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Eur Heart J. 2018 Nov 21;39(44):3961-3969. doi: 10.1093/eurheartj/ehy474.

A comprehensive evaluation of the genetic architecture of sudden cardiac arrest.

Author information

1
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins, 733 N Broadway, Baltimore, MD, USA.
2
Divisions of Preventive Medicine and Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, 900 Commonwealth Ave East, 3rd Floor, Boston, MA, USA.
3
Center for Human Genetic Research & Cardiovascular Research Center, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, USA.
4
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, 1730 Minor Ave, Seattle, WA, USA.
5
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstraße 1, Neuherberg, Germany.
6
Chair of Genetic Epidemiology, Institute for Medical Informatics, Biometry and Epidemiology, Faculty of Medicine, Ludwig-Maximilians University, Marchioninistr. 15, Munich, Germany.
7
Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University, Marchioninistr. 15, Munich, Germany.
8
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Biedersteiner Strasse 29, Munich, Germany.
9
Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, Neuherberg, Germany.
10
Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, Munich, Germany.
11
Cardiovascular Research Institute and Institute for Human Genetics, University of California, San Francisco, 1550 4th Street, San Francisco, CA, USA.
12
Research Unit of Internal Medicine, University Hospital and University of Oulu, Kajaaninkatu 50, Oulu, Finland.
13
Montreal Heart Institute, Université de Montréal, 5000 rue Bélanger, Montréal, Quebec, Canada.
14
Department of Genetics, Center for Molecular Medicine, University Medical Centre Utrecht, Heidelberglaan 100, Utrecht, The Netherlands.
15
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Hospital, Praed St, Paddington, London, UK.
16
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Meibergdreef 9, AZ Amsterdam, The Netherlands.
17
Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, Meibergdreef 9, AZ Amsterdam, The Netherlands.
18
CVPath Institute, 19 Firstfield Road, Gaithersburg, MD, USA.
19
National Institute for Health and Welfare, Mannerheimintie 166, Helsinki, Finland.
20
Department of Cardiology, Rigshospitalet, Inge Lehmanns Vej 7, Copenhagen, Denmark.
21
Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Heidelberglaan 100, Utrecht, The Netherlands.
22
Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Barngatan 4, Skånes universitetssjukhus, Malmo, Sweden.
23
Department of Epidemiology, Johns Hopkins University, 615 N Wolfe Street, Baltimore, MD, USA.
24
Public Health Sciences, Wake Forest University, Medical Center Boulevard, Winston-Salem, NC, USA.
25
Institute of Social and Preventative Medicine, University of Bern, Mittelstrasse 43, Bern, Switzerland.
26
Department of Epidemiology, Erasmus MC, Dr. Molewaterplein 50, GE Rotterdam, The Netherlands.
27
Department of Statistics, University of Auckland, Private Bag 92014, Auckland, New Zealand.
28
Paris Sudden Death Expertise Center, University Paris Descartes, Sorbonne Paris Cité, INSERM U970, 56 rue Leblanc, Paris, France.
29
Department of Biostatistics, University of Washington, F-600, Health Sciences Building 1705 NE Pacific Street, Seattle, WA, USA.
30
The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA, USA.
31
Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, 1959 NE Pacific St, Seattle, WA, USA.
32
NHLBI Framingham Heart Study, 73 Mount Wayte Avenue, Suite #2, Framingham, MA, USA.
33
Cardiology Section, Department of Medicine, Boston VA Healthcare System, 1400 VFW Parkway, Boston, MA, USA.
34
Erasmus MC University Medical Center, Department of Internal Medicine, Dr. Molewaterplein 40, CD Rotterdam, The Netherlands.
35
Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands.
36
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands.
37
Department of Public Health and Clinical Medicine, Research Unit Skelleftea, Umea University, University Hospital, Building 1A, 4st, Umea, Sweden.
38
Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, 69-75 Chenies Mews, London, UK.
39
Institute of Health Informatics, University College London, 222 Euston Road London, UK.
40
Department of Pathology, Division of Cardiovascular Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Rm 632B, Baltimore, MD, USA.
41
Department of Laboratory Medicine & Pathology, Mayo Clinic, 3050 Superior Drive, Rochester, MN, USA.
42
Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Inge Lehmanns Vej 7, Copenhagen, Denmark.
43
Department of Cardiology, University of Lund, Getingevägen 4, Lund, Sweden.
44
Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, AZ, Amsterdam, The Netherlands.
45
Department of Nephrology, University Medical Center Groningen, Hanzeplein 1, GZ, Groningen, The Netherlands.
46
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, 1730 Minor Ave, suite #1360, Seattle, WA, USA.
47
The New York Academy of Medicine, 1216 5th Ave, New York, New York, USA.
48
Cardiovascular Health Research Unit, Division of Cardiology, Departments of Medicine and Epidemiology, University of Washington, 1730 Minor Ave, Seattle, WA, USA.

Abstract

Aims:

Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.

Methods and results:

We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.

Conclusions:

Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

PMID:
30169657
PMCID:
PMC6247663
[Available on 2019-11-21]
DOI:
10.1093/eurheartj/ehy474

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