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 -