Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram

Niek Verweij; Irene Mateo Leach; Aaron Isaacs; Dan E Arking; Joshua C Bis; Tune H Pers; Marten E Van Den Berg; Leo-Pekka Lyytikäinen; Phil Barnett; Xinchen Wang; LifeLines Cohort Study; Elsayed Z Soliman; Cornelia M Van Duijn; Mika Kähönen; Dirk J Van Veldhuisen; Jan A Kors; Olli T Raitakari; Claudia T Silva; Terho Lehtimäki; Hans L Hillege; Joel N Hirschhorn; Laurie A Boyer; Wiek H Van Gilst; Alvaro Alonso; Nona Sotoodehnia; Mark Eijgelsheim; Rudolf A De Boer; Paul I W De Bakker; Lude Franke; Pim Van Der Harst

doi:10.1093/hmg/ddw058

Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram

Hum Mol Genet. 2016 May 15;25(10):2093-2103. doi: 10.1093/hmg/ddw058. Epub 2016 Mar 8.

Authors

Niek Verweij¹, Irene Mateo Leach², Aaron Isaacs³, Dan E Arking⁴, Joshua C Bis⁵, Tune H Pers⁶, Marten E Van Den Berg⁷, Leo-Pekka Lyytikäinen⁸, Phil Barnett⁹, Xinchen Wang¹⁰; LifeLines Cohort Study; Elsayed Z Soliman¹¹, Cornelia M Van Duijn¹², Mika Kähönen¹³, Dirk J Van Veldhuisen², Jan A Kors⁷, Olli T Raitakari¹⁴, Claudia T Silva¹², Terho Lehtimäki⁸, Hans L Hillege¹⁵, Joel N Hirschhorn¹⁶, Laurie A Boyer¹⁰, Wiek H Van Gilst², Alvaro Alonso¹⁷, Nona Sotoodehnia¹⁸, Mark Eijgelsheim⁷, Rudolf A De Boer², Paul I W De Bakker¹⁹, Lude Franke²⁰, Pim Van Der Harst²¹

Affiliations

¹ Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 301 Binney Street, Cambridge, MA 02142, USA Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, The Netherlands.
² Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
³ Department of Epidemiology, Genetic Epidemiology Unit, Rotterdam, The Netherlands CARIM School of Cardiovascular Diseases, Maastricht Centre for Systems Biology (MaCSBio), and Department of Biochemistry, Maastricht University, Maastricht, The Netherlands.
⁴ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Medicine, Cardiovascular Health Research Unit, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
⁶ Division of Endocrinology, Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, USA Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 301 Binney Street, Cambridge, MA 02142, USA.
⁷ Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁸ Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere 33520, Finland.
⁹ Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
¹⁰ Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
¹¹ Division of Public Health Sciences, Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston Salem, NC, USA.
¹² Department of Epidemiology, Genetic Epidemiology Unit, Rotterdam, The Netherlands.
¹³ Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere 33521, Finland.
¹⁴ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20520, Finland Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland.
¹⁵ Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands Trial Coordination Center, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
¹⁶ Division of Endocrinology, Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, USA Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 301 Binney Street, Cambridge, MA 02142, USA Department of Genetics, Harvard Medical School, Boston, USA.
¹⁷ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
¹⁸ Division of Cardiology, Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
¹⁹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 301 Binney Street, Cambridge, MA 02142, USA Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
²⁰ Department of Genetics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
²¹ Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands Department of Genetics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, 3511 GC Utrecht, The Netherlands p.van.der.harst@umcg.nl.

Abstract

The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Arrhythmias, Cardiac / genetics*
Arrhythmias, Cardiac / physiopathology
Basic Helix-Loop-Helix Transcription Factors / genetics
Brugada Syndrome / genetics*
Brugada Syndrome / physiopathology
Cardiac Conduction System Disease
Death, Sudden, Cardiac / pathology
Electrocardiography*
Female
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Heart Conduction System / physiopathology
Humans
Male
NAV1.5 Voltage-Gated Sodium Channel / genetics
Polymorphism, Single Nucleotide / genetics
Repressor Proteins / genetics
Shab Potassium Channels / genetics
Shal Potassium Channels / genetics

Substances

Adaptor Proteins, Signal Transducing
Basic Helix-Loop-Helix Transcription Factors
HEY2 protein, human
KCNB1 protein, human
KCND3 protein, human
NAV1.5 Voltage-Gated Sodium Channel
NOS1AP protein, human
Repressor Proteins
SCN5A protein, human
Shab Potassium Channels
Shal Potassium Channels

Abstract

MeSH terms

Substances

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