Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias

Research output: Contribution to journalJournal articleResearchpeer-review

  • Lu Chen Weng
  • Shaan Khurshid
  • Amelia Weber Hall
  • Victor Nauffal
  • Valerie N. Morrill
  • Yan V. Sun
  • Joel T. Rämö
  • Dominik Beer
  • Simon Lee
  • Girish Nadkarni
  • Renee Johnson
  • Anne Clayton
  • Clive R. Pullinger
  • Zachary T. Yoneda
  • Daniel J. Friedman
  • Matthew C. Hyman
  • Renae L. Judy
  • Allan C. Skanes
  • Kate M. Orland
  • Paloma Jordà
  • Timothy M. Treu
  • Matthew T. Oetjens
  • Rajesh Subbiah
  • Jacob P. Hartmann
  • Heidi T. May
  • John P. Kane
  • Tariq Z. Issa
  • Navid A. Nafissi
  • Peter Leong-Sit
  • Marie Pierre Dubé
  • Carolina Roselli
  • Seung Hoan Choi
  • Jean Claude Tardif
  • Habib R. Khan
  • Stacey Knight
  • Bruce Walker
  • Richard Karlsson Linnér
  • J. Michael Gaziano
  • Rafik Tadros
  • Diane Fatkin
  • Daniel J. Rader
  • Svati H. Shah
  • Dan M. Roden
  • Gregory M. Marcus
  • Scott M. Damrauer
  • Christopher M. Haggerty
  • Kelly Cho
  • Aarno Palotie
  • Lee L. Eckhardt
  • Jason D. Roberts
  • Michael J. Cutler
  • M. Benjamin Shoemaker
  • Peter W.F. Wilson
  • Patrick T. Ellinor
  • Steven A. Lubitz

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.

Original languageEnglish
Article numbere004320
JournalCirculation: Genomic and Precision Medicine
Volume17
Issue number3
ISSN2574-8300
DOIs
Publication statusPublished - 2024

Bibliographical note

Publisher Copyright:
© 2024 American Heart Association, Inc.

    Research areas

  • atrial fibrillation, genome-wide association study, heart rate, heart ventricles, supraventricular, tachycardia

ID: 396730981