Journal
EUROPEAN HEART JOURNAL
Volume 39, Issue 44, Pages 3961-+Publisher
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehy474
Keywords
Sudden cardiac arrest; Genome-wide association study; Mendelian randomization
Categories
Funding
- Netherlands Heart Foundation [2001D019, 2003T302, 2007B202, 2005T024]
- Netherlands Heart Foundation (CVON project PREDICT)
- Leducq Foundation [05-CVD]
- Center for Translational Molecular Medicine (CTMM COHFAR)
- Netherlands Organization for Scientific Research (NWO) [016.150.610, 918.86.616]
- Netherlands Heart Foundation, CVON project [2017-15 RESCUED]
- European Union's Horizon 2020 research and innovation programme under acronym ESCAPE-NET [733381]
- Medicines Evaluation Board Netherlands (CBG/MEB)
- National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, HL111089, HL088456, HL088576, HL091244, HL116747, HL092111]
- National Human Genome Research Institute [U01HG004402]
- National Institutes of Health [HL111089, HL116747, HHSN268200625226C, R01HL11267, R01HL116747]
- National Institutes of Health
- NIH Roadmap for Medical Research [UL1RR025005]
- Laughlin Family
- John Locke Foundation
- Medic One Foundation
- French National Institute of Medical and Scientific Research (INSERM)
- Direction Generale de la Sante (French ministry of Health)
- French German grant BMBF-ANR
- National Institute of Neurological Disorders and Stroke
- National Institute on Aging [AG023629]
- National Center for Advancing Translational Sciences [UL1TR001881]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center [DK063491]
- Laughlin Family Endowment
- United States Department of Agriculture Research Service [53-K06-5-10, 58-1950-9-001]
- Affymetrix, Inc. [N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine
- Boston Medical Center
- Sigrid Juselius Foundation (Helsinki, Finland)
- Council of Health of the Academy of Finland (Helsinki, Finland)
- Montreal Heart Institute Foundation
- Finnish Foundation for Cardiovascular Research
- University of Copenhagen (Copenhagen, Denmark)
- Danish National Research Foundation (Copenhagen, Denmark)
- John and Birthe Meyer Foundation (Copenhagen, Denmark)
- Research Foundation of the Heart Center Rigshospitalet (Copenhagen, Denmark)
- Bikuben Scholar-Danmark-Amerika Fonden & Fulbright Commission (Copenhagen, Denmark)
- Helmholtz Zentrum Munchen -German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF)
- State of Bavaria
- Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ
- National Cancer Institute [CA-34944, CA-40360, CA-55075, CA-87969, CA-97193]
- Erasmus Medical Center
- Erasmus University, Rotterdam
- Netherlands Organization for the Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- Netherlands Organisation of Scientific Research NWO Investments [75.010.2005.011, 911-03-012]
- Research Institute for Diseases in the Elderly (RIDE2) [014-93-015]
- Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]
- [HHSN268201200036C]
- [HHSN268200800007C]
- [HHSN268201800001C]
- [N01HC55222]
- [N01HC85079]
- [N01HC85080]
- [N01HC85081]
- [N01HC85082]
- [N01HC85083]
- [N01HC85086]
- [U01HL080295]
- [R01HL085251]
- [R01HL087652]
- [R01HL105756]
- [R01HL103612]
- [R01HL120393]
- [U01HL130114]
- [R01HL59367]
- [R01HL086694]
- [HL-54776]
- [HL-092111]
- [HL-068070]
- [HL-26490]
- [HL-34595]
- [HL-34594]
- [HL-35464]
- [HL-46959]
- [HL-080467]
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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.
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