Genome-Wide Association Study of Accessory Atrioventricular Pathways
-
Published:2024-09-04
Issue:
Volume:
Page:
-
ISSN:2380-6583
-
Container-title:JAMA Cardiology
-
language:en
-
Short-container-title:JAMA Cardiol
Author:
Aegisdottir Hildur M.12, Andreasen Laura34, Thorolfsdottir Rosa B.1, Sveinbjornsson Gardar1, Jonsdottir Andrea B.12, Stefansdottir Lilja1, Thorleifsson Gudmar1, Sigurdsson Asgeir1, Halldorsson Gisli H.1, Barc Julien56, Simonet Floriane5, Tragante Vinicius1, Oddsson Asmundur1, Ferkingstad Egil1, Svendsen Jesper Hastrup37, Ghouse Jonas34, Ahlberg Gustav34, Paludan-Müller Christian34, Hadji-Turdeghal Katra3, Bustamante Mariana1, Ulfarsson Magnus O.18, Helgadottir Anna1, Gretarsdottir Solveig1, Saevarsdottir Saedis129, Jonsdottir Ingileif1210, Erikstrup Christian1112, Ullum Henrik13, Sørensen Erik14, Brunak Søren15, Jøns Christian3, Zheng Chaoqun3, Bezzina Connie R.616, Knowlton Kirk U.1718, Nadauld Lincoln D.1920, Sulem Patrick1, Ostrowski Sisse R.714, Pedersen Ole B.721, Arnar David O.129, Gudbjartsson Daniel F.122, Olesen Morten S.34, Bundgaard Henning37, Holm Hilma1, Stefansson Kari12, , Banasik Karina23, Bay Jakob23, Boldsen Jens K.23, Brodersen Thorsten23, Brunak Søren23, Buil Demur Alfonso23, Christoffersen Lea A. N.23, Didriksen Maria23, Dinh Khoa M.23, Dowsett Joseph23, Erikstrup Christian23, Feenstra Bjarke23, Geller Frank23, Gudbjartsson Daniel23, Hansen Thomas F.23, Helenius Mikkelsen Dorte23, Hindhede Lotte23, Hjalgrim Henrik23, Stemann Jakob H. V.23, Jensen Bitten A.23, Joseph Schork Andrew23, Kaspersen Katrine23, Kjerulff Bertram D.23, Kongstad Mette23, Mikkelsen Susan23, Mikkelsen Christina23, Nissen Ioanna23, Nyegaard Mette23, Ostrowski Sisse R.23, Pedersen Ole B.23, Quinn Liam J. E.23, Rafnar Þórunn23, Rohde Palle D.23, Rostgaard Klaus23, Schwinn Michael23, Stefansson Kari23, Stefánsson Hreinn23, Sørensen Erik23, Thorsteinsdóttir Unnur23, Thørner Lise W.23, Topholm Bruun Mie23, Ullum Henrik23, Werge Thomas23, Westergaard David23
Affiliation:
1. deCODE Genetics, Reykjavik, Iceland 2. Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland 3. Department of Cardiology, University Hospital of Copenhagen - Rigshospitalet, Copenhagen, Denmark 4. Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark 5. Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax, Nantes, France 6. European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart, Amsterdam, the Netherlands 7. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark 8. Faculty of Electrical and Computer Engineering, University of Iceland, Reykjavik, Iceland 9. Department of Medicine, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland 10. Department of Immunology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland 11. Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark 12. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark 13. Statens Serums Institut, Copenhagen, Denmark 14. Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark 15. Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 16. Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands 17. Intermountain Medical Center, Intermountain Heart Institute, Salt Lake City, Utah 18. School of Medicine, University of Utah, Salt Lake City 19. Precision Genomics, Intermountain Healthcare, Saint George, Utah 20. School of Medicine, Stanford University, Stanford, California 21. Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark 22. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland 23. and the DBDS consortium
Abstract
ImportanceUnderstanding of the genetics of accessory atrioventricular pathways (APs) and affiliated arrhythmias is limited.ObjectiveTo investigate the genetics of APs and affiliated arrhythmias.Design, Setting, and ParticipantsThis 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.ExposuresSequence variants.Main Outcomes and MeasuresGenome-wide significant association of sequence variants with APs.ResultsThe 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 RelevanceAssociations 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.
Publisher
American Medical Association (AMA)
|
|