The impact of common and rare genetic variants on bradyarrhythmia development
Weng, L.-C. ; van der Pals, J. LU ; Smith, J.G. LU
and Lubitz, S.A.
(2025)
In Nature Genetics
57.
p.53-64
- 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... (More)
- 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. © The Author(s) 2025. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/9b3b1418-1fb5-41e4-80a5-7c4706bfcd80
- author
- Weng, L.-C.
; van der Pals, J.
LU
; Smith, J.G.
LU
and Lubitz, S.A.
- author collaboration
- organization
-
- Arrhytmias and Cardiac Device treatment (research group)
- Cardiology
- Molecular Cardiology (research group)
- WCMM-Wallenberg Centre for Molecular Medicine
- Heart Failure and Mechanical Support (research group)
- Cardiovascular Epigenetics (research group)
- EpiHealth: Epidemiology for Health
- EXODIAB: Excellence of Diabetes Research in Sweden
- Molecular Epidemiology and Cardiology (research group)
- publishing date
- 2025
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nature Genetics
- volume
- 57
- pages
- 12 pages
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85213950182
- pmid:39747593
- ISSN
- 1061-4036
- DOI
- 10.1038/s41588-024-01978-2
- language
- English
- LU publication?
- yes
- id
- 9b3b1418-1fb5-41e4-80a5-7c4706bfcd80
- date added to LUP
- 2025-12-16 14:06:40
- date last changed
- 2025-12-17 03:00:13
@article{9b3b1418-1fb5-41e4-80a5-7c4706bfcd80,
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. © The Author(s) 2025.}},
author = {{Weng, L.-C. and van der Pals, J. and Smith, J.G. and Lubitz, S.A.}},
issn = {{1061-4036}},
language = {{eng}},
pages = {{53--64}},
publisher = {{Nature Publishing Group}},
series = {{Nature Genetics}},
title = {{The impact of common and rare genetic variants on bradyarrhythmia development}},
url = {{http://dx.doi.org/10.1038/s41588-024-01978-2}},
doi = {{10.1038/s41588-024-01978-2}},
volume = {{57}},
year = {{2025}},
}