Genetic variants associated with syncope implicate neural and autonomic processes
Authors: Aegisdottir Hildur M , Thorolfsdottir Rosa B , Sveinbjornsson Gardar , Stefansson Olafur A , Gunnarsson Bjarni , Tragante Vinicius , Thorleifsson Gudmar , Stefansdottir Lilja , Thorgeirsson Thorgeir E , Ferkingstad Egil , Sulem Patrick , Norddahl Gudmundur , Rutsdottir Gudrun , Banasik Karina , Christensen Alex Hoerby , Mikkelsen Christina , Pedersen Ole Birger , Brunak Søren , Bruun Mie Topholm , Erikstrup Christian , Jacobsen Rikke Louise , Nielsen Kaspar Rene , Sørensen Erik , Frigge Michael L , Hjorleifsson Kristjan E , Ivarsdottir Erna V , Helgadottir Anna , Gretarsdottir Solveig , Steinthorsdottir Valgerdur , Oddsson Asmundur , Eggertsson Hannes P , Halldorsson Gisli H , Jones David A , Anderson Jeffrey L , Knowlton Kirk U , Nadauld Lincoln D ,   DBDS Genomic Consortium, Andersen Steffen , Burgdorf Kristoffer , Didriksen Maria , Dinh Khoa Manh , Hansen Thomas Folkmann , Hjalgrim Henrik , Jemec Gregor , Jennum Poul , Johansson Pär Ingemar , Larsen Margit Anita Hørup , Mikkelsen Susan , Nyegaard Mette , Stefánsson Hreinn , Sækmose Susanne , Ullum Henrik , Werge Thomas , Banasik Karina , Pedersen Ole Birger , Brunak Søren , Bruun Mie Topholm , Erikstrup Christian , Nielsen Kaspar Rene , Sørensen Erik , Thorsteinsdottir Unnur , Gudbjartsson Daniel F , Ostrowski Sisse R , Stefansson Kari , Haraldsson Magnus , Thorgeirsson Gudmundur , Bundgaard Henning , Arnar David O , Thorsteinsdottir Unnur , Gudbjartsson Daniel F , Ostrowski Sisse R , Holm Hilma , Stefansson Kari 
Published: February 2023

Abstract

Aims
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.

Conclusion
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.