Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
BACKGROUND: Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT). METHODS: We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies. RESULTS: Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate SCN5A, SCN10A, and TTN/CCDC141. Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals. CONCLUSIONS: Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | e004320 |
| Tidsskrift | Circulation: Genomic and Precision Medicine |
| Vol/bind | 17 |
| Udgave nummer | 3 |
| ISSN | 2574-8300 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
This work was supported by the National Institutes of Health (grants 1R01HL139731 to Drs Weng, Ellinor, and Lubitz; R01HL157635 to Dr Lubitz; 1R01HL092577 to Dr Ellinor, 1R01HL157635 to Dr Ellinor, R01HL141901 to Dr Haggerty, R01HL157635 to Dr Haggerty, K23HL169839 to Dr Khurshid, T32HL007101 to Dr Nafissi, R01HL163987-01 to Dr Eckhardt, R01HL139738-01 to Dr Eckhardt), the American Heart Association (grants 18SFRN34110082 to Drs Weng and Ellinor, 18SFRN34250007 to Dr Lubitz, and 2023CDA1050571 to Dr Khurshid), the European Union (grant MAESTRIA 965286 to Dr Ellinor), the Heart Foundation of Australia (grant 105516 to Dr Fatkin), the National Health and Medical Research Council of Australia (grant 1186500 to Dr Fatkin), NSW Health (to Dr Fatkin), Australian Genomics (to Dr Fatkin), Sigrid Jus\u00E9lius Foundation (to Dr R\u00E4m\u00F6), the Academy of Finland Centre of Excellence in Complex Disease Genetics (grants 312074 and 336824 to Dr Palotie), the US Department of Veterans Affairs (grant IK2-CX001780 to Dr Damrauer), the Fondation Leducq (grant TNE FANTASY 19CV03 to Dr Hyman), and the Canada Research Chairs Program (to Drs Tadros, Tardif, and Dub\u00E9). This publication does not represent the views of the Department of Veterans Affairs or the US Government. Funding for participating studies is listed in the Supplemental Material.
Funding Information:
Dr Lubitz is a full-time employee of Novartis as of July 2022. Previously, Dr Lubitz received research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, IBM, Medtronic, and Premier, Inc, and consulted for Bristol Myers Squibb/Pfizer, Bayer AG, Blackstone Life Sciences, and Invitae. Dr Ellinor receives research support from Bayer AG, IBM, and Bristol Myers Squibb/Pfizer and has consulted for Novartis, MyoKardia, and Bayer AG. Dr Damrauer receives research support for RenalytixAI and has consulted for Calico Labs. Dr Svendsen is a member of Medtronic advisory boards and has received speaker honoraria and research grants from Medtronic outside this work. Dr Cutler has consulted for Janssen Scientific. Dr Roselli is supported by a grant from Bayer AG to the Broad Institute focused on the development of therapeutics for cardiovascular disease. The other authors report no conflicts.
Publisher Copyright:
© 2024 American Heart Association, Inc.
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