title: Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram.
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.
authors.affiliation: 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.
authors.forename: Niek
authors.initials: N
authors.lastname: Verweij
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Irene
authors.initials: I
authors.lastname: Mateo Leach
authors.affiliation: 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.
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.affiliation: Department of Medicine, Cardiovascular Health Research Unit, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.affiliation: 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.
authors.forename: Tune H
authors.initials: TH
authors.lastname: Pers
authors.affiliation: Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Marten E
authors.initials: ME
authors.lastname: Van Den Berg
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere 33520, Finland.
authors.forename: Leo-Pekka
authors.initials: LP
authors.lastname: Lyytikäinen
authors.affiliation: Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Phil
authors.initials: P
authors.lastname: Barnett
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Xinchen
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Public Health Sciences, Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston Salem, NC, USA.
authors.forename: Elsayed Z
authors.initials: EZ
authors.lastname: Soliman
authors.affiliation: Department of Epidemiology, Genetic Epidemiology Unit, Rotterdam, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Van Duijn
authors.affiliation: Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere 33521, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Van Veldhuisen
authors.affiliation: Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Kors
authors.affiliation: 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.
authors.forename: Olli T
authors.initials: OT
authors.lastname: Raitakari
authors.affiliation: Department of Epidemiology, Genetic Epidemiology Unit, Rotterdam, The Netherlands.
authors.forename: Claudia T
authors.initials: CT
authors.lastname: Silva
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere 33520, Finland.
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.affiliation: 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.
authors.forename: Hans L
authors.initials: HL
authors.lastname: Hillege
authors.affiliation: 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.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Boyer
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Wiek H
authors.initials: WH
authors.lastname: Van Gilst
authors.affiliation: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Alonso
authors.affiliation: 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.
authors.forename: Nona
authors.initials: N
authors.lastname: Sotoodehnia
authors.affiliation: Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Eijgelsheim
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: De Boer
authors.affiliation: 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.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: De Bakker
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: 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.
authors.forename: Pim
authors.initials: P
authors.lastname: Van Der Harst
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D053840:Brugada Syndrome / Q000235:genetics* / Q000503:physiopathology; D000075224:Cardiac Conduction System Disease; D016757:Death, Sudden, Cardiac / Q000473:pathology; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006329:Heart Conduction System / Q000503:physiopathology; D006801:Humans; D008297:Male; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D051669:Shab Potassium Channels / Q000235:genetics; D051672:Shal Potassium Channels / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012097:Repressor Proteins; D051669:Shab Potassium Channels; D051672:Shal Potassium Channels; C405693:HEY2 protein, human; C496988:KCNB1 protein, human; C497021:KCND3 protein, human; C488081:NOS1AP protein, human; C568320:SCN5A protein, human