Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias
Lu‐Chen Weng, Shaan Khurshid, Amelia Weber Hall, Victor Nauffal, Valerie N. Morrill, Yan V. Sun, Joel Rämö, Dominik Beer, Simon Lee, Girish N. Nadkarni, Renée Johnson, Laura Andreasen, Anne Clayton, Clive R. Pullinger, Zachary T. Yoneda, Daniel J. Friedman, Matthew C. Hyman, Renae Judy, Allan C. Skanes, Kate M. Orland, Paloma Jordà, Timothy Treu, Matthew T. Oetjens, Rajesh Subbiah, Jacob Peter 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 Khan, Stacey Knight, Jesper Hastrup Svendsen, Bruce D. Walker, Richard Karlsson Linnér, J. Michael Gaziano, Rafik Tadros, Diane Fatkin, Daniel J. Rader, Svati H. Shah, Dan M. Roden, Gregory M. Marcus, Ruth J. F. Loos, Scott M. Damrauer, Christopher M. Haggerty, Kelly Cho, Aarno Palotie, Morten S. Olesen, Lee L. Eckhardt, Jason D. Roberts, Michael J. Cutler, M. Benjamin Shoemaker, Peter W.F. Wilson, Patrick T. Ellinor, Steven A. Lubitz
Abstract
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.