Genome-Wide Association Study of Accessory Atrioventricular Pathways

Hildur M. Aegisdottir; Laura Andreasen; Rosa B. Thorolfsdottir; Gardar Sveinbjornsson; Andrea B. Jonsdottir; Lilja Stefansdottir; Gudmar Thorleifsson; Asgeir Sigurdsson; Gisli H. Halldorsson; Julien Barc; Floriane Simonet; Vinicius Tragante; Asmundur Oddsson; Egil Ferkingstad; Jesper Hastrup Svendsen; Jonas Ghouse; Gustav Ahlberg; Christian Paludan-Müller; Katra Hadji-Turdeghal; Mariana Bustamante; Magnus O. Ulfarsson; Anna Helgadottir; Solveig Gretarsdottir; Saedis Saevarsdottir; Ingileif Jonsdottir; Christian Erikstrup; Henrik Ullum; Erik Sørensen; Søren Brunak; Christian Jøns; Chaoqun Zheng; Connie R. Bezzina; Kirk U. Knowlton; Lincoln D. Nadauld; Patrick Sulem; Sisse R. Ostrowski; Ole B. Pedersen; David O. Arnar; Daniel F. Gudbjartsson; Morten S. Olesen; Henning Bundgaard; Hilma Holm; Kari Stefansson; DBDS Consortium

doi:10.1001/jamacardio.2024.2684

Genome-Wide Association Study of Accessory Atrioventricular Pathways

Hildur M. Aegisdottir, Laura Andreasen, Rosa B. Thorolfsdottir, Gardar Sveinbjornsson, Andrea B. Jonsdottir, Lilja Stefansdottir, Gudmar Thorleifsson, Asgeir Sigurdsson, Gisli H. Halldorsson, Julien Barc, Floriane Simonet, Vinicius Tragante, Asmundur Oddsson, Egil Ferkingstad, Jesper Hastrup Svendsen, Jonas Ghouse, Gustav Ahlberg, Christian Paludan-Müller, Katra Hadji-Turdeghal, Mariana BustamanteMagnus O. Ulfarsson, Anna Helgadottir, Solveig Gretarsdottir, Saedis Saevarsdottir, Ingileif Jonsdottir, Christian Erikstrup, Henrik Ullum, Erik Sørensen, Søren Brunak, Christian Jøns, Chaoqun Zheng, Connie R. Bezzina, Kirk U. Knowlton, Lincoln D. Nadauld, Patrick Sulem, Sisse R. Ostrowski, Ole B. Pedersen, David O. Arnar, Daniel F. Gudbjartsson, Morten S. Olesen, Henning Bundgaard, Hilma Holm, Kari Stefansson, DBDS Consortium

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

Abstract

IMPORTANCE: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited.

OBJECTIVE: To investigate the genetics of APs and affiliated arrhythmias.

DESIGN, SETTING, AND PARTICIPANTS: This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases (ICD) codes and/or confirmed by electrophysiology (EP) study. Genome-wide significant AP variants were tested for association with AP-affiliated arrhythmias: paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), ventricular tachycardia, and cardiac arrest. AP variants were also tested in data on other heart diseases and measures of cardiac physiology. Individuals with APs and control individuals from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank, Danish Blood Donor Study, and SupraGen/the Danish General Suburban Population Study [GESUS]), the US (Intermountain Healthcare), and the United Kingdom (UK Biobank) were included. Time of phenotype data collection ranged from January 1983 to December 2022. Data were analyzed from August 2022 to January 2024.

EXPOSURES: Sequence variants.

MAIN OUTCOMES AND MEASURES: Genome-wide significant association of sequence variants with APs.

RESULTS: The GWAS included 2310 individuals with APs (median [IQR] age, 43 [28-57] years; 1252 [54.2%] male and 1058 [45.8%] female) and 1 206 977 control individuals (median [IQR] year of birth, 1955 [1945-1970]; 632 888 [52.4%] female and 574 089 [47.6%] male). Of the individuals with APs, 909 had been confirmed in EP study. Three common missense variants were associated with APs, in the genes CCDC141 (p.Arg935Trp: adjusted odds ratio [aOR], 1.37; 95% CI, 1.24-1.52, and p.Ala141Val: aOR, 1.55; 95% CI 1.34-1.80) and SCN10A (p.Ala1073Val: OR, 1.22; 95% CI, 1.15-1.30). The 3 variants associated with PSVT and the SCN10A variant associated with AF, supporting an effect on AP-affiliated arrhythmias. All 3 AP risk alleles were associated with higher heart rate and shorter PR interval, and have reported associations with chronotropic response.

CONCLUSIONS AND RELEVANCE: Associations were found between sequence variants and APs that were also associated with risk of PSVT, and thus likely atrioventricular reentrant tachycardia, but had allele-specific associations with AF and conduction disorders. Genetic variation in the modulation of heart rate, chronotropic response, and atrial or atrioventricular node conduction velocity may play a role in the risk of AP-affiliated arrhythmias. Further research into CCDC141 could provide insights for antiarrhythmic therapeutic targeting in the presence of an AP.

Original language	English
Journal	JAMA Cardiology
ISSN	2380-6583
DOIs	https://doi.org/10.1001/jamacardio.2024.2684
Publication status	E-pub ahead of print - 4 Sep 2024

Access to Document

10.1001/jamacardio.2024.2684

Cite this

Aegisdottir, H. M., Andreasen, L., Thorolfsdottir, R. B., Sveinbjornsson, G., Jonsdottir, A. B., Stefansdottir, L., Thorleifsson, G., Sigurdsson, A., Halldorsson, G. H., Barc, J., Simonet, F., Tragante, V., Oddsson, A., Ferkingstad, E., Svendsen, J. H., Ghouse, J., Ahlberg, G., Paludan-Müller, C., Hadji-Turdeghal, K., ... DBDS Consortium (2024). Genome-Wide Association Study of Accessory Atrioventricular Pathways. JAMA Cardiology. https://doi.org/10.1001/jamacardio.2024.2684

Genome-Wide Association Study of Accessory Atrioventricular Pathways. / Aegisdottir, Hildur M.; Andreasen, Laura; Thorolfsdottir, Rosa B.; Sveinbjornsson, Gardar; Jonsdottir, Andrea B.; Stefansdottir, Lilja; Thorleifsson, Gudmar; Sigurdsson, Asgeir; Halldorsson, Gisli H.; Barc, Julien; Simonet, Floriane; Tragante, Vinicius; Oddsson, Asmundur; Ferkingstad, Egil; Svendsen, Jesper Hastrup; Ghouse, Jonas; Ahlberg, Gustav ; Paludan-Müller, Christian; Hadji-Turdeghal, Katra; Bustamante, Mariana; Ulfarsson, Magnus O.; Helgadottir, Anna; Gretarsdottir, Solveig; Saevarsdottir, Saedis; Jonsdottir, Ingileif; Erikstrup, Christian; Ullum, Henrik; Sørensen, Erik; Brunak, Søren; Jøns, Christian; Zheng, Chaoqun; Bezzina, Connie R.; Knowlton, Kirk U.; Nadauld, Lincoln D.; Sulem, Patrick; Ostrowski, Sisse R.; Pedersen, Ole B.; Arnar, David O.; Gudbjartsson, Daniel F.; Olesen, Morten S.; Bundgaard, Henning; Holm, Hilma; Stefansson, Kari; DBDS Consortium.

In: JAMA Cardiology, 04.09.2024.

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

Aegisdottir, HM, Andreasen, L, Thorolfsdottir, RB, Sveinbjornsson, G, Jonsdottir, AB, Stefansdottir, L, Thorleifsson, G, Sigurdsson, A, Halldorsson, GH, Barc, J, Simonet, F, Tragante, V, Oddsson, A, Ferkingstad, E, Svendsen, JH, Ghouse, J, Ahlberg, G , Paludan-Müller, C, Hadji-Turdeghal, K, Bustamante, M, Ulfarsson, MO, Helgadottir, A, Gretarsdottir, S, Saevarsdottir, S, Jonsdottir, I, Erikstrup, C, Ullum, H, Sørensen, E, Brunak, S, Jøns, C, Zheng, C, Bezzina, CR, Knowlton, KU, Nadauld, LD, Sulem, P, Ostrowski, SR , Pedersen, OB, Arnar, DO, Gudbjartsson, DF, Olesen, MS , Bundgaard, H, Holm, H, Stefansson, K & DBDS Consortium 2024, 'Genome-Wide Association Study of Accessory Atrioventricular Pathways', JAMA Cardiology. https://doi.org/10.1001/jamacardio.2024.2684

Aegisdottir, Hildur M. ; Andreasen, Laura ; Thorolfsdottir, Rosa B. ; Sveinbjornsson, Gardar ; Jonsdottir, Andrea B. ; Stefansdottir, Lilja ; Thorleifsson, Gudmar ; Sigurdsson, Asgeir ; Halldorsson, Gisli H. ; Barc, Julien ; Simonet, Floriane ; Tragante, Vinicius ; Oddsson, Asmundur ; Ferkingstad, Egil ; Svendsen, Jesper Hastrup ; Ghouse, Jonas ; Ahlberg, Gustav ; Paludan-Müller, Christian ; Hadji-Turdeghal, Katra ; Bustamante, Mariana ; Ulfarsson, Magnus O. ; Helgadottir, Anna ; Gretarsdottir, Solveig ; Saevarsdottir, Saedis ; Jonsdottir, Ingileif ; Erikstrup, Christian ; Ullum, Henrik ; Sørensen, Erik ; Brunak, Søren ; Jøns, Christian ; Zheng, Chaoqun ; Bezzina, Connie R. ; Knowlton, Kirk U. ; Nadauld, Lincoln D. ; Sulem, Patrick ; Ostrowski, Sisse R. ; Pedersen, Ole B. ; Arnar, David O. ; Gudbjartsson, Daniel F. ; Olesen, Morten S. ; Bundgaard, Henning ; Holm, Hilma ; Stefansson, Kari ; DBDS Consortium. / Genome-Wide Association Study of Accessory Atrioventricular Pathways. In: JAMA Cardiology. 2024.

@article{b25452ef778c4670a36747ffa4700a71,

title = "Genome-Wide Association Study of Accessory Atrioventricular Pathways",

abstract = "IMPORTANCE: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited.OBJECTIVE: To investigate the genetics of APs and affiliated arrhythmias.DESIGN, SETTING, AND PARTICIPANTS: This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases (ICD) codes and/or confirmed by electrophysiology (EP) study. Genome-wide significant AP variants were tested for association with AP-affiliated arrhythmias: paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), ventricular tachycardia, and cardiac arrest. AP variants were also tested in data on other heart diseases and measures of cardiac physiology. Individuals with APs and control individuals from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank, Danish Blood Donor Study, and SupraGen/the Danish General Suburban Population Study [GESUS]), the US (Intermountain Healthcare), and the United Kingdom (UK Biobank) were included. Time of phenotype data collection ranged from January 1983 to December 2022. Data were analyzed from August 2022 to January 2024.EXPOSURES: Sequence variants.MAIN OUTCOMES AND MEASURES: Genome-wide significant association of sequence variants with APs.RESULTS: The GWAS included 2310 individuals with APs (median [IQR] age, 43 [28-57] years; 1252 [54.2%] male and 1058 [45.8%] female) and 1 206 977 control individuals (median [IQR] year of birth, 1955 [1945-1970]; 632 888 [52.4%] female and 574 089 [47.6%] male). Of the individuals with APs, 909 had been confirmed in EP study. Three common missense variants were associated with APs, in the genes CCDC141 (p.Arg935Trp: adjusted odds ratio [aOR], 1.37; 95% CI, 1.24-1.52, and p.Ala141Val: aOR, 1.55; 95% CI 1.34-1.80) and SCN10A (p.Ala1073Val: OR, 1.22; 95% CI, 1.15-1.30). The 3 variants associated with PSVT and the SCN10A variant associated with AF, supporting an effect on AP-affiliated arrhythmias. All 3 AP risk alleles were associated with higher heart rate and shorter PR interval, and have reported associations with chronotropic response.CONCLUSIONS AND RELEVANCE: Associations were found between sequence variants and APs that were also associated with risk of PSVT, and thus likely atrioventricular reentrant tachycardia, but had allele-specific associations with AF and conduction disorders. Genetic variation in the modulation of heart rate, chronotropic response, and atrial or atrioventricular node conduction velocity may play a role in the risk of AP-affiliated arrhythmias. Further research into CCDC141 could provide insights for antiarrhythmic therapeutic targeting in the presence of an AP.",

author = "Aegisdottir, {Hildur M.} and Laura Andreasen and Thorolfsdottir, {Rosa B.} and Gardar Sveinbjornsson and Jonsdottir, {Andrea B.} and Lilja Stefansdottir and Gudmar Thorleifsson and Asgeir Sigurdsson and Halldorsson, {Gisli H.} and Julien Barc and Floriane Simonet and Vinicius Tragante and Asmundur Oddsson and Egil Ferkingstad and Svendsen, {Jesper Hastrup} and Jonas Ghouse and Gustav Ahlberg and Christian Paludan-M{\"u}ller and Katra Hadji-Turdeghal and Mariana Bustamante and Ulfarsson, {Magnus O.} and Anna Helgadottir and Solveig Gretarsdottir and Saedis Saevarsdottir and Ingileif Jonsdottir and Christian Erikstrup and Henrik Ullum and Erik S{\o}rensen and S{\o}ren Brunak and Christian J{\o}ns and Chaoqun Zheng and Bezzina, {Connie R.} and Knowlton, {Kirk U.} and Nadauld, {Lincoln D.} and Patrick Sulem and Ostrowski, {Sisse R.} and Pedersen, {Ole B.} and Arnar, {David O.} and Gudbjartsson, {Daniel F.} and Olesen, {Morten S.} and Henning Bundgaard and Hilma Holm and Kari Stefansson and {DBDS Consortium}",

year = "2024",

month = sep,

day = "4",

doi = "10.1001/jamacardio.2024.2684",

language = "English",

journal = "JAMA Cardiology",

issn = "2380-6583",

publisher = "American Medical Association",

}

TY - JOUR

T1 - Genome-Wide Association Study of Accessory Atrioventricular Pathways

AU - Aegisdottir, Hildur M.

AU - Andreasen, Laura

AU - Thorolfsdottir, Rosa B.

AU - Sveinbjornsson, Gardar

AU - Jonsdottir, Andrea B.

AU - Stefansdottir, Lilja

AU - Thorleifsson, Gudmar

AU - Sigurdsson, Asgeir

AU - Halldorsson, Gisli H.

AU - Barc, Julien

AU - Simonet, Floriane

AU - Tragante, Vinicius

AU - Oddsson, Asmundur

AU - Ferkingstad, Egil

AU - Svendsen, Jesper Hastrup

AU - Ghouse, Jonas

AU - Ahlberg, Gustav

AU - Paludan-Müller, Christian

AU - Hadji-Turdeghal, Katra

AU - Bustamante, Mariana

AU - Ulfarsson, Magnus O.

AU - Helgadottir, Anna

AU - Gretarsdottir, Solveig

AU - Saevarsdottir, Saedis

AU - Jonsdottir, Ingileif

AU - Erikstrup, Christian

AU - Ullum, Henrik

AU - Sørensen, Erik

AU - Brunak, Søren

AU - Jøns, Christian

AU - Zheng, Chaoqun

AU - Bezzina, Connie R.

AU - Knowlton, Kirk U.

AU - Nadauld, Lincoln D.

AU - Sulem, Patrick

AU - Ostrowski, Sisse R.

AU - Pedersen, Ole B.

AU - Arnar, David O.

AU - Gudbjartsson, Daniel F.

AU - Olesen, Morten S.

AU - Bundgaard, Henning

AU - Holm, Hilma

AU - Stefansson, Kari

AU - DBDS Consortium

PY - 2024/9/4

Y1 - 2024/9/4

N2 - IMPORTANCE: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited.OBJECTIVE: To investigate the genetics of APs and affiliated arrhythmias.DESIGN, SETTING, AND PARTICIPANTS: This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases (ICD) codes and/or confirmed by electrophysiology (EP) study. Genome-wide significant AP variants were tested for association with AP-affiliated arrhythmias: paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), ventricular tachycardia, and cardiac arrest. AP variants were also tested in data on other heart diseases and measures of cardiac physiology. Individuals with APs and control individuals from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank, Danish Blood Donor Study, and SupraGen/the Danish General Suburban Population Study [GESUS]), the US (Intermountain Healthcare), and the United Kingdom (UK Biobank) were included. Time of phenotype data collection ranged from January 1983 to December 2022. Data were analyzed from August 2022 to January 2024.EXPOSURES: Sequence variants.MAIN OUTCOMES AND MEASURES: Genome-wide significant association of sequence variants with APs.RESULTS: The GWAS included 2310 individuals with APs (median [IQR] age, 43 [28-57] years; 1252 [54.2%] male and 1058 [45.8%] female) and 1 206 977 control individuals (median [IQR] year of birth, 1955 [1945-1970]; 632 888 [52.4%] female and 574 089 [47.6%] male). Of the individuals with APs, 909 had been confirmed in EP study. Three common missense variants were associated with APs, in the genes CCDC141 (p.Arg935Trp: adjusted odds ratio [aOR], 1.37; 95% CI, 1.24-1.52, and p.Ala141Val: aOR, 1.55; 95% CI 1.34-1.80) and SCN10A (p.Ala1073Val: OR, 1.22; 95% CI, 1.15-1.30). The 3 variants associated with PSVT and the SCN10A variant associated with AF, supporting an effect on AP-affiliated arrhythmias. All 3 AP risk alleles were associated with higher heart rate and shorter PR interval, and have reported associations with chronotropic response.CONCLUSIONS AND RELEVANCE: Associations were found between sequence variants and APs that were also associated with risk of PSVT, and thus likely atrioventricular reentrant tachycardia, but had allele-specific associations with AF and conduction disorders. Genetic variation in the modulation of heart rate, chronotropic response, and atrial or atrioventricular node conduction velocity may play a role in the risk of AP-affiliated arrhythmias. Further research into CCDC141 could provide insights for antiarrhythmic therapeutic targeting in the presence of an AP.

AB - IMPORTANCE: Understanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited.OBJECTIVE: To investigate the genetics of APs and affiliated arrhythmias.DESIGN, SETTING, AND PARTICIPANTS: This was a genome-wide association study (GWAS) of APs, defined by International Classification of Diseases (ICD) codes and/or confirmed by electrophysiology (EP) study. Genome-wide significant AP variants were tested for association with AP-affiliated arrhythmias: paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), ventricular tachycardia, and cardiac arrest. AP variants were also tested in data on other heart diseases and measures of cardiac physiology. Individuals with APs and control individuals from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank, Danish Blood Donor Study, and SupraGen/the Danish General Suburban Population Study [GESUS]), the US (Intermountain Healthcare), and the United Kingdom (UK Biobank) were included. Time of phenotype data collection ranged from January 1983 to December 2022. Data were analyzed from August 2022 to January 2024.EXPOSURES: Sequence variants.MAIN OUTCOMES AND MEASURES: Genome-wide significant association of sequence variants with APs.RESULTS: The GWAS included 2310 individuals with APs (median [IQR] age, 43 [28-57] years; 1252 [54.2%] male and 1058 [45.8%] female) and 1 206 977 control individuals (median [IQR] year of birth, 1955 [1945-1970]; 632 888 [52.4%] female and 574 089 [47.6%] male). Of the individuals with APs, 909 had been confirmed in EP study. Three common missense variants were associated with APs, in the genes CCDC141 (p.Arg935Trp: adjusted odds ratio [aOR], 1.37; 95% CI, 1.24-1.52, and p.Ala141Val: aOR, 1.55; 95% CI 1.34-1.80) and SCN10A (p.Ala1073Val: OR, 1.22; 95% CI, 1.15-1.30). The 3 variants associated with PSVT and the SCN10A variant associated with AF, supporting an effect on AP-affiliated arrhythmias. All 3 AP risk alleles were associated with higher heart rate and shorter PR interval, and have reported associations with chronotropic response.CONCLUSIONS AND RELEVANCE: Associations were found between sequence variants and APs that were also associated with risk of PSVT, and thus likely atrioventricular reentrant tachycardia, but had allele-specific associations with AF and conduction disorders. Genetic variation in the modulation of heart rate, chronotropic response, and atrial or atrioventricular node conduction velocity may play a role in the risk of AP-affiliated arrhythmias. Further research into CCDC141 could provide insights for antiarrhythmic therapeutic targeting in the presence of an AP.

U2 - 10.1001/jamacardio.2024.2684

DO - 10.1001/jamacardio.2024.2684

M3 - Journal article

C2 - 39230897

JO - JAMA Cardiology

JF - JAMA Cardiology

SN - 2380-6583

ER -