@article{618e544716db420a93c7c141b5288763,
title = "The impact of common and rare genetic variants on bradyarrhythmia development",
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.",
author = "FinnGen and {Million Veteran Program} and {Regeneron Genetics Center} and Weng, {Lu Chen} and R{\"a}m{\"o}, {Joel T.} and Jurgens, {Sean J.} and Shaan Khurshid and Mark Chaffin and Hall, {Amelia Weber} and Morrill, {Valerie N.} and Xin Wang and Victor Nauffal and Sun, {Yan V.} and Dominik Beer and Simon Lee and Nadkarni, {Girish N.} and Duong, {Thuy Vy} and Biqi Wang and Tomasz Czuba and Austin, {Thomas R.} and Yoneda, {Zachary T.} and Friedman, {Daniel J.} and Anne Clayton and Hyman, {Matthew C.} and Judy, {Renae L.} and Skanes, {Allan C.} and Orland, {Kate M.} and Treu, {Timothy M.} and Oetjens, {Matthew T.} and Alvaro Alonso and Soliman, {Elsayed Z.} and Honghuang Lin and Lunetta, {Kathryn L.} and {van der Pals}, Jesper and Issa, {Tariq Z.} and Nafissi, {Navid A.} and May, {Heidi T.} and Peter Leong-Sit and Carolina Roselli and Choi, {Seung Hoan} and Mitnaul, {Lyndon J.} and Jones, {Marcus B.} and Staples, {Jeffrey C.} and William Salerno and Ayesha Rasool and Tommy Polanco and Razvan Panea and Max Orelus and Sean O{\textquoteright}Keeffe and Mrunali Nafde and Maxwell, {Evan K.} and Mansfield, {Adam J.} and Arking, {Dan E.}",
note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",
year = "2025",
month = jan,
doi = "10.1038/s41588-024-01978-2",
language = "English (US)",
volume = "57",
pages = "53--64",
journal = "Nature genetics",
issn = "1061-4036",
publisher = "Nature Research",
number = "1",
}