A comprehensive evaluation of the genetic architecture of sudden cardiac arrest

Foram N. Ashar, Rebecca N. Mitchell, Christine M. Albert, Christopher Newton-Cheh, Jennifer A. Brody, Martina Müller-Nurasyid, Anna Moes, Thomas Meitinger, Angel Mak, Heikki Huikuri, M. Juhani Junttila, Philippe Goyette, Sara L. Pulit, Raha Pazoki, Michael W. Tanck, Marieke T. Blom, Xiaoqing Zhao, Aki S. Havulinna, Reza Jabbari, Charlotte GlingeVinicius Tragante, Stefan A. Escher, Aravinda Chakravarti, Georg Ehret, Josef Coresh, Man Li, Ronald J. Prineas, Oscar H. Franco, Pui Yan Kwok, Thomas Lumley, Florence Dumas, Barbara McKnight, Jerome I. Rotter, Rozenn N. Lemaitre, Susan R. Heckbert, Christopher J. O'Donnell, Shih Jen Hwang, Jean Claude Tardif, Martin VanDenburgh, André G. Uitterlinden, Albert Hofman, Bruno H.C. Stricker, Paul I.W. De Bakker, Paul W. Franks, Jan Hakan Jansson, Folkert W. Asselbergs, Marc K. Halushka, Joseph J. Maleszewski, Jacob Tfelt-Hansen, Thomas Engstrøm, Veikko Salomaa, Renu Virmani, Frank Kolodgie, Arthur A.M. Wilde, Hanno L. Tan, Connie R. Bezzina, Mark Eijgelsheim, John D. Rioux, Xavier Jouven, Stefan Kääb, Bruce M. Psaty, David S. Siscovick, Dan E. Arking, Nona Sotoodehnia

Research output: Contribution to journalArticle

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3961-3969
Number of pages9
JournalEuropean heart journal
Volume39
Issue number44
DOIs
StatePublished - Nov 21 2018

Keywords

  • Genome-wide association study
  • Mendelian randomization
  • Sudden cardiac arrest

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Ashar, F. N., Mitchell, R. N., Albert, C. M., Newton-Cheh, C., Brody, J. A., Müller-Nurasyid, M., Moes, A., Meitinger, T., Mak, A., Huikuri, H., Junttila, M. J., Goyette, P., Pulit, S. L., Pazoki, R., Tanck, M. W., Blom, M. T., Zhao, X., Havulinna, A. S., Jabbari, R., ... Sotoodehnia, N. (2018). A comprehensive evaluation of the genetic architecture of sudden cardiac arrest. European heart journal, 39(44), 3961-3969. https://doi.org/10.1093/eurheartj/ehy474