The impact of common and rare genetic variants on bradyarrhythmia development
Lu‐Chen Weng, Joel Rämö, Sean J. Jurgens, Shaan Khurshid, Mark Chaffin, Amelia Weber Hall, Valerie N. Morrill, Xin Wang, Victor Nauffal, Yan V. Sun, Dominik Beer, Simon Lee, Girish N. Nadkarni, ThuyVy Duong, Biqi Wang, Tomasz Czuba, Thomas R. Austin, Zachary T. Yoneda, Daniel J. Friedman, Anne Clayton, Matthew C. Hyman, Renae Judy, Allan C. Skanes, Kate M. Orland, Timothy Treu, Matthew T. Oetjens, Álvaro Alonso, Elsayed Z. Soliman, Honghuang Lin, Kathryn L. Lunetta, Jesper van der Pals, Tariq Z. Issa, Navid A. Nafissi, Heidi T. May, Peter Leong‐Sit, Carolina Roselli, Seung Hoan Choi, FinnGen, Million Veteran Program, Goncalo Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Aris N. Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan R. Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Andrew Blumenfeld, Boris Boutkov, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan K. Maxwell, Mrunali Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Jeffrey Staples, Marcus B. Jones, Lyndon J. Mitnaul, Habib Khan, Stacey Knight, Richard Karlsson Linnér, Connie R. Bezzina, Samuli Ripatti, Susan R. Heckbert, J. Michael Gaziano, Ruth J. F. Loos, Bruce M. Psaty, J. Gustav Smith, Emelia J. Benjamin, Dan E. Arking, Daniel J. Rader, Svati H. Shah, Dan M. Roden, Scott M. Damrauer, Lee L. Eckhardt
Abstract
To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 common variant loci for SND, DCD and PM, respectively. Four well-known loci (SCN5A/SCN10A, CCDC141, TBX20 and CAMK2D) were shared for SND and DCD, while others were more specific for SND or DCD. SND and DCD showed a moderate genetic correlation (rg = 0.63). Cardiomyocyte-expressed genes were enriched for contributions to DCD heritability. Rare-variant analyses implicated LMNA for all bradyarrhythmia phenotypes, SMAD6 and SCN5A for DCD and TTN, MYBPC3 and SCN5A for PM. These results show that variation in multiple genetic pathways (for example, ion channel function, cardiac developmental programs, sarcomeric structure and cellular homeostasis) appear critical to the development of bradyarrhythmias. Genome-wide analyses identify variants associated with sinus node dysfunction, distal conduction disease and pacemaker implantation, implicating ion channel function, cardiac developmental programs and sarcomeric structure in bradyarrhythmia susceptibility.