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 Erikstrup; Rikke 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

doi:10.1093/eurheartj/ehad016

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

Department of Finance

Research output: Contribution to journal › Journal article › Research › peer-review

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.

Original language	English
Article number	ehad016
Journal	European Heart Journal
Volume	44
Issue number	12
Pages (from-to)	1070-1080
Number of pages	11
ISSN	0195-668X
DOIs	https://doi.org/10.1093/eurheartj/ehad016
Publication status	Published - 2023

Keywords

Syncope
GWAS
Meta-analysis
Vasovagal reaction
PTPRN2
Imprinting

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Aegisdottir, H. M., Thorolfsdottir, R. B., Sveinbjornsson, G., Stefansson, O. A., Gunnarsson, B., Tragante, V., Thorleifsson, G., Stefansdottir, L., Thorgeirsson, T. E., Ferkingstad, E., Sulem, P., Norddahl, G., Rutsdottir, G., Banasik, K., Christensen, A. H., Mikkelsen, C., Pedersen, O. B., Brunak, S., Bruun, M. T., ... Werge, T. (2023). Genetic Variants Associated with Syncope Implicate Neural and Autonomic Processes. European Heart Journal, 44(12), 1070-1080. Article ehad016. https://doi.org/10.1093/eurheartj/ehad016

@article{cd076913ce7d494580ccbded068504c0,

title = "Genetic Variants Associated with Syncope Implicate Neural and Autonomic Processes",

abstract = "AimsSyncope 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 resultsThis 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.ConclusionThe 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.",

keywords = "Syncope, GWAS, Meta-analysis, Vasovagal reaction, PTPRN2, Imprinting, Syncope, GWAS, Meta-analysis, Vasovagal reaction, PTPRN2, Imprinting",

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

year = "2023",

doi = "10.1093/eurheartj/ehad016",

language = "English",

volume = "44",

pages = "1070--1080",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "12",

}

Aegisdottir, HM, Thorolfsdottir, RB, Sveinbjornsson, G, Stefansson, OA, Gunnarsson, B, Tragante, V, Thorleifsson, G, Stefansdottir, L, Thorgeirsson, TE, Ferkingstad, E, Sulem, P, Norddahl, G, Rutsdottir, G, Banasik, K, Christensen, AH, Mikkelsen, C, Pedersen, OB, Brunak, S, Bruun, MT, Erikstrup, C, Jacobsen, RL, Nielsen, KR, Sørensen, E, Frigge, ML, Hjorleifsson, KE, Ivarsdottir, EV, Helgadottir, A, Gretarsdottir, S, Steinthorsdottir, V, Oddsson, A, Eggertsson, HP, Halldorsson, GH, Jones, DA, Andersson, JL, Knowlton, KU, Nadauld, LD, DBDS Genomic Consortium, Haraldsson, M, Thorgeirsson, G, Bundgaard, H, Arnar, DO, Thorsteinsdottir, U, Gudbjartsson, DF, Ostrowski, SR, Holm, H, Stefansson, K, Andersen, S, Burgdorf, KS, Didriksen, M, Dinh, KM, Folkmann Hansen, T, Hjalgrim, H, Jemec, GBE, Jennum, P, Johansson, PI, Hørup Larsen, MA, Mikkelsen, S, Nyegaard, M, Stefánsson, H, Sækmose, S, Ullum, H & Werge, T 2023, 'Genetic Variants Associated with Syncope Implicate Neural and Autonomic Processes', European Heart Journal, vol. 44, no. 12, ehad016, pp. 1070-1080. https://doi.org/10.1093/eurheartj/ehad016

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 René

AU - Sørensen, Erik

AU - Frigge, Michael L.

AU - Hjorleifsson, Kristjan E.

AU - Ivarsdottir, Erna V.

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 - Andersson, Jeffrey L.

AU - Knowlton, Kirk U.

AU - Nadauld, Lincoln D.

AU - DBDS Genomic Consortium

AU - Haraldsson, Magnus

AU - Thorgeirsson, Gudmundur

AU - Bundgaard, Henning

AU - Arnar, David O.

AU - Thorsteinsdottir, Unnur

AU - Gudbjartsson, Daniel F.

AU - Ostrowski, Sisse Rye

AU - Holm, Hilma

AU - Stefansson, Kari

AU - Andersen, Steffen

AU - Burgdorf, Kristoffer Sølvsten

AU - Didriksen, Maria

AU - Dinh, Khoa Manh

AU - Folkmann Hansen, Thomas

AU - Hjalgrim, Henrik

AU - Jemec, Gregor Borut Ernst

AU - Jennum, Poul

AU - Johansson, Pär Ingemar

AU - Hørup Larsen, Margit Anita

AU - Mikkelsen, Susan

AU - Nyegaard, Mette

AU - Stefánsson, Hreinn

AU - Sækmose, Susanne

AU - Ullum, Henrik

AU - Werge, Thomas

PY - 2023

Y1 - 2023

N2 - AimsSyncope 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 resultsThis 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.ConclusionThe 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 - AimsSyncope 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 resultsThis 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.ConclusionThe 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 - Syncope

KW - GWAS

KW - Meta-analysis

KW - Vasovagal reaction

KW - PTPRN2

KW - Imprinting

U2 - 10.1093/eurheartj/ehad016

DO - 10.1093/eurheartj/ehad016

M3 - Journal article

SN - 0195-668X

VL - 44

SP - 1070

EP - 1080

JO - European Heart Journal

JF - European Heart Journal

IS - 12

M1 - ehad016

ER -