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 Rene 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. Anderson; Kirk U. Knowlton; Lincoln D. Nadauld; DBDS Genomic Consortium; Mette Nyegaard; Magnus Haraldsson; Gudmundur Thorgeirsson; Henning Bundgaard; David O. Arnar; Unnur Thorsteinsdottir; Daniel F. Gudbjartsson; Sisse R. Ostrowski; Hilma Holm; Kari Stefansson

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 Rene 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. Anderson, Kirk U. Knowlton, Lincoln D. Nadauld, DBDS Genomic Consortium, Mette Nyegaard (Medlem af forfattergruppering), Magnus Haraldsson, Gudmundur Thorgeirsson, Henning Bundgaard, David O. Arnar, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Sisse R. Ostrowski, Hilma Holm^*, Kari Stefansson^*

^*Kontaktforfatter

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

5 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	ehad016
Tidsskrift	European Heart Journal
Vol/bind	44
Udgave nummer	12
Sider (fra-til)	1070-1080
Antal sider	11
ISSN	0195-668X
DOI	https://doi.org/10.1093/eurheartj/ehad016
Status	Udgivet - 21 mar. 2023

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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., ... Stefansson, K. (2023). Genetic variants associated with syncope implicate neural and autonomic processes. European Heart Journal, 44(12), 1070-1080. Artikel ehad016. Advance online publication. https://doi.org/10.1093/eurheartj/ehad016

@article{45c15d73cc3c41db9edf922b39228dc7,

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

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 Rene} 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 Anderson, {Jeffrey L.} and Knowlton, {Kirk U.} and Nadauld, {Lincoln D.} and {DBDS Genomic Consortium} and Mette Nyegaard and Magnus Haraldsson and Gudmundur Thorgeirsson and Henning Bundgaard and Arnar, {David O.} and Unnur Thorsteinsdottir and Gudbjartsson, {Daniel F.} and Ostrowski, {Sisse R.} and Hilma Holm and Kari Stefansson",

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: journals.permissions@oup.com.",

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",

}

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, Anderson, JL, Knowlton, KU, Nadauld, LD, DBDS Genomic Consortium, Nyegaard, M, Haraldsson, M, Thorgeirsson, G, Bundgaard, H, Arnar, DO, Thorsteinsdottir, U, Gudbjartsson, DF, Ostrowski, SR, Holm, H & Stefansson, K 2023, 'Genetic variants associated with syncope implicate neural and autonomic processes', European Heart Journal, bind 44, nr. 12, ehad016, s. 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 Rene

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 - Anderson, 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 R.

AU - Holm, Hilma

AU - Stefansson, Kari

A2 - Nyegaard, Mette

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 - GWAS

KW - Imprinting

KW - Meta-analysis

KW - PTPRN2

KW - Syncope

KW - Vasovagal reaction

UR - http://www.scopus.com/inward/record.url?scp=85150751952&partnerID=8YFLogxK

U2 - 10.1093/eurheartj/ehad016

DO - 10.1093/eurheartj/ehad016

M3 - Journal article

C2 - 36747475

SN - 0195-668X

VL - 44

SP - 1070

EP - 1080

JO - European Heart Journal

JF - European Heart Journal

IS - 12

M1 - ehad016

ER -

Genetic variants associated with syncope implicate neural and autonomic processes

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