TY - JOUR

T1 - Genetic variants associated with syncope implicate neural and autonomic processes

AU - Aegisdottir, Hildur M.

AU - Thorolfsdottir, Rosa B.

AU - Sveinbjornsson, Gardar

AU - Stefansson, Olafur A.

AU - Gunnarsson, Bjarni

AU - Tragante, Vinicius

AU - Thorleifsson, Gudmar

AU - Stefansdottir, Lilja

AU - Thorgeirsson, Thorgeir E.

AU - Ferkingstad, Egil

AU - Sulem, Patrick

AU - Norddahl, Gudmundur

AU - Rutsdottir, Gudrun

AU - Banasik, Karina

AU - Christensen, Alex Hoerby

AU - Mikkelsen, Christina

AU - Pedersen, Ole Birger

AU - Brunak, Søren

AU - Bruun, Mie Topholm

AU - Erikstrup, Christian

AU - Jacobsen, Rikke Louise

AU - Nielsen, Kaspar Rene

AU - Sorensen, Erik

AU - Frigge, Michael L.

AU - Hjorleifsson, Kristjan E.

AU - Ivarsdottir, Erna

AU - Helgadottir, Anna

AU - Gretarsdottir, Solveig

AU - Steinthorsdottir, Valgerdur

AU - Oddsson, Asmundur

AU - Eggertsson, Hannes P.

AU - Halldorsson, Gisli H.

AU - Jones, David A.

AU - Anderson, Jeffrey L.

AU - Knowlton, Kirk U.

AU - Nadauld, Lincoln D.

AU - DBDS Genomic Consortium, D. B. D. S. Genomic Consortium

AU - Haraldsson, Magnus

AU - Thorgeirsson, Gudmundur

AU - Bundgaard, Henning

AU - Arnar, David O.

AU - Thorsteinsdottir, Unnur

AU - Gudbjartsson, Daniel F.

AU - Ostrowsk, Sisse R.

AU - Holm, Hilma

AU - Stefansson, Kari

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - Syncope

KW - GWAS

KW - Meta-analysis

KW - Vasovagal reaction

KW - PTPRN2

KW - Imprinting

KW - GENOME-WIDE ASSOCIATION

KW - RESTING HEART-RATE

KW - QUALITY-OF-LIFE

KW - VASOVAGAL SYNCOPE

KW - MENDELIAN RANDOMIZATION

KW - FAMILY-HISTORY

KW - UP TILT

KW - IDENTIFICATION

KW - PREVALENCE

KW - ARCHITECTURE

U2 - 10.1093/eurheartj/ehad016

DO - 10.1093/eurheartj/ehad016

M3 - Journal article

C2 - 36747475

VL - 44

SP - 1070

EP - 1080

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

IS - 12

ER -