Genetic Variants Associated with Syncope Implicate Neural and Autonomic Processes

Hildur M. Aegisdottir, Rosa B. Thorolfsdottir, Gardar Sveinbjornsson, Olafur A. Stefansson, Bjarni Gunnarsson, Vinicius Tragante, Gudmar Thorleifsson, Lilja Stefansdottir, Thorgeir E. Thorgeirsson, Egil Ferkingstad, Patrick Sulem, Gudmundur Norddahl, Gudrun Rutsdottir, Karina Banasik, Alex Hoerby Christensen, Christina Mikkelsen, Ole Birger Pedersen, Søren Brunak, Mie Topholm Bruun, Christian ErikstrupRikke Louise Jacobsen, Kaspar René Nielsen, Erik Sørensen, Michael L. Frigge, Kristjan E. Hjorleifsson, Erna V. Ivarsdottir, Anna Helgadottir, Solveig Gretarsdottir, Valgerdur Steinthorsdottir, Asmundur Oddsson, Hannes P. Eggertsson, Gisli H. Halldorsson, David A. Jones, Jeffrey L. Andersson, Kirk U. Knowlton, Lincoln D. Nadauld, DBDS Genomic Consortium, Magnus Haraldsson, Gudmundur Thorgeirsson, Henning Bundgaard, David O. Arnar, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Sisse Rye Ostrowski, Hilma Holm*, Kari Stefansson*, Steffen Andersen, Kristoffer Sølvsten Burgdorf, Maria Didriksen, Khoa Manh Dinh, Thomas Folkmann Hansen, Henrik Hjalgrim, Gregor Borut Ernst Jemec, Poul Jennum, Pär Ingemar Johansson, Margit Anita Hørup Larsen, Susan Mikkelsen, Mette Nyegaard, Hreinn Stefánsson, Susanne Sækmose, Henrik Ullum, Thomas Werge

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


Syncope is a common and clinically challenging condition. In this study, the genetics of syncope were investigated to seek knowledge about its pathophysiology and prognostic implications.

Methods and results
This genome-wide association meta-analysis included 56 071 syncope cases and 890 790 controls from deCODE genetics (Iceland), UK Biobank (United Kingdom), and Copenhagen Hospital Biobank Cardiovascular Study/Danish Blood Donor Study (Denmark), with a follow-up assessment of variants in 22 412 cases and 286 003 controls from Intermountain (Utah, USA) and FinnGen (Finland). The study yielded 18 independent syncope variants, 17 of which were novel. One of the variants, p.Ser140Thr in PTPRN2, affected syncope only when maternally inherited. Another variant associated with a vasovagal reaction during blood donation and five others with heart rate and/or blood pressure regulation, with variable directions of effects. None of the 18 associations could be attributed to cardiovascular or other disorders. Annotation with regard to regulatory elements indicated that the syncope variants were preferentially located in neural-specific regulatory regions. Mendelian randomization analysis supported a causal effect of coronary artery disease on syncope. A polygenic score (PGS) for syncope captured genetic correlation with cardiovascular disorders, diabetes, depression, and shortened lifespan. However, a score based solely on the 18 syncope variants performed similarly to the PGS in detecting syncope risk but did not associate with other disorders.

The results demonstrate that syncope has a distinct genetic architecture that implicates neural regulatory processes and a complex relationship with heart rate and blood pressure regulation. A shared genetic background with poor cardiovascular health was observed, supporting the importance of a thorough assessment of individuals presenting with syncope.
Original languageEnglish
Article numberehad016
JournalEuropean Heart Journal
Issue number12
Pages (from-to)1070-1080
Number of pages11
Publication statusPublished - 2023


  • Syncope
  • GWAS
  • Meta-analysis
  • Vasovagal reaction
  • PTPRN2
  • Imprinting

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