@article {9870,
	title = {The impact of common and rare genetic variants on bradyarrhythmia development.},
	journal = {Nat Genet},
	volume = {57},
	year = {2025},
	month = {2025 Jan},
	pages = {53-64},
	abstract = {<p>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 (r = 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.</p>},
	keywords = {Bradycardia, Cardiac Conduction System Disease, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Pacemaker, Artificial, Phenotype, Polymorphism, Single Nucleotide, Sick Sinus Syndrome},
	issn = {1546-1718},
	doi = {10.1038/s41588-024-01978-2},
	author = {Weng, Lu-Chen and R{\"a}m{\"o}, Joel T and Jurgens, Sean J and Khurshid, Shaan and Chaffin, Mark and Hall, Amelia Weber and Morrill, Valerie N and Wang, Xin and Nauffal, Victor and Sun, Yan V and Beer, Dominik and Lee, Simon and Nadkarni, Girish N and Duong, ThuyVy and Wang, Biqi and Czuba, Tomasz and Austin, Thomas R and Yoneda, Zachary T and Friedman, Daniel J and Clayton, Anne 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 Alonso, Alvaro and Soliman, Elsayed Z and Lin, Honghuang and Lunetta, Kathryn L and van der Pals, Jesper and Issa, Tariq Z and Nafissi, Navid A and May, Heidi T and Leong-Sit, Peter and Roselli, Carolina and Choi, Seung Hoan and Khan, Habib R and Knight, Stacey and Karlsson Linn{\'e}r, Richard and Bezzina, Connie R and Ripatti, Samuli and Heckbert, Susan R and Gaziano, J Michael and Loos, Ruth J F and Psaty, Bruce M and Smith, J Gustav and Benjamin, Emelia J and Arking, Dan E and Rader, Daniel J and Shah, Svati H and Roden, Dan M and Damrauer, Scott M and Eckhardt, Lee L and Roberts, Jason D and Cutler, Michael J and Shoemaker, M Benjamin and Haggerty, Christopher M and Cho, Kelly and Palotie, Aarno and Wilson, Peter W F and Ellinor, Patrick T and Lubitz, Steven A}
}
