Genome-Wide Association Study of Accessory Atrioventricular Pathways
Authors: 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, Banasik Karina , Bay Jakob , Boldsen Jens K. , Brodersen Thorsten , Brunak Søren , Buil Demur Alfonso , Christoffersen Lea A. N. , Didriksen Maria , Dinh Khoa M. , Dowsett Joseph , Erikstrup Christian , Feenstra Bjarke , Geller Frank , Gudbjartsson Daniel , Hansen Thomas F. , Helenius Mikkelsen Dorte , Hindhede Lotte , Hjalgrim Henrik , Stemann Jakob H. V. , Jensen Bitten A. , Joseph Schork Andrew , Kaspersen Katrine , Kjerulff Bertram D. , Kongstad Mette , Mikkelsen Susan , Mikkelsen Christina , Nissen Ioanna , Nyegaard Mette , Ostrowski Sisse R. , Pedersen Ole B. , Quinn Liam J. E. , Rafnar Þórunn , Rohde Palle D. , Rostgaard Klaus , Schwinn Michael , Stefansson Kari , Stefánsson Hreinn , Sørensen Erik , Thorsteinsdóttir Unnur , Thørner Lise W. , Topholm Bruun Mie , Ullum Henrik , Werge Thomas , Westergaard David 
Published: September 2024

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.