article
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Wouter, MD, PhD ; Kääb, Stefan, MD, PhD ; Felix, Stephan B., MD ; Heckbert, Susan R., MD, PhD ; de Boer, Rudolf A., MD, PhD ; Newton-Cheh, Christopher, MD, MPH ; Hicks, Andrew A., PhD ; Chambers, John C., MBBS, PhD ; Jamshidi, Yalda, PhD ; Visel, Axel, PhD ; Christoffels, Vincent M., PhD ; Samani, Nilesh J., MD ; de Bakker, Paul I.W., PhD</creator><creatorcontrib>van der Harst, Pim, MD, PhD ; Verweij, Niek, PhD ; Vogler, Georg, PhD ; Franke, Lude, PhD ; Maurano, Matthew T., PhD ; Mateo Leach, Irene, PhD ; Eijgelsheim, Mark, MD, PhD ; Sotoodehnia, Nona, MD, MPH ; Hayward, Caroline, PhD ; Sorice, Rossella, PhD ; Lyytikäinen, Leo-Pekka, MD ; Polašek, Ozren, MD, PhD ; Tanaka, Toshiko, PhD ; Dörr, Marcus, MD ; Magnani, Jared W., MD, MSc ; Del Greco M., Fabiola, PhD ; Zhang, Weihua, PhD ; Tragante, Vinicius, PhD ; Abecasis, Gonçalo R., PhD ; Adriaens, Michiel E., PhD ; Barnett, Phil, PhD ; Bis, Joshua C., PhD ; Bodmer, Rolf, PhD ; Campbell, Harry, MD ; Chakravarti, Aravinda, PhD ; Delitala, Alessandro, PhD ; Devereux, Richard B., MD ; Doevendans, Pieter A., MD, PhD ; Ferrucci, Luigi, MD, PhD ; Gieger, Christian, PhD ; Harris, Tamara B., PhD ; Haugen, Eric ; Heinig, Matthias, PhD ; Hernandez, Dena G., MSc ; Hillege, Hans L., MD, PhD ; Hirschhorn, Joel N., MD, PhD ; Hofman, Albert, MD, PhD ; Hubner, Norbert, MD ; Hwang, Shih-Jen, PhD ; Kähönen, Mika, MD, PhD ; Kolcic, Ivana, MD, PhD ; Kooner, Ishminder K., MD, PhD ; Kooner, Jaspal S., MBBS, MD ; Lakatta, Edward G., MD ; Lage, Kasper, PhD ; Launer, Lenore J., PhD ; Levy, Daniel, MD ; Macfarlane, Peter W., DSc ; May, Dalit, MD ; Meitinger, Thomas, MD, MSc ; Metspalu, Andres, PhD ; Nappo, Stefania, MSc ; Neph, Shane, BS ; Nutile, Teresa, PhD ; Okin, Peter M., MD ; Olsen, Jesper V., PhD ; Oostra, Ben A., PhD ; Penninger, Josef M., MD ; Pennacchio, Len A., PhD ; Pers, Tune H., PhD ; Peters, Annette, PhD ; Pinto, Yigal M., MD, PhD ; Pramstaller, Peter P., MD ; Prins, Bram P., MSc ; Raychaudhuri, Soumya, MD, PhD ; Rice, Ken M., PhD ; Schmidt, Carsten O., PhD ; Silljé, Herman H.W., PhD ; Sinagra, Gianfranco, MD ; Sinner, Moritz F., MD, MPH ; Soliman, Elsayed Z., MD, MSc ; Spector, Timothy D., MBBS, MD, MSc ; Strauch, Konstantin, PhD ; Tan, Sian-Tsung, MD ; Tarasov, Kirill V., MD, PhD ; Trinh, Bosco, BSc ; Uitterlinden, Andre G., PhD ; van Duijn, Cornelia M., PhD ; Viikari, Jorma S., MD, PhD ; Völker, Uwe, PhD ; Westra, Harm-Jan, PhD ; Yang, Jian, PhD ; Munroe, Patricia B., PhD ; Snieder, Harold, PhD ; Wright, Alan F., MBChB, PhD ; Boyer, Laurie A., PhD ; Alonso, Alvaro, MD, PhD ; Jukema, J. Wouter, MD, PhD ; Kääb, Stefan, MD, PhD ; Felix, Stephan B., MD ; Heckbert, Susan R., MD, PhD ; de Boer, Rudolf A., MD, PhD ; Newton-Cheh, Christopher, MD, MPH ; Hicks, Andrew A., PhD ; Chambers, John C., MBBS, PhD ; Jamshidi, Yalda, PhD ; Visel, Axel, PhD ; Christoffels, Vincent M., PhD ; Samani, Nilesh J., MD ; de Bakker, Paul I.W., PhD</creatorcontrib><description>Abstract Background Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. Objectives This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. Methods We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. Results We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10−8 . These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus . We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. Conclusions Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.</description><identifier>ISSN: 0735-1097</identifier><identifier>EISSN: 1558-3597</identifier><identifier>DOI: 10.1016/j.jacc.2016.07.729</identifier><identifier>PMID: 27659466</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Binding sites ; Cardiology ; Cardiomegaly - genetics ; Cardiomyopathy ; Cardiovascular ; Deoxyribonucleic acid ; DNA ; Drosophila melanogaster ; electrocardiogram ; Experiments ; Gene expression ; Gene loci ; genetic association study ; Genetic Loci ; Genome-Wide Association Study ; Genomes ; Heart failure ; Humans ; Internal Medicine ; left ventricular hypertrophy ; Mortality ; Mus musculus ; QRS ; Quality control ; Statistical analysis ; Stem cells ; Studies</subject><ispartof>Journal of the American College of Cardiology, 2016-09, Vol.68 (13), p.1435-1448</ispartof><rights>The Authors</rights><rights>2016 The Authors</rights><rights>Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.</rights><rights>Copyright Elsevier Limited Sep 27, 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c571t-5621e81939764ebeab0e6fd9762d7871a5ce7219ea6154d72f3e8747c813e3b43</citedby><cites>FETCH-LOGICAL-c571t-5621e81939764ebeab0e6fd9762d7871a5ce7219ea6154d72f3e8747c813e3b43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0735109716346642$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27659466$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>van der Harst, Pim, MD, PhD</creatorcontrib><creatorcontrib>Verweij, Niek, PhD</creatorcontrib><creatorcontrib>Vogler, Georg, PhD</creatorcontrib><creatorcontrib>Franke, Lude, PhD</creatorcontrib><creatorcontrib>Maurano, Matthew T., PhD</creatorcontrib><creatorcontrib>Mateo Leach, Irene, PhD</creatorcontrib><creatorcontrib>Eijgelsheim, Mark, MD, PhD</creatorcontrib><creatorcontrib>Sotoodehnia, Nona, MD, MPH</creatorcontrib><creatorcontrib>Hayward, Caroline, PhD</creatorcontrib><creatorcontrib>Sorice, Rossella, PhD</creatorcontrib><creatorcontrib>Lyytikäinen, Leo-Pekka, MD</creatorcontrib><creatorcontrib>Polašek, Ozren, MD, PhD</creatorcontrib><creatorcontrib>Tanaka, Toshiko, PhD</creatorcontrib><creatorcontrib>Dörr, Marcus, MD</creatorcontrib><creatorcontrib>Magnani, Jared W., MD, MSc</creatorcontrib><creatorcontrib>Del Greco M., Fabiola, PhD</creatorcontrib><creatorcontrib>Zhang, Weihua, PhD</creatorcontrib><creatorcontrib>Tragante, Vinicius, PhD</creatorcontrib><creatorcontrib>Abecasis, Gonçalo R., PhD</creatorcontrib><creatorcontrib>Adriaens, Michiel E., PhD</creatorcontrib><creatorcontrib>Barnett, Phil, PhD</creatorcontrib><creatorcontrib>Bis, Joshua C., PhD</creatorcontrib><creatorcontrib>Bodmer, Rolf, PhD</creatorcontrib><creatorcontrib>Campbell, Harry, MD</creatorcontrib><creatorcontrib>Chakravarti, Aravinda, PhD</creatorcontrib><creatorcontrib>Delitala, Alessandro, PhD</creatorcontrib><creatorcontrib>Devereux, Richard B., MD</creatorcontrib><creatorcontrib>Doevendans, Pieter A., MD, PhD</creatorcontrib><creatorcontrib>Ferrucci, Luigi, MD, PhD</creatorcontrib><creatorcontrib>Gieger, Christian, PhD</creatorcontrib><creatorcontrib>Harris, Tamara B., PhD</creatorcontrib><creatorcontrib>Haugen, Eric</creatorcontrib><creatorcontrib>Heinig, Matthias, PhD</creatorcontrib><creatorcontrib>Hernandez, Dena G., MSc</creatorcontrib><creatorcontrib>Hillege, Hans L., MD, PhD</creatorcontrib><creatorcontrib>Hirschhorn, Joel N., MD, PhD</creatorcontrib><creatorcontrib>Hofman, Albert, MD, PhD</creatorcontrib><creatorcontrib>Hubner, Norbert, MD</creatorcontrib><creatorcontrib>Hwang, Shih-Jen, PhD</creatorcontrib><creatorcontrib>Kähönen, Mika, MD, PhD</creatorcontrib><creatorcontrib>Kolcic, Ivana, MD, PhD</creatorcontrib><creatorcontrib>Kooner, Ishminder K., MD, PhD</creatorcontrib><creatorcontrib>Kooner, Jaspal S., MBBS, MD</creatorcontrib><creatorcontrib>Lakatta, Edward G., MD</creatorcontrib><creatorcontrib>Lage, Kasper, PhD</creatorcontrib><creatorcontrib>Launer, Lenore J., PhD</creatorcontrib><creatorcontrib>Levy, Daniel, MD</creatorcontrib><creatorcontrib>Macfarlane, Peter W., DSc</creatorcontrib><creatorcontrib>May, Dalit, MD</creatorcontrib><creatorcontrib>Meitinger, Thomas, MD, MSc</creatorcontrib><creatorcontrib>Metspalu, Andres, PhD</creatorcontrib><creatorcontrib>Nappo, Stefania, MSc</creatorcontrib><creatorcontrib>Neph, Shane, BS</creatorcontrib><creatorcontrib>Nutile, Teresa, PhD</creatorcontrib><creatorcontrib>Okin, Peter M., MD</creatorcontrib><creatorcontrib>Olsen, Jesper V., PhD</creatorcontrib><creatorcontrib>Oostra, Ben A., PhD</creatorcontrib><creatorcontrib>Penninger, Josef M., MD</creatorcontrib><creatorcontrib>Pennacchio, Len A., PhD</creatorcontrib><creatorcontrib>Pers, Tune H., PhD</creatorcontrib><creatorcontrib>Peters, Annette, PhD</creatorcontrib><creatorcontrib>Pinto, Yigal M., MD, PhD</creatorcontrib><creatorcontrib>Pramstaller, Peter P., MD</creatorcontrib><creatorcontrib>Prins, Bram P., MSc</creatorcontrib><creatorcontrib>Raychaudhuri, Soumya, MD, PhD</creatorcontrib><creatorcontrib>Rice, Ken M., PhD</creatorcontrib><creatorcontrib>Schmidt, Carsten O., PhD</creatorcontrib><creatorcontrib>Silljé, Herman H.W., PhD</creatorcontrib><creatorcontrib>Sinagra, Gianfranco, MD</creatorcontrib><creatorcontrib>Sinner, Moritz F., MD, MPH</creatorcontrib><creatorcontrib>Soliman, Elsayed Z., MD, MSc</creatorcontrib><creatorcontrib>Spector, Timothy D., MBBS, MD, MSc</creatorcontrib><creatorcontrib>Strauch, Konstantin, PhD</creatorcontrib><creatorcontrib>Tan, Sian-Tsung, MD</creatorcontrib><creatorcontrib>Tarasov, Kirill V., MD, PhD</creatorcontrib><creatorcontrib>Trinh, Bosco, BSc</creatorcontrib><creatorcontrib>Uitterlinden, Andre G., PhD</creatorcontrib><creatorcontrib>van Duijn, Cornelia M., PhD</creatorcontrib><creatorcontrib>Viikari, Jorma S., MD, PhD</creatorcontrib><creatorcontrib>Völker, Uwe, PhD</creatorcontrib><creatorcontrib>Westra, Harm-Jan, PhD</creatorcontrib><creatorcontrib>Yang, Jian, PhD</creatorcontrib><creatorcontrib>Munroe, Patricia B., PhD</creatorcontrib><creatorcontrib>Snieder, Harold, PhD</creatorcontrib><creatorcontrib>Wright, Alan F., MBChB, PhD</creatorcontrib><creatorcontrib>Boyer, Laurie A., PhD</creatorcontrib><creatorcontrib>Alonso, Alvaro, MD, PhD</creatorcontrib><creatorcontrib>Jukema, J. Wouter, MD, PhD</creatorcontrib><creatorcontrib>Kääb, Stefan, MD, PhD</creatorcontrib><creatorcontrib>Felix, Stephan B., MD</creatorcontrib><creatorcontrib>Heckbert, Susan R., MD, PhD</creatorcontrib><creatorcontrib>de Boer, Rudolf A., MD, PhD</creatorcontrib><creatorcontrib>Newton-Cheh, Christopher, MD, MPH</creatorcontrib><creatorcontrib>Hicks, Andrew A., PhD</creatorcontrib><creatorcontrib>Chambers, John C., MBBS, PhD</creatorcontrib><creatorcontrib>Jamshidi, Yalda, PhD</creatorcontrib><creatorcontrib>Visel, Axel, PhD</creatorcontrib><creatorcontrib>Christoffels, Vincent M., PhD</creatorcontrib><creatorcontrib>Samani, Nilesh J., MD</creatorcontrib><creatorcontrib>de Bakker, Paul I.W., PhD</creatorcontrib><title>52 Genetic Loci Influencing Myocardial Mass</title><title>Journal of the American College of Cardiology</title><addtitle>J Am Coll Cardiol</addtitle><description>Abstract Background Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. Objectives This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. Methods We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. Results We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10−8 . These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus . We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. Conclusions Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.</description><subject>Animals</subject><subject>Binding sites</subject><subject>Cardiology</subject><subject>Cardiomegaly - genetics</subject><subject>Cardiomyopathy</subject><subject>Cardiovascular</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Drosophila melanogaster</subject><subject>electrocardiogram</subject><subject>Experiments</subject><subject>Gene expression</subject><subject>Gene loci</subject><subject>genetic association study</subject><subject>Genetic Loci</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Heart failure</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>left ventricular hypertrophy</subject><subject>Mortality</subject><subject>Mus musculus</subject><subject>QRS</subject><subject>Quality control</subject><subject>Statistical analysis</subject><subject>Stem cells</subject><subject>Studies</subject><issn>0735-1097</issn><issn>1558-3597</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kstu1DAUhi0EokPhBVigkdiwIMGX2CeWUKWqglJpKhbA2vI4J8UhYxc7qTRvw7PwZDiaUqALVrbl7_zn8h9CnjNaM8rUm6EerHM1L_eaQg1cPyArJmVbCanhIVlRELJiVMMReZLzQClVLdOPyREHJXWj1Iq8lnx9jgEn79ab6Pz6IvTjjMH5cLW-3EdnU-ft-PPHpc35KXnU2zHjs9vzmHx5_-7z2Ydq8_H84ux0UzkJbKqk4gxLIqFBNbhFu6Wo-q68eActMCsdAmcarWKy6YD3AltowLVMoNg24picHHSv5-0OO4dhSnY018nvbNqbaL359yf4r-Yq3hjZQMsUFIFXtwIpfp8xT2bns8NxtAHjnA1rOWgqJVUFfXkPHeKcQmlvoXjTglK6UPxAuRRzTtjfFcOoWcwwg1nMMIsZhoIpZpSgF3-3cRfye_oFeHsAsAzzxmMy2fkye-x8QjeZLvr_65_cC3ejD97Z8RvuMf_pw2RuqPm0rMOyDUyJkr3h4hdA-a6H</recordid><startdate>20160927</startdate><enddate>20160927</enddate><creator>van der Harst, Pim, MD, PhD</creator><creator>Verweij, Niek, PhD</creator><creator>Vogler, Georg, PhD</creator><creator>Franke, Lude, PhD</creator><creator>Maurano, Matthew T., PhD</creator><creator>Mateo Leach, Irene, PhD</creator><creator>Eijgelsheim, Mark, MD, PhD</creator><creator>Sotoodehnia, Nona, MD, MPH</creator><creator>Hayward, Caroline, PhD</creator><creator>Sorice, Rossella, PhD</creator><creator>Lyytikäinen, Leo-Pekka, MD</creator><creator>Polašek, Ozren, MD, PhD</creator><creator>Tanaka, Toshiko, PhD</creator><creator>Dörr, Marcus, MD</creator><creator>Magnani, Jared W., MD, MSc</creator><creator>Del Greco M., Fabiola, PhD</creator><creator>Zhang, Weihua, PhD</creator><creator>Tragante, Vinicius, PhD</creator><creator>Abecasis, Gonçalo R., PhD</creator><creator>Adriaens, Michiel E., PhD</creator><creator>Barnett, Phil, PhD</creator><creator>Bis, Joshua C., PhD</creator><creator>Bodmer, Rolf, PhD</creator><creator>Campbell, Harry, MD</creator><creator>Chakravarti, Aravinda, PhD</creator><creator>Delitala, Alessandro, PhD</creator><creator>Devereux, Richard B., MD</creator><creator>Doevendans, Pieter A., MD, PhD</creator><creator>Ferrucci, Luigi, MD, PhD</creator><creator>Gieger, Christian, PhD</creator><creator>Harris, Tamara B., PhD</creator><creator>Haugen, Eric</creator><creator>Heinig, Matthias, PhD</creator><creator>Hernandez, Dena G., MSc</creator><creator>Hillege, Hans L., MD, PhD</creator><creator>Hirschhorn, Joel N., MD, PhD</creator><creator>Hofman, Albert, MD, PhD</creator><creator>Hubner, Norbert, MD</creator><creator>Hwang, Shih-Jen, PhD</creator><creator>Kähönen, Mika, MD, PhD</creator><creator>Kolcic, Ivana, MD, PhD</creator><creator>Kooner, Ishminder K., MD, PhD</creator><creator>Kooner, Jaspal S., MBBS, MD</creator><creator>Lakatta, Edward G., MD</creator><creator>Lage, Kasper, PhD</creator><creator>Launer, Lenore J., PhD</creator><creator>Levy, Daniel, MD</creator><creator>Macfarlane, Peter W., DSc</creator><creator>May, Dalit, MD</creator><creator>Meitinger, Thomas, MD, MSc</creator><creator>Metspalu, Andres, PhD</creator><creator>Nappo, Stefania, MSc</creator><creator>Neph, Shane, BS</creator><creator>Nutile, Teresa, PhD</creator><creator>Okin, Peter M., MD</creator><creator>Olsen, Jesper V., PhD</creator><creator>Oostra, Ben A., PhD</creator><creator>Penninger, Josef M., MD</creator><creator>Pennacchio, Len A., PhD</creator><creator>Pers, Tune H., PhD</creator><creator>Peters, Annette, PhD</creator><creator>Pinto, Yigal M., MD, PhD</creator><creator>Pramstaller, Peter P., MD</creator><creator>Prins, Bram P., MSc</creator><creator>Raychaudhuri, Soumya, MD, PhD</creator><creator>Rice, Ken M., PhD</creator><creator>Schmidt, Carsten O., PhD</creator><creator>Silljé, Herman H.W., PhD</creator><creator>Sinagra, Gianfranco, MD</creator><creator>Sinner, Moritz F., MD, MPH</creator><creator>Soliman, Elsayed Z., MD, MSc</creator><creator>Spector, Timothy D., MBBS, MD, MSc</creator><creator>Strauch, Konstantin, PhD</creator><creator>Tan, Sian-Tsung, MD</creator><creator>Tarasov, Kirill V., MD, PhD</creator><creator>Trinh, Bosco, BSc</creator><creator>Uitterlinden, Andre G., PhD</creator><creator>van Duijn, Cornelia M., PhD</creator><creator>Viikari, Jorma S., MD, PhD</creator><creator>Völker, Uwe, PhD</creator><creator>Westra, Harm-Jan, PhD</creator><creator>Yang, Jian, PhD</creator><creator>Munroe, Patricia B., PhD</creator><creator>Snieder, Harold, PhD</creator><creator>Wright, Alan F., MBChB, PhD</creator><creator>Boyer, Laurie A., PhD</creator><creator>Alonso, Alvaro, MD, PhD</creator><creator>Jukema, J. Wouter, MD, PhD</creator><creator>Kääb, Stefan, MD, PhD</creator><creator>Felix, Stephan B., MD</creator><creator>Heckbert, Susan R., MD, PhD</creator><creator>de Boer, Rudolf A., MD, PhD</creator><creator>Newton-Cheh, Christopher, MD, MPH</creator><creator>Hicks, Andrew A., PhD</creator><creator>Chambers, John C., MBBS, PhD</creator><creator>Jamshidi, Yalda, PhD</creator><creator>Visel, Axel, PhD</creator><creator>Christoffels, Vincent M., PhD</creator><creator>Samani, Nilesh J., MD</creator><creator>de Bakker, Paul I.W., PhD</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TK</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>5PM</scope></search><sort><creationdate>20160927</creationdate><title>52 Genetic Loci Influencing Myocardial Mass</title><author>van der Harst, Pim, MD, PhD ; Verweij, Niek, PhD ; Vogler, Georg, PhD ; Franke, Lude, PhD ; Maurano, Matthew T., PhD ; Mateo Leach, Irene, PhD ; Eijgelsheim, Mark, MD, PhD ; Sotoodehnia, Nona, MD, MPH ; Hayward, Caroline, PhD ; Sorice, Rossella, PhD ; Lyytikäinen, Leo-Pekka, MD ; Polašek, Ozren, MD, PhD ; Tanaka, Toshiko, PhD ; Dörr, Marcus, MD ; Magnani, Jared W., MD, MSc ; Del Greco M., Fabiola, PhD ; Zhang, Weihua, PhD ; Tragante, Vinicius, PhD ; Abecasis, Gonçalo R., PhD ; Adriaens, Michiel E., PhD ; Barnett, Phil, PhD ; Bis, Joshua C., PhD ; Bodmer, Rolf, PhD ; Campbell, Harry, MD ; Chakravarti, Aravinda, PhD ; Delitala, Alessandro, PhD ; Devereux, Richard B., MD ; Doevendans, Pieter A., MD, PhD ; Ferrucci, Luigi, MD, PhD ; Gieger, Christian, PhD ; Harris, Tamara B., PhD ; Haugen, Eric ; Heinig, Matthias, PhD ; Hernandez, Dena G., MSc ; Hillege, Hans L., MD, PhD ; Hirschhorn, Joel N., MD, PhD ; Hofman, Albert, MD, PhD ; Hubner, Norbert, MD ; Hwang, Shih-Jen, PhD ; Kähönen, Mika, MD, PhD ; Kolcic, Ivana, MD, PhD ; Kooner, Ishminder K., MD, PhD ; Kooner, Jaspal S., MBBS, MD ; Lakatta, Edward G., MD ; Lage, Kasper, PhD ; Launer, Lenore J., PhD ; Levy, Daniel, MD ; Macfarlane, Peter W., DSc ; May, Dalit, MD ; Meitinger, Thomas, MD, MSc ; Metspalu, Andres, PhD ; Nappo, Stefania, MSc ; Neph, Shane, BS ; Nutile, Teresa, PhD ; Okin, Peter M., MD ; Olsen, Jesper V., PhD ; Oostra, Ben A., PhD ; Penninger, Josef M., MD ; Pennacchio, Len A., PhD ; Pers, Tune H., PhD ; Peters, Annette, PhD ; Pinto, Yigal M., MD, PhD ; Pramstaller, Peter P., MD ; Prins, Bram P., MSc ; Raychaudhuri, Soumya, MD, PhD ; Rice, Ken M., PhD ; Schmidt, Carsten O., PhD ; Silljé, Herman H.W., PhD ; Sinagra, Gianfranco, MD ; Sinner, Moritz F., MD, MPH ; Soliman, Elsayed Z., MD, MSc ; Spector, Timothy D., MBBS, MD, MSc ; Strauch, Konstantin, PhD ; Tan, Sian-Tsung, MD ; Tarasov, Kirill V., MD, PhD ; Trinh, Bosco, BSc ; Uitterlinden, Andre G., PhD ; van Duijn, Cornelia M., PhD ; Viikari, Jorma S., MD, PhD ; Völker, Uwe, PhD ; Westra, Harm-Jan, PhD ; Yang, Jian, PhD ; Munroe, Patricia B., PhD ; Snieder, Harold, PhD ; Wright, Alan F., MBChB, PhD ; Boyer, Laurie A., PhD ; Alonso, Alvaro, MD, PhD ; Jukema, J. Wouter, MD, PhD ; Kääb, Stefan, MD, PhD ; Felix, Stephan B., MD ; Heckbert, Susan R., MD, PhD ; de Boer, Rudolf A., MD, PhD ; Newton-Cheh, Christopher, MD, MPH ; Hicks, Andrew A., PhD ; Chambers, John C., MBBS, PhD ; Jamshidi, Yalda, PhD ; Visel, Axel, PhD ; Christoffels, Vincent M., PhD ; Samani, Nilesh J., MD ; de Bakker, Paul I.W., PhD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c571t-5621e81939764ebeab0e6fd9762d7871a5ce7219ea6154d72f3e8747c813e3b43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Binding sites</topic><topic>Cardiology</topic><topic>Cardiomegaly - genetics</topic><topic>Cardiomyopathy</topic><topic>Cardiovascular</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Drosophila melanogaster</topic><topic>electrocardiogram</topic><topic>Experiments</topic><topic>Gene expression</topic><topic>Gene loci</topic><topic>genetic association study</topic><topic>Genetic Loci</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Heart failure</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>left ventricular hypertrophy</topic><topic>Mortality</topic><topic>Mus musculus</topic><topic>QRS</topic><topic>Quality control</topic><topic>Statistical analysis</topic><topic>Stem cells</topic><topic>Studies</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>van der Harst, Pim, MD, PhD</creatorcontrib><creatorcontrib>Verweij, Niek, PhD</creatorcontrib><creatorcontrib>Vogler, Georg, PhD</creatorcontrib><creatorcontrib>Franke, Lude, PhD</creatorcontrib><creatorcontrib>Maurano, Matthew T., PhD</creatorcontrib><creatorcontrib>Mateo Leach, Irene, PhD</creatorcontrib><creatorcontrib>Eijgelsheim, Mark, MD, PhD</creatorcontrib><creatorcontrib>Sotoodehnia, Nona, MD, MPH</creatorcontrib><creatorcontrib>Hayward, Caroline, 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PhD</creatorcontrib><creatorcontrib>Launer, Lenore J., PhD</creatorcontrib><creatorcontrib>Levy, Daniel, MD</creatorcontrib><creatorcontrib>Macfarlane, Peter W., DSc</creatorcontrib><creatorcontrib>May, Dalit, MD</creatorcontrib><creatorcontrib>Meitinger, Thomas, MD, MSc</creatorcontrib><creatorcontrib>Metspalu, Andres, PhD</creatorcontrib><creatorcontrib>Nappo, Stefania, MSc</creatorcontrib><creatorcontrib>Neph, Shane, BS</creatorcontrib><creatorcontrib>Nutile, Teresa, PhD</creatorcontrib><creatorcontrib>Okin, Peter M., MD</creatorcontrib><creatorcontrib>Olsen, Jesper V., PhD</creatorcontrib><creatorcontrib>Oostra, Ben A., PhD</creatorcontrib><creatorcontrib>Penninger, Josef M., MD</creatorcontrib><creatorcontrib>Pennacchio, Len A., PhD</creatorcontrib><creatorcontrib>Pers, Tune H., PhD</creatorcontrib><creatorcontrib>Peters, Annette, PhD</creatorcontrib><creatorcontrib>Pinto, Yigal M., MD, PhD</creatorcontrib><creatorcontrib>Pramstaller, Peter P., MD</creatorcontrib><creatorcontrib>Prins, Bram P., MSc</creatorcontrib><creatorcontrib>Raychaudhuri, Soumya, MD, PhD</creatorcontrib><creatorcontrib>Rice, Ken M., PhD</creatorcontrib><creatorcontrib>Schmidt, Carsten O., PhD</creatorcontrib><creatorcontrib>Silljé, Herman H.W., PhD</creatorcontrib><creatorcontrib>Sinagra, Gianfranco, MD</creatorcontrib><creatorcontrib>Sinner, Moritz F., MD, MPH</creatorcontrib><creatorcontrib>Soliman, Elsayed Z., MD, MSc</creatorcontrib><creatorcontrib>Spector, Timothy D., MBBS, MD, MSc</creatorcontrib><creatorcontrib>Strauch, Konstantin, PhD</creatorcontrib><creatorcontrib>Tan, Sian-Tsung, MD</creatorcontrib><creatorcontrib>Tarasov, Kirill V., MD, PhD</creatorcontrib><creatorcontrib>Trinh, Bosco, BSc</creatorcontrib><creatorcontrib>Uitterlinden, Andre G., PhD</creatorcontrib><creatorcontrib>van Duijn, Cornelia M., PhD</creatorcontrib><creatorcontrib>Viikari, Jorma S., MD, PhD</creatorcontrib><creatorcontrib>Völker, Uwe, 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Wouter, MD, PhD</creatorcontrib><creatorcontrib>Kääb, Stefan, MD, PhD</creatorcontrib><creatorcontrib>Felix, Stephan B., MD</creatorcontrib><creatorcontrib>Heckbert, Susan R., MD, PhD</creatorcontrib><creatorcontrib>de Boer, Rudolf A., MD, PhD</creatorcontrib><creatorcontrib>Newton-Cheh, Christopher, MD, MPH</creatorcontrib><creatorcontrib>Hicks, Andrew A., PhD</creatorcontrib><creatorcontrib>Chambers, John C., MBBS, PhD</creatorcontrib><creatorcontrib>Jamshidi, Yalda, PhD</creatorcontrib><creatorcontrib>Visel, Axel, PhD</creatorcontrib><creatorcontrib>Christoffels, Vincent M., PhD</creatorcontrib><creatorcontrib>Samani, Nilesh J., MD</creatorcontrib><creatorcontrib>de Bakker, Paul I.W., PhD</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of the American College of Cardiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>van der Harst, Pim, MD, PhD</au><au>Verweij, Niek, PhD</au><au>Vogler, Georg, PhD</au><au>Franke, Lude, PhD</au><au>Maurano, Matthew T., PhD</au><au>Mateo Leach, Irene, PhD</au><au>Eijgelsheim, Mark, MD, PhD</au><au>Sotoodehnia, Nona, MD, MPH</au><au>Hayward, Caroline, PhD</au><au>Sorice, Rossella, PhD</au><au>Lyytikäinen, Leo-Pekka, MD</au><au>Polašek, Ozren, MD, PhD</au><au>Tanaka, Toshiko, PhD</au><au>Dörr, Marcus, MD</au><au>Magnani, Jared W., MD, MSc</au><au>Del Greco M., Fabiola, PhD</au><au>Zhang, Weihua, PhD</au><au>Tragante, Vinicius, PhD</au><au>Abecasis, Gonçalo R., PhD</au><au>Adriaens, Michiel E., PhD</au><au>Barnett, Phil, PhD</au><au>Bis, Joshua C., PhD</au><au>Bodmer, Rolf, PhD</au><au>Campbell, Harry, MD</au><au>Chakravarti, Aravinda, PhD</au><au>Delitala, Alessandro, PhD</au><au>Devereux, Richard B., MD</au><au>Doevendans, Pieter A., MD, PhD</au><au>Ferrucci, Luigi, MD, PhD</au><au>Gieger, Christian, PhD</au><au>Harris, Tamara B., PhD</au><au>Haugen, Eric</au><au>Heinig, Matthias, PhD</au><au>Hernandez, Dena G., MSc</au><au>Hillege, Hans L., MD, PhD</au><au>Hirschhorn, Joel N., MD, PhD</au><au>Hofman, Albert, MD, PhD</au><au>Hubner, Norbert, MD</au><au>Hwang, Shih-Jen, PhD</au><au>Kähönen, Mika, MD, PhD</au><au>Kolcic, Ivana, MD, PhD</au><au>Kooner, Ishminder K., MD, PhD</au><au>Kooner, Jaspal S., MBBS, MD</au><au>Lakatta, Edward G., MD</au><au>Lage, Kasper, PhD</au><au>Launer, Lenore J., PhD</au><au>Levy, Daniel, MD</au><au>Macfarlane, Peter W., DSc</au><au>May, Dalit, MD</au><au>Meitinger, Thomas, MD, MSc</au><au>Metspalu, Andres, PhD</au><au>Nappo, Stefania, MSc</au><au>Neph, Shane, BS</au><au>Nutile, Teresa, PhD</au><au>Okin, Peter M., MD</au><au>Olsen, Jesper V., PhD</au><au>Oostra, Ben A., PhD</au><au>Penninger, Josef M., MD</au><au>Pennacchio, Len A., PhD</au><au>Pers, Tune H., PhD</au><au>Peters, Annette, PhD</au><au>Pinto, Yigal M., MD, PhD</au><au>Pramstaller, Peter P., MD</au><au>Prins, Bram P., MSc</au><au>Raychaudhuri, Soumya, MD, PhD</au><au>Rice, Ken M., PhD</au><au>Schmidt, Carsten O., PhD</au><au>Silljé, Herman H.W., PhD</au><au>Sinagra, Gianfranco, MD</au><au>Sinner, Moritz F., MD, MPH</au><au>Soliman, Elsayed Z., MD, MSc</au><au>Spector, Timothy D., MBBS, MD, MSc</au><au>Strauch, Konstantin, PhD</au><au>Tan, Sian-Tsung, MD</au><au>Tarasov, Kirill V., MD, PhD</au><au>Trinh, Bosco, BSc</au><au>Uitterlinden, Andre G., PhD</au><au>van Duijn, Cornelia M., PhD</au><au>Viikari, Jorma S., MD, PhD</au><au>Völker, Uwe, PhD</au><au>Westra, Harm-Jan, PhD</au><au>Yang, Jian, PhD</au><au>Munroe, Patricia B., PhD</au><au>Snieder, Harold, PhD</au><au>Wright, Alan F., MBChB, PhD</au><au>Boyer, Laurie A., PhD</au><au>Alonso, Alvaro, MD, PhD</au><au>Jukema, J. Wouter, MD, PhD</au><au>Kääb, Stefan, MD, PhD</au><au>Felix, Stephan B., MD</au><au>Heckbert, Susan R., MD, PhD</au><au>de Boer, Rudolf A., MD, PhD</au><au>Newton-Cheh, Christopher, MD, MPH</au><au>Hicks, Andrew A., PhD</au><au>Chambers, John C., MBBS, PhD</au><au>Jamshidi, Yalda, PhD</au><au>Visel, Axel, PhD</au><au>Christoffels, Vincent M., PhD</au><au>Samani, Nilesh J., MD</au><au>de Bakker, Paul I.W., PhD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>52 Genetic Loci Influencing Myocardial Mass</atitle><jtitle>Journal of the American College of Cardiology</jtitle><addtitle>J Am Coll Cardiol</addtitle><date>2016-09-27</date><risdate>2016</risdate><volume>68</volume><issue>13</issue><spage>1435</spage><epage>1448</epage><pages>1435-1448</pages><issn>0735-1097</issn><eissn>1558-3597</eissn><abstract>Abstract Background Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. Objectives This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. Methods We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. Results We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10−8 . These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus . We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. Conclusions Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>27659466</pmid><doi>10.1016/j.jacc.2016.07.729</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record>
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subjects	Animals Binding sites Cardiology Cardiomegaly - genetics Cardiomyopathy Cardiovascular Deoxyribonucleic acid DNA Drosophila melanogaster electrocardiogram Experiments Gene expression Gene loci genetic association study Genetic Loci Genome-Wide Association Study Genomes Heart failure Humans Internal Medicine left ventricular hypertrophy Mortality Mus musculus QRS Quality control Statistical analysis Stem cells Studies
title	52 Genetic Loci Influencing Myocardial Mass
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