You are here
The impact of common and rare genetic variants on bradyarrhythmia development.
Tuesday,2025-02-11 15:36 America/Los_Angeles — ecterry
| Title | The impact of common and rare genetic variants on bradyarrhythmia development. |
| Publication Type | Journal Article |
| Year of Publication | 2025 |
| Authors | Weng, L-C, Rämö, JT, Jurgens, SJ, Khurshid, S, Chaffin, M, Hall, AWeber, Morrill, VN, Wang, X, Nauffal, V, Sun, YV, Beer, D, Lee, S, Nadkarni, GN, Duong, TV, Wang, B, Czuba, T, Austin, TR, Yoneda, ZT, Friedman, DJ, Clayton, A, Hyman, MC, Judy, RL, Skanes, AC, Orland, KM, Treu, TM, Oetjens, MT, Alonso, A, Soliman, EZ, Lin, H, Lunetta, KL, van der Pals, J, Issa, TZ, Nafissi, NA, May, HT, Leong-Sit, P, Roselli, C, Choi, SHoan, Khan, HR, Knight, S, Linnér, RKarlsson, Bezzina, CR, Ripatti, S, Heckbert, SR, J Gaziano, M, Loos, RJF, Psaty, BM, J Smith, G, Benjamin, EJ, Arking, DE, Rader, DJ, Shah, SH, Roden, DM, Damrauer, SM, Eckhardt, LL, Roberts, JD, Cutler, MJ, M Shoemaker, B, Haggerty, CM, Cho, K, Palotie, A, Wilson, PWF, Ellinor, PT, Lubitz, SA |
| Corporate/Institutional Authors | FinnGen, Million Veteran Program, Regeneron Genetics Center |
| Journal | Nat Genet |
| Volume | 57 |
| Issue | 1 |
| Pagination | 53-64 |
| Date Published | 2025 Jan |
| ISSN | 1546-1718 |
| 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 |
| 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> |
| DOI | 10.1038/s41588-024-01978-2 |
| Alternate Journal | Nat Genet |
| PubMed ID | 39747593 |
| PubMed Central ID | PMC11735381 |
| Grant List | R01 HL141901 / HL / NHLBI NIH HHS / United States R01 HL139731 / HL / NHLBI NIH HHS / United States R01 HL139738 / HL / NHLBI NIH HHS / United States 18SFRN34250007 / / American Heart Association (American Heart Association, Inc.) / TNE FANTASY 19CV03 / / Fondation Leducq / R01 HL092577 / HL / NHLBI NIH HHS / United States 18SFRN34110082 / / American Heart Association (American Heart Association, Inc.) / R01 HL157635 / HL / NHLBI NIH HHS / United States R01 HL163987 / HL / NHLBI NIH HHS / United States 23CDA1050571 / / American Heart Association (American Heart Association, Inc.) / T32 HL007101 / HL / NHLBI NIH HHS / United States 18SFRN34230127 / / American Heart Association (American Heart Association, Inc.) / IK2 CX001780 / CX / CSRD VA / United States 75N92019D00031 / HL / NHLBI NIH HHS / United States K23 HL169839 / HL / NHLBI NIH HHS / United States 03-007-2022-0035 / / Hartstichting (Dutch Heart Foundation) / |
ePub date:
25/01