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 Muller-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, Xiao Qing 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, Marja Leena Kortelainen, Martin VanDenburgh, Andre 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 Engstrom, Veikko Salomaa, Renu Virmani, Frank Kolodgie, Arthur A.M. Wilde, Hanno L. Tan, Connie R. Bezzina, Mark Eijgelsheim, John D. Rioux, Xavier Jouven, Stefan Kaab, Bruce M. Psaty, David S. Siscovick, Dan E. Arking, Nona Sotoodehnia

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. While several risk factors are observationally associated with SCA, the genetic architecture of SCA in the general population remains unknown. Furthermore, understanding which risk factors are causal may help target prevention strategies. Methods: We carried out a large genome-wide association study (GWAS) for SCA (n=3,939 cases, 25,989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. Results: 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 (1) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (2) height and BMI, and (3) electrical instability traits (QT and atrial fibrillation), suggesting etiologic 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)
JournalUnknown Journal
DOIs
StatePublished - Dec 16 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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