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

TitleA comprehensive evaluation of the genetic architecture of sudden cardiac arrest.
Publication TypeJournal Article
Year of Publication2018
AuthorsAshar FN, Mitchell RN, Albert CM, Newton-Cheh C, Brody JA, Müller-Nurasyid M, Moes A, Meitinger T, Mak A, Huikuri H, M Junttila J, Goyette P, Pulit SL, Pazoki R, Tanck MW, Blom MT, Zhao XQ, Havulinna AS, Jabbari R, Glinge C, Tragante V, Escher SA, Chakravarti A, Ehret G, Coresh JJ, Li M, Prineas RJ, Franco OH, Kwok P-Y, Lumley T, Dumas F, McKnight B, Rotter JI, Lemaitre RN, Heckbert SR, O'Donnell CJ, Hwang S-J, Tardif J-C, VanDenburgh M, Uitterlinden AG, Hofman A, Stricker BHC, de Bakker PIW, Franks PW, Jansson J-H, Asselbergs FW, Halushka MK, Maleszewski JJ, Tfelt-Hansen J, Engstrøm T, Salomaa V, Virmani R, Kolodgie F, Wilde AAM, Tan HL, Bezzina CR, Eijgelsheim M, Rioux JD, Jouven X, Kääb S, Psaty BM, Siscovick DS, Arking DE
Secondary AuthorsSotoodehnia N
JournalEur Heart J
Volume39
Issue44
Pagination3961-3969
Date Published2018 11 21
ISSN1522-9645
KeywordsArrhythmias, Cardiac, Body Mass Index, Coronary Artery Disease, Death, Sudden, Cardiac, Female, Genome-Wide Association Study, Heart Conduction System, Humans, Male, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Sex Factors
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.

DOI10.1093/eurheartj/ehy474
Alternate JournalEur Heart J
PubMed ID30169657
PubMed Central IDPMC6247663
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 HL046959 / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
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R01 HL068070 / HL / NHLBI NIH HHS / United States
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R01 HL088576 / HL / NHLBI NIH HHS / United States
R01 CA040360 / CA / NCI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
T32 GM007814 / GM / NIGMS NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
P01 CA087969 / CA / NCI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
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HHSN268201100007C / HL / NHLBI NIH HHS / United States
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HHSN268200800007C / HL / NHLBI NIH HHS / United States
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HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
R01 HL091244 / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL088456 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
HHSN268201800001C / HL / NHLBI NIH HHS / United States
R01 HL080467 / HL / NHLBI NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
R01 HL035464 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
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R01 HL092111 / HL / NHLBI NIH HHS / United States