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Eur J Hum Genet. 2019 Jun;27(6):952-962. doi: 10.1038/s41431-018-0295-z. Epub 2019 Jan 24.

Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits.

Author information

1
Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands. J.vanSetten@umcutrecht.nl.
2
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
3
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4
Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
5
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
6
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
7
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
8
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
9
Research Unit, AREA Science Park, Trieste, Italy.
10
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
11
Department of Cardiovascular Sciences, University of Leicester, Leicester, England.
12
NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Groby Road, Leicester, UK.
13
Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
14
CAPES Foundation, Ministry of Education of Brazil, Brasília, DF, 70040-020, Brazil.
15
Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, 33520, Tampere, Finland.
16
Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
17
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
18
Department of Medicine I, Ludwig-Maximilians-Universität, Munich, Germany.
19
DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
20
Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Germany.
21
Human Genetics Research Centre, ICCS, St George's University of London, London, UK.
22
Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy.
23
Icelandic Heart Association, Kopavogur, Iceland.
24
Faculty of Medicine, University of Iceland, Reykavik, Iceland.
25
William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.
26
NIHR Barts Cardiovascular Research Centre, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.
27
Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, The Netherlands.
28
Institute of Cardiovascular Science, Faculty of Population Health Sciences, and Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, UK.
29
Department of Nephrology, University Medical Center Groningen, Groningen, The Netherlands.
30
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
31
Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, MD, USA.
32
Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.
33
Cardiovascular Department, "Ospedali Riuniti and University of Trieste", Trieste, Italy.
34
Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands.
35
Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital-The Capital Region, Copenhagen, Denmark.
36
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
37
Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
38
Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
39
Institute of Human Genetics, Technische Universität München, Munich, Germany.
40
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, 20520, Finland.
41
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
42
Doctoral Program in Biomedical Sciences, Universidad del Rosario, Bogotá, Colombia.
43
Institute of translational Medicine-IMT-Center For Research in Genetics and Genomics-CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Rosario, Colombia.
44
Epidemiological Cardiology Research Center (EPICARE), Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
45
CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.
46
Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands.
47
Department of Biochemistry, Maastricht University, Maastricht, The Netherlands.
48
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
49
Research unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
50
Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
51
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
52
DSM, University of Trieste, Trieste, Italy.
53
IRCCS-Burlo Garofolo Children Hospital, Via dell'Istria 65, Trieste, Italy.
54
Laboratory of Experimental Cardiology, University of Copenhagen, Copenhagen, Denmark.
55
German Center for Diabetes Research, Neuherberg, Germany.
56
Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, Seattle, WA, USA.
57
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
58
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
59
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
60
Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
61
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
62
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
63
CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands. a.isaacs@maastrichtuniversity.nl.
64
Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands. a.isaacs@maastrichtuniversity.nl.
65
Department of Biochemistry, Maastricht University, Maastricht, The Netherlands. a.isaacs@maastrichtuniversity.nl.

Abstract

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.

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