52 Genetic Loci Influencing Myocardial Mass

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Title: 52 Genetic Loci Influencing Myocardial Mass
Author(s): Van der Harst, P
Van Setten, J
Verweij, N
Vogler, G
Franke, L
Maurano, MT
Wang, X
Leach, IM
Eijgelsheim, M
Sotoodehnia, N
Hayward, C
Sorice, R
Meirelles, O
Lyytikainen, L-P
Polasek, O
Tanaka, T
Arking, DE
Ulivi, S
Trompet, S
Mueller-Nurasyid, M
Smith, AV
Doerr, M
Kerr, KF
Magnani, JW
Del Greco, F
Zhang, W
Nolte, IM
Silva, CT
Padmanabhan, S
Tragante, V
Esko, T
Abecasis, GR
Adriaens, ME
Andersen, K
Barnett, P
Bis, JC
Bodmer, R
Buckley, BM
Campbell, H
Cannon, MV
Chakravarti, A
Chen, LY
Delitala, A
Devereux, RB
Doevendans, PA
Dominiczak, AF
Ferrucci, L
Ford, I
Gieger, C
Harris, TB
Haugen, E
Heinig, M
Hernandez, DG
Hillege, HL
Hirschhorn, JN
Hofman, A
Hubner, N
Hwang, S-J
Iorio, A
Kahonen, M
Kellis, M
Kolcic, I
Kooner, IK
Kooner, JS
Kors, JA
Lakatta, EG
Lage, K
Launer, LJ
Levy, D
Lundby, A
Macfarlane, PW
May, D
Meitinger, T
Metspalu, A
Nappo, S
Naitza, S
Neph, S
Nord, AS
Nutile, T
Okin, PM
Olsen, JV
Oostra, BA
Penninger, JM
Pennacchio, LA
Pers, TH
Perz, S
Peters, A
Pinto, YM
Pfeufer, A
Pilia, MG
Pramstaller, PP
Prins, BP
Raitakari, OT
Raychaudhuri, S
Rice, KM
Rossin, EJ
Rotter, JI
Schafer, S
Schlessinger, D
Schmidt, CO
Sehmi, J
Sillje, HHW
Sinagra, G
Sinner, MF
Slowikowski, K
Soliman, EZ
Spector, TD
Spiering, W
Stamatoyannopoulos, JA
Stolk, RP
Strauch, K
Tan, S-T
Tarasov, KV
Trinh, B
Uitterlinden, AG
Van den Boogaard, M
Van Duijn, CM
Van Gilst, WH
Viikari, JS
Visscher, PM
Vitart, V
Voelker, U
Waldenberger, M
Weichenberger, CX
Westra, H-J
Wijmenga, C
Wolffenbuttel, BH
Yang, J
Bezzina, CR
Munroe, PB
Snieder, H
Wright, AF
Rudan, I
Boyer, LA
Asselbergs, FW
Van Veldhuisen, DJ
Stricker, BH
Psaty, BM
Ciullo, M
Sanna, S
Lehtimaki, T
Wilson, JF
Bandinelli, S
Alonso, A
Gasparini, P
Jukema, JW
Kaeaeb, S
Gudnason, V
Felix, SB
Heckbert, SR
De Boer, RA
Newton-Cheh, C
Hicks, AA
Chambers, JC
Jamshidi, Y
Visel, A
Christoffels, VM
Isaacs, A
Samani, NJ
De Bakker, PIW
Item Type: Journal Article
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.
Publication Date: 27-Sep-2016
Date of Acceptance: 14-Jul-2016
URI: http://hdl.handle.net/10044/1/45764
DOI: https://dx.doi.org/10.1016/j.jacc.2016.07.729
ISSN: 1558-3597
Publisher: Elsevier
Start Page: 1435
End Page: 1448
Journal / Book Title: Journal of the American College of Cardiology
Volume: 68
Issue: 13
Copyright Statement: © 2016 by the American College of Cardiology Foundation. Published by Elsevier. This is an open access article under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (https://creativecommons.org/licenses/by-nc-nd/4.0/)
Keywords: Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Cardiovascular System & Cardiology
electrocardiogram
genetic association study
heart failure
left ventricular hypertrophy
QRS
LEFT-VENTRICULAR HYPERTROPHY
CARDIAC-HYPERTROPHY
REGULATORY DNA
ELECTROCARDIOGRAM
MORTALITY
DISEASE
VOLTAGE
DYSFUNCTION
GENOME
HEART
QRS
electrocardiogram
genetic association study
heart failure
left ventricular hypertrophy
Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Cardiovascular System & Cardiology
electrocardiogram
genetic association study
heart failure
left ventricular hypertrophy
QRS
LEFT-VENTRICULAR HYPERTROPHY
CARDIAC-HYPERTROPHY
REGULATORY DNA
ELECTROCARDIOGRAM
MORTALITY
DISEASE
VOLTAGE
DYSFUNCTION
GENOME
HEART
Cardiovascular System & Hematology
1102 Cardiovascular Medicine And Haematology
1117 Public Health And Health Services
Publication Status: Published
Appears in Collections:Faculty of Medicine
Epidemiology, Public Health and Primary Care



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