| Title: |
The impact of common and rare genetic variants on bradyarrhythmia development |
| Authors: |
FinnGen; Million Veteran Program; Regeneron Genetics Center; Weng, Lu-Chen; Rämö, Joel T.; Jurgens, Sean J.; Khurshid, Shaan; Chaffin, Mark; Hall, Amelia Weber; Morrill, Valerie N.; Wang, Xin; Nauffal, Victor; Sun, Yan V.; Beer, Dominik; Lee, Simon; Nadkarni, Girish N.; Duong, Thuy Vy; Wang, Biqi; Czuba, Tomasz; Austin, Thomas R.; Yoneda, Zachary T.; Friedman, Daniel J.; Clayton, Anne; Hyman, Matthew C.; Judy, Renae L.; Skanes, Allan C.; Orland, Kate M.; Treu, Timothy M.; Oetjens, Matthew T.; Alonso, Alvaro; Soliman, Elsayed Z.; Lin, Honghuang; Lunetta, Kathryn L.; van der Pals, Jesper; Issa, Tariq Z.; Nafissi, Navid A.; May, Heidi T.; Leong-Sit, Peter; Roselli, Carolina; Choi, Seung Hoan; Mitnaul, Lyndon J.; Jones, Marcus B.; Staples, Jeffrey C.; Salerno, William; Rasool, Ayesha; Polanco, Tommy; Panea, Razvan; Orelus, Max; O’Keeffe, Sean; Nafde, Mrunali; Maxwell, Evan K.; Ripatti, Samuli; Palotie, Aarno |
| Contributors: |
Institute for Molecular Medicine Finland; Genomics of Neurological and Neuropsychiatric Disorders; Complex Disease Genetics; Helsinki Institute of Life Science HiLIFE; HUS Group; Department of Public Health; Samuli Olli Ripatti / Principal Investigator; Centre of Excellence in Complex Disease Genetics; Research Programs Unit; Aarno Palotie / Principal Investigator |
| Publisher Information: |
Nature Research |
| Publication Year: |
2025 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
Genetics; developmental biology; physiology |
| Description: |
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. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
We thank all participants, study staff and participating study centers in this project. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (NIH) and by National Cancer Institute (NCI), NHGRI, National Heart, Lung, and Blood Institute (NHLBI), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH) and National Institute of Neurological Disorders and Stroke (NINDS). The data used for the analyses described in this manuscript were obtained from the Single-Tissue cis-QTL Data from Datasets at the GTEx Portal on December 17, 2021. This research has been conducted using the UKBB Resource under Application number 17488.This work was supported by grants from the NIH (R01HL139731 and R01HL157635 to P.T.E. and S.A.L.; RO1HL092577 to K.L.L., E.J.B. and P.T.E.; K23HL169839 to S. Khurshid and R01HL163987-01 and R01HL139738-01 to L.L.E.; and 75N92019D00031 to the Framingham Heart Study, Boston University Medical Center), the American Heart Association Strategically Focused Research Networks (18SFRN34250007 to S.A.L., 18SFRN34230127 to P.T.E., 18SFRN34110082 to L.C.W. and E.J.B.), the American Heart Association (23CDA1050571 to S. Khurshid) and from the European Union (MAESTRIA 965286 to P.T.E.). S.J.J. is supported by the Junior Clinical Scientist Fellowship from the Dutch Heart Foundation (Hartstichting; grant 03-007-2022-0035). C.M.H. is supported by NIH (grants R01HL141901 and R01HL157635). N.A.N. is supported by NIH (grant T32HL007101). J.T.R. is supported by a Sigrid Juselius Foundation Fellowship grant. A.P. is supported by the Academy of Finland Centre of Excellence in Complex Disease Genetics (grants 312074 and 336824). M.C.H. is supported by Fondation Leducq (TNE FANTASY 19CV03). J.G.S. is supported by grants from the Swedish Heart-Lung Foundation (2022-0344 and 2022-0345), the Swedish Research Council (2021-02273), the European Research Council (ERC-STG-2015-679242), Gothenburg University, Skane University Hospital, the Scania County, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg Foundation to the Wallenberg Center for Molecular Medicine in Lund and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and the Swedish Foundation for Strategic Research (Dnr IRC15-0067) to the Lund University Diabetes Center. S.M.D. is supported by the US Department of Veterans Affairs Clinical Research and Development award IK2-CX001780. Part of this research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award MVP001. This publication does not represent the views of the Department of Veterans Affairs or the United States Government. Additional funding sources and study acknowledgments are listed in the Supplementary Note.; https://hdl.handle.net/10138/593321; 85213950182; 001406653700002 |
| Availability: |
https://hdl.handle.net/10138/593321 |
| Rights: |
cc_by_nc_nd ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.62F71DCC |
| Database: |
BASE |