| Title: | Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk |
| Journal: | Nature Genetics |
| Published: | 6 Mar 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40050430/ |
| DOI: | https://doi.org/10.1038/s41588-025-02074-9 |
| URL: | https://research.rug.nl/en/publications/1448e489-f443-44ad-85fb-d53f28a934f2 |
Publication 15645
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.</p>
8 Keywords
- Atrial Fibrillation
- Case-Control Studies
- Exome Sequencing
- Genetic Predisposition to Disease
- Genetic Variation
- Genome-Wide Association Study
- Humans
- Myocytes, Cardiac
103 Authors
- Seung Hoan Choi
- Sean J. Jurgens
- Ling Xiao
- Matthew C. Hill
- Christopher M. Haggerty
- Garðar Sveinbjörnsson
- Valerie N. Morrill
- Nicholas A. Marston
- Lu-Chen Weng
- James P. Pirruccello
- David O. Arnar
- Daniel Fannar Gudbjartsson
- Helene Mantineo
- Aenne S. von Falkenhausen
- Andrea Natale
- Arnljot Tveit
- Bastiaan Geelhoed
- Carolina Roselli
- David R. Van Wagoner
- Dawood Darbar
- Doreen Haase
- Elsayed Z. Soliman
- Giovanni E. Davogustto
- Goo Jun
- Hugh Calkins
- Jeffrey L. Anderson
- Jennifer A. Brody
- Jennifer L. Halford
- John Barnard
- John E. Hokanson
- Jonathan D. Smith
- Joshua C. Bis
- Kendra Young
- Linda S. B. Johnson
- Lorenz Risch
- Lorne J. Gula
- Lydia Coulter Kwee
- Mark D. Chaffin
- Michael Kühne
- Michael Preuss
- Namrata Gupta
- Navid A. Nafissi
- Nicholas L. Smith
- Peter M. Nilsson
- Pim van der Harst
- Quinn S. Wells
- Renae L. Judy
- Renate B. Schnabel
- Renee Johnson
- Roelof A. J. Smit
- Stacey Gabriel
- Stacey Knight
- Tetsushi Furukawa
- Thomas W. Blackwell
- Victor Nauffal
- Xin Wang
- Yuan-I Min
- Zachary T. Yoneda
- Zachary W. M. Laksman
- Connie R. Bezzina
- Alvaro Alonso
- Bruce M. Psaty
- Christine M. Albert
- Dan E. Arking
- Dan M. Roden
- Daniel I. Chasman
- Daniel J. Rader
- David Conen
- David D. McManus
- Diane Fatkin
- Emelia J. Benjamin
- Eric Boerwinkle
- Gregory M. Marcus
- Ingrid E. Christophersen
- J. Gustav Smith
- Jason D. Roberts
- Laura M. Raffield
- M. Benjamin Shoemaker
- Michael H. Cho
- Michael J. Cutler
- Michiel Rienstra
- Mina K. Chung
- Morten S. Olesen
- Moritz F. Sinner
- Nona Sotoodehnia
- Paulus Kirchhof
- Ruth J. F. Loos
- Saman Nazarian
- Sanghamitra Mohanty
- Scott M. Damrauer
- Stefan Kaab
- Susan R. Heckbert
- Susan Redline
- Svati H. Shah
- Toshihiro Tanaka
- Yusuke Ebana
- Hilma Holm
- Kari Stefansson
- Christian T. Ruff
- Marc S. Sabatine
- Kathryn L. Lunetta
- Steven A. Lubitz
- Patrick T. Ellinor
1 Application
| Application ID | Title |
|---|---|
| 17488 | Understanding the Genetic Basis of Cardiac Arrhythmias |
Enabling scientific discoveries that improve human health