Genetic variants associated with syncope implicate neural and autonomic processes

DBDS Genomic Consortium; Hildur Margrét Ægisdóttir; Rosa Björk Thorolfsdottir; Garðar Sveinbjörnsson; Ólafur Andri Stefánsson; Bjarni Gunnarsson; Vinicius Tragante; Gudmar Thorleifsson; Lilja Stefánsdóttir; Thorgeir E. Thorgeirsson; Egil Ferkingstad; patrick sulem; Gudmundur Norddahl; Guðrún Rútsdóttir; Karina Banasik; Alex Hoerby Christensen; Christina Mikkelsen; Ole Birger Pedersen; Søren Brunak; Mie Topholm Bruun; Christian Erikstrup; Rikke Louise Jacobsen; Kaspar Rene Nielsen; Erik Sørensen; Michael L. Frigge; Kristján Eldjárn Hjörleifsson; Erna V. Ivarsdottir; Anna Helgadottir; Solveig Grétarsdóttir; Valgerður Steinthórsdóttir; Ásmundur Oddson; Hannes P. Eggertsson; Gísli Hreinn Halldórsson; David A. Jones; Jeffrey L. Anderson; Kirk U. Knowlton; Lincoln D. Nadauld; Magnús Haraldsson; Guðmundur Þorgeirsson; Henning Bundgaard; Davíð Ottó Arnar; Unnur Þorsteinsdóttir; Daniel Fannar Gudbjartsson; Sisse R Ostrowski; Hilma Hólm; Kári Stefánsson

doi:10.1093/eurheartj/ehad016

Genetic variants associated with syncope implicate neural and autonomic processes

DBDS Genomic Consortium
, Hildur Margrét Ægisdóttir
, Rosa Björk Thorolfsdottir
, Garðar Sveinbjörnsson
, Ólafur Andri Stefánsson
, Bjarni Gunnarsson
, Vinicius Tragante
, Gudmar Thorleifsson
, Lilja Stefánsdóttir
, Thorgeir E. Thorgeirsson
, Egil Ferkingstad
, patrick sulem
, Gudmundur Norddahl
, Guðrún Rútsdóttir
, Karina Banasik
, Alex Hoerby Christensen
, Christina Mikkelsen
, Ole Birger Pedersen
, Søren Brunak
, Mie Topholm Bruun

Christian Erikstrup, Rikke Louise Jacobsen, Kaspar Rene Nielsen, Erik Sørensen, Michael L. Frigge, Kristján Eldjárn Hjörleifsson, Erna V. Ivarsdottir, Anna Helgadottir, Solveig Grétarsdóttir, Valgerður Steinthórsdóttir, Ásmundur Oddson, Hannes P. Eggertsson, Gísli Hreinn Halldórsson, David A. Jones, Jeffrey L. Anderson, Kirk U. Knowlton, Lincoln D. Nadauld, Magnús Haraldsson, Guðmundur Þorgeirsson, Henning Bundgaard, Davíð Ottó Arnar, Unnur Þorsteinsdóttir, Daniel Fannar Gudbjartsson, Sisse R Ostrowski, Hilma Hólm, Kári Stefánsson

University of Iceland, Landspitali

Research output: Contribution to journal › Article › 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
Pages (from-to)	1070-1080
Number of pages	11
Journal	European heart journal
Volume	44
Issue number	12
DOIs	https://doi.org/10.1093/eurheartj/ehad016
Publication status	Published - 21 Mar 2023

Bibliographical note

© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected]. Funding Information: This work was partly supported by NordForsk through the funding to PM Heart (project number 90580). This work was partly funded by the Innovation Fund Denmark (IFD) under File No. 8114-00033B and also by the Technology Development Fund, Iceland (project number 90580). Funding Information: Karina Banasik and Søren Brunak acknowledge the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001). Funding Information: We wish to express special gratitude to the individual participants in the deCODE genetics, UK Biobank, Copenhagen Hospital Biobank, Danish Blood Donor Study, FinnGen, and Intermountain cohorts. We also thank those who worked on generating these resources through data and sample collection, genotyping, and analysis. This work was partly supported by NordForsk through the funding to PM Heart (project number 90580). This work was partly funded by the Innovation Fund Denmark (IFD) under File No. 8114-00033B and also by the Technology Development Fund, Iceland (project number 90580). Publisher Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected].

Other keywords

Autonomic Nervous System
Cardiovascular Diseases/genetics
Diabetes Mellitus
GWAS
Genome-Wide Association Study/methods
Humans
Imprinting
Mendelian Randomization Analysis
Meta-analysis
PTPRN2
Syncope
Syncope/genetics
Vasovagal reaction

UN SDGs

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

Access to Document

10.1093/eurheartj/ehad016

Cite this

DBDS Genomic Consortium, Ægisdóttir, H. M., Thorolfsdottir, R. B., Sveinbjörnsson, G., Andri Stefánsson, Ó., Gunnarsson, B., Tragante, V., Thorleifsson, G., Stefánsdóttir, L., Thorgeirsson, T. E., Ferkingstad, E., sulem, P., Norddahl, G., Rútsdóttir, G., Banasik, K., Christensen, A. H., Mikkelsen, C., Pedersen, O. B., Brunak, S., ... Stefánsson, K. (2023). Genetic variants associated with syncope implicate neural and autonomic processes. European heart journal, 44(12), 1070-1080. https://doi.org/10.1093/eurheartj/ehad016

@article{38ea5506eb344d708db6fb8590ccac03,

title = "Genetic variants associated with syncope implicate neural and autonomic processes",

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.",

keywords = "Autonomic Nervous System, Cardiovascular Diseases/genetics, Diabetes Mellitus, GWAS, Genome-Wide Association Study/methods, Humans, Imprinting, Mendelian Randomization Analysis, Meta-analysis, PTPRN2, Syncope, Syncope/genetics, Vasovagal reaction",

author = "\{DBDS Genomic Consortium\} and {\AE}gisd{\'o}ttir, \{Hildur Margr{\'e}t\} and Thorolfsdottir, \{Rosa Bj{\"o}rk\} and Gar{\dh}ar Sveinbj{\"o}rnsson and \{Andri Stef{\'a}nsson\}, {\'O}lafur and Bjarni Gunnarsson and Vinicius Tragante and Gudmar Thorleifsson and Lilja Stef{\'a}nsd{\'o}ttir and Thorgeirsson, \{Thorgeir E.\} and Egil Ferkingstad and patrick sulem and Gudmundur Norddahl and Gu{\dh}r{\'u}n R{\'u}tsd{\'o}ttir 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 Rene\} and Erik S{\o}rensen and Frigge, \{Michael L.\} and Hj{\"o}rleifsson, \{Kristj{\'a}n Eldj{\'a}rn\} and Ivarsdottir, \{Erna V.\} and Anna Helgadottir and Solveig Gr{\'e}tarsd{\'o}ttir and Valger{\dh}ur Steinth{\'o}rsd{\'o}ttir and {\'A}smundur Oddson and Eggertsson, \{Hannes P.\} and Halld{\'o}rsson, \{G{\'i}sli Hreinn\} and Jones, \{David A.\} and Anderson, \{Jeffrey L.\} and Knowlton, \{Kirk U.\} and Nadauld, \{Lincoln D.\} and Magn{\'u}s Haraldsson and Gu{\dh}mundur {\TH}orgeirsson and Henning Bundgaard and Arnar, \{Dav{\'i}{\dh} Ott{\'o}\} and Unnur {\TH}orsteinsd{\'o}ttir and Gudbjartsson, \{Daniel Fannar\} and Ostrowski, \{Sisse R\} and Hilma H{\'o}lm and K{\'a}ri Stef{\'a}nsson",

note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected]. Funding Information: This work was partly supported by NordForsk through the funding to PM Heart (project number 90580). This work was partly funded by the Innovation Fund Denmark (IFD) under File No. 8114-00033B and also by the Technology Development Fund, Iceland (project number 90580). Funding Information: Karina Banasik and S{\o}ren Brunak acknowledge the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001). Funding Information: We wish to express special gratitude to the individual participants in the deCODE genetics, UK Biobank, Copenhagen Hospital Biobank, Danish Blood Donor Study, FinnGen, and Intermountain cohorts. We also thank those who worked on generating these resources through data and sample collection, genotyping, and analysis. This work was partly supported by NordForsk through the funding to PM Heart (project number 90580). This work was partly funded by the Innovation Fund Denmark (IFD) under File No. 8114-00033B and also by the Technology Development Fund, Iceland (project number 90580). Publisher Copyright: {\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. {\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected].",

year = "2023",

month = mar,

day = "21",

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",

}

DBDS Genomic Consortium, Ægisdóttir, HM, Thorolfsdottir, RB, Sveinbjörnsson, G, Andri Stefánsson, Ó, Gunnarsson, B, Tragante, V, Thorleifsson, G, Stefánsdóttir, L, Thorgeirsson, TE, Ferkingstad, E, sulem, P, Norddahl, G, Rútsdóttir, G, Banasik, K, Christensen, AH, Mikkelsen, C, Pedersen, OB, Brunak, S, Bruun, MT, Erikstrup, C, Jacobsen, RL, Nielsen, KR, Sørensen, E, Frigge, ML, Hjörleifsson, KE, Ivarsdottir, EV, Helgadottir, A, Grétarsdóttir, S, Steinthórsdóttir, V, Oddson, Á, Eggertsson, HP, Halldórsson, GH, Jones, DA, Anderson, JL, Knowlton, KU, Nadauld, LD, Haraldsson, M , Þorgeirsson, G, Bundgaard, H, Arnar, DO , Þorsteinsdóttir, U, Gudbjartsson, DF, Ostrowski, SR, Hólm, H & Stefánsson, K 2023, 'Genetic variants associated with syncope implicate neural and autonomic processes', European heart journal, vol. 44, no. 12, pp. 1070-1080. https://doi.org/10.1093/eurheartj/ehad016

TY - JOUR

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

AU - DBDS Genomic Consortium

AU - Ægisdóttir, Hildur Margrét

AU - Thorolfsdottir, Rosa Björk

AU - Sveinbjörnsson, Garðar

AU - Andri Stefánsson, Ólafur

AU - Gunnarsson, Bjarni

AU - Tragante, Vinicius

AU - Thorleifsson, Gudmar

AU - Stefánsdóttir, Lilja

AU - Thorgeirsson, Thorgeir E.

AU - Ferkingstad, Egil

AU - sulem, patrick

AU - Norddahl, Gudmundur

AU - Rútsdóttir, Guðrún

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 - Sørensen, Erik

AU - Frigge, Michael L.

AU - Hjörleifsson, Kristján Eldjárn

AU - Ivarsdottir, Erna V.

AU - Helgadottir, Anna

AU - Grétarsdóttir, Solveig

AU - Steinthórsdóttir, Valgerður

AU - Oddson, Ásmundur

AU - Eggertsson, Hannes P.

AU - Halldórsson, Gísli Hreinn

AU - Jones, David A.

AU - Anderson, Jeffrey L.

AU - Knowlton, Kirk U.

AU - Nadauld, Lincoln D.

AU - Haraldsson, Magnús

AU - Þorgeirsson, Guðmundur

AU - Bundgaard, Henning

AU - Arnar, Davíð Ottó

AU - Þorsteinsdóttir, Unnur

AU - Gudbjartsson, Daniel Fannar

AU - Ostrowski, Sisse R

AU - Hólm, Hilma

AU - Stefánsson, Kári

N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected]. Funding Information: This work was partly supported by NordForsk through the funding to PM Heart (project number 90580). This work was partly funded by the Innovation Fund Denmark (IFD) under File No. 8114-00033B and also by the Technology Development Fund, Iceland (project number 90580). Funding Information: Karina Banasik and Søren Brunak acknowledge the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001). Funding Information: We wish to express special gratitude to the individual participants in the deCODE genetics, UK Biobank, Copenhagen Hospital Biobank, Danish Blood Donor Study, FinnGen, and Intermountain cohorts. We also thank those who worked on generating these resources through data and sample collection, genotyping, and analysis. This work was partly supported by NordForsk through the funding to PM Heart (project number 90580). This work was partly funded by the Innovation Fund Denmark (IFD) under File No. 8114-00033B and also by the Technology Development Fund, Iceland (project number 90580). Publisher Copyright: © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: [email protected].

PY - 2023/3/21

Y1 - 2023/3/21

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 - Autonomic Nervous System

KW - Cardiovascular Diseases/genetics

KW - Diabetes Mellitus

KW - GWAS

KW - Genome-Wide Association Study/methods

KW - Humans

KW - Imprinting

KW - Mendelian Randomization Analysis

KW - Meta-analysis

KW - PTPRN2

KW - Syncope

KW - Syncope/genetics

KW - Vasovagal reaction

UR - https://www.scopus.com/pages/publications/85150751952

U2 - 10.1093/eurheartj/ehad016

DO - 10.1093/eurheartj/ehad016

M3 - Article

C2 - 36747475

SN - 0195-668X

VL - 44

SP - 1070

EP - 1080

JO - European heart journal

JF - European heart journal

IS - 12

ER -

Genetic variants associated with syncope implicate neural and autonomic processes

Abstract

Bibliographical note

Other keywords

UN SDGs

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