TY - JOUR

T1 - 52 Genetic Loci Influencing Myocardial Mass

AU - van der Harst, Pim

AU - van Setten, Jessica

AU - Verweij, Niek

AU - Vogler, Georg

AU - Franke, Lude

AU - Maurano, Matthew T

AU - Wang, Xinchen

AU - Mateo Leach, Irene

AU - Eijgelsheim, Mark

AU - Sotoodehnia, Nona

AU - Hayward, Caroline

AU - Sorice, Rossella

AU - Meirelles, Osorio

AU - Lyytikäinen, Leo-Pekka

AU - Polašek, Ozren

AU - Tanaka, Toshiko

AU - Arking, Dan E

AU - Ulivi, Sheila

AU - Trompet, Stella

AU - Müller-Nurasyid, Martina

AU - Smith, Albert V

AU - Dörr, Marcus

AU - Kerr, Kathleen F

AU - Magnani, Jared W

AU - Del Greco M, Fabiola

AU - Zhang, Weihua

AU - Nolte, Ilja M

AU - Silva, Claudia T

AU - Padmanabhan, Sandosh

AU - Tragante, Vinicius

AU - Esko, Tõnu

AU - Abecasis, Gonçalo R

AU - Adriaens, Michiel E

AU - Andersen, Karl

AU - Barnett, Phil

AU - Bis, Joshua C

AU - Bodmer, Rolf

AU - Buckley, Brendan M

AU - Campbell, Harry

AU - Cannon, Megan V

AU - Chakravarti, Aravinda

AU - Chen, Lin Y

AU - Delitala, Alessandro

AU - Devereux, Richard B

AU - Doevendans, Pieter A

AU - Dominiczak, Anna F

AU - Ferrucci, Luigi

AU - Ford, Ian

AU - Gieger, Christian

AU - Harris, Tamara B

AU - Haugen, Eric

AU - Heinig, Matthias

AU - Hernandez, Dena G

AU - Hillege, Hans L

AU - Hirschhorn, Joel N

AU - Hofman, Albert

AU - Hubner, Norbert

AU - Hwang, Shih-Jen

AU - Iorio, Annamaria

AU - Kähönen, Mika

AU - Kellis, Manolis

AU - Kolcic, Ivana

AU - Kooner, Ishminder K

AU - Kooner, Jaspal S

AU - Kors, Jan A

AU - Lakatta, Edward G

AU - Lage, Kasper

AU - Launer, Lenore J

AU - Levy, Daniel

AU - Lundby, Alicia

AU - Macfarlane, Peter W

AU - May, Dalit

AU - Meitinger, Thomas

AU - Metspalu, Andres

AU - Nappo, Stefania

AU - Naitza, Silvia

AU - Neph, Shane

AU - Nord, Alex S

AU - Nutile, Teresa

AU - Okin, Peter M

AU - Olsen, Jesper V

AU - Oostra, Ben A

AU - Penninger, Josef M

AU - Pennacchio, Len A

AU - Pers, Tune H

AU - Perz, Siegfried

AU - Peters, Annette

AU - Pinto, Yigal M

AU - Pfeufer, Arne

AU - Pilia, Maria Grazia

AU - Pramstaller, Peter P

AU - Prins, Bram P

AU - Raitakari, Olli T

AU - Raychaudhuri, Soumya

AU - Rice, Ken M

AU - Rossin, Elizabeth J

AU - Rotter, Jerome I

AU - Schafer, Sebastian

AU - Schlessinger, David

AU - Schmidt, Carsten O

AU - Sehmi, Jobanpreet

AU - Silljé, Herman H W

AU - Sinagra, Gianfranco

AU - Sinner, Moritz F

AU - Slowikowski, Kamil

AU - Soliman, Elsayed Z

AU - Spector, Timothy D

AU - Spiering, Wilko

AU - Stamatoyannopoulos, John A

AU - Stolk, Ronald P

AU - Strauch, Konstantin

AU - Tan, Sian-Tsung

AU - Tarasov, Kirill V

AU - Trinh, Bosco

AU - Uitterlinden, Andre G

AU - van den Boogaard, Malou

AU - van Duijn, Cornelia M

AU - van Gilst, Wiek H

AU - Viikari, Jorma S

AU - Visscher, Peter M

AU - Vitart, Veronique

AU - Völker, Uwe

AU - Waldenberger, Melanie

AU - Weichenberger, Christian X

AU - Westra, Harm-Jan

AU - Wijmenga, Cisca

AU - Wolffenbuttel, Bruce H

AU - Yang, Jian

AU - Bezzina, Connie R

AU - Munroe, Patricia B

AU - Snieder, Harold

AU - Wright, Alan F

AU - Rudan, Igor

AU - Boyer, Laurie A

AU - Asselbergs, Folkert W

AU - van Veldhuisen, Dirk J

AU - Stricker, Bruno H

AU - Psaty, Bruce M

AU - Ciullo, Marina

AU - Sanna, Serena

AU - Lehtimäki, Terho

AU - Wilson, James F

AU - Bandinelli, Stefania

AU - Alonso, Alvaro

AU - Gasparini, Paolo

AU - Jukema, J Wouter

AU - Kääb, Stefan

AU - Gudnason, Vilmundur

AU - Felix, Stephan B

AU - Heckbert, Susan R

AU - de Boer, Rudolf A

AU - Newton-Cheh, Christopher

AU - Hicks, Andrew A

AU - Chambers, John C

AU - Jamshidi, Yalda

AU - Visel, Axel

AU - Christoffels, Vincent M

AU - Isaacs, Aaron

AU - Samani, Nilesh J

AU - de Bakker, Paul I W

N1 - Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

PY - 2016/9/27

Y1 - 2016/9/27

N2 - 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.

AB - 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.

U2 - 10.1016/j.jacc.2016.07.729

DO - 10.1016/j.jacc.2016.07.729

M3 - Journal article

C2 - 27659466

VL - 68

SP - 1435

EP - 1448

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

IS - 13

ER -