A comprehensive evaluation of the genetic architecture of sudden cardiac arrest
- 28 August 2018
- journal article
- research article
- Published by Oxford University Press (OUP) in European Heart Journal
- Vol. 39 (44), 3961-3969
- https://doi.org/10.1093/eurheartj/ehy474
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.Funding Information
- Netherlands Heart Foundation (2001D019, 2003T302, 2007B202, 2005T024)
- CVON project PREDICT
- Leducq Foundation (05-CVD)
- Center for Translational Molecular Medicine
- Netherlands Organization for Scientific Research (016.150.610)
- Netherlands Heart Foundation
- European Union’s Horizon 2020 Research and Innovation Programme (733381)
- Netherlands Organization for Scientific Research (918.86.616)
- Medicines Evaluation Board Netherlands
- National Heart, Lung, and Blood Institute (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694)
- National Human Genome Research Institute (U01HG004402)
- National Institutes of Health (HHSN268200625226C)
- National Institutes of Health
- NIH Roadmap for Medical Research (UL1RR025005)
- National Institutes of Health (R01HL11267, R01HL116747)
- National Heart, Lung, and Blood Institute (HL111089, HL088456, HL088576, HL091244, HL116747, HL092111)
- John Locke and Medic One Foundations
- National Heart, Lung, and Blood Institute (HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, U01HL130114)
- 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)
- National Institutes of Health (HL111089, HL116747)
- National Heart, Lung, and Blood Institute (HL-54776, HL-54776)
- United States Department of Agriculture Research Service (53-K06-5-10, 58-1950-9-001)
- National Heart, Lung, and Blood Institute Framingham Heart Study (N01-HC-25195)
- Affymetrix, Inc (N02-HL-6-4278)
- Sigrid Juselius Foundation
- National Heart, Lung, and Blood Institute (HL-092111, HL-068070, HL-26490, HL-34595, HL-34594, HL-35464, HL-46959, HL-080467)
- National Cancer Institute (CA-34944, CA-40360, CA-55075, CA-87969, CA-97193)
- Netherlands Organisation of Scientific Research NWO Investments (175.010.2005.011, 911-03-012)
- Research Institute for Diseases in the Elderly (014-93-015)
- Netherlands Genomics Initiative
- Netherlands Organisation for Scientific Research (050-060-810)
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