The impact of common and rare genetic variants on bradyarrhythmia development

FinnGen; Million Veteran Program; Regeneron Genetics Center; Lu-Chen Weng; Joel T. Rämö; Sean J. Jurgens; Shaan Khurshid; Mark Chaffin; Amelia Weber Hall; Valerie N. Morrill; Xin Wang; Victor Nauffal; Yan V. Sun; Dominik Beer; Simon Lee; Girish N. Nadkarni; Thuy Vy Duong; Biqi Wang; Tomasz Czuba; Thomas R. Austin; Zachary T. Yoneda; Daniel J. Friedman; Anne Clayton; Matthew C. Hyman; Renae L. Judy; Allan C. Skanes; Kate M. Orland; Timothy M. Treu; Matthew T. Oetjens; Alvaro Alonso; Elsayed Z. Soliman; Honghuang Lin; Kathryn L. Lunetta; Jesper van der Pals; Tariq Z. Issa; Navid A. Nafissi; Heidi T. May; Peter Leong-Sit; Carolina Roselli; Seung Hoan Choi; Lyndon J. Mitnaul; Marcus B. Jones; Jeffrey C. Staples; William Salerno; Ayesha Rasool; Tommy Polanco; Razvan Panea; Max Orelus; Sean O’Keeffe; Mrunali Nafde; Evan K. Maxwell; Samuli Ripatti; Aarno Palotie

doi:10.1038/s41588-024-01978-2

The impact of common and rare genetic variants on bradyarrhythmia development

FinnGen
, Million Veteran Program
, Regeneron Genetics Center
, Lu-Chen Weng
, Joel T. Rämö
, Sean J. Jurgens
, Shaan Khurshid
, Mark Chaffin
, Amelia Weber Hall
, Valerie N. Morrill
, Xin Wang
, Victor Nauffal
, Yan V. Sun
, Dominik Beer
, Simon Lee
, Girish N. Nadkarni
, Thuy Vy Duong
, Biqi Wang
, Tomasz Czuba
, Thomas R. Austin

Zachary T. Yoneda, Daniel J. Friedman, Anne Clayton, Matthew C. Hyman, Renae L. Judy, Allan C. Skanes, Kate M. Orland, Timothy M. Treu, Matthew T. Oetjens, Alvaro Alonso, Elsayed Z. Soliman, Honghuang Lin, Kathryn L. Lunetta, Jesper van der Pals, Tariq Z. Issa, Navid A. Nafissi, Heidi T. May, Peter Leong-Sit, Carolina Roselli, Seung Hoan Choi, Lyndon J. Mitnaul, Marcus B. Jones, Jeffrey C. Staples, William Salerno, Ayesha Rasool, Tommy Polanco, Razvan Panea, Max Orelus, Sean O’Keeffe, Mrunali Nafde, Evan K. Maxwell, Samuli Ripatti, Aarno Palotie

Forskningsoutput: Tidskriftsbidrag › Artikel › Vetenskaplig › Peer review

Sammanfattning

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_g = 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.

Originalspråk	engelska
Tidskrift	Nature Genetics
Volym	57
Nummer	1
Sidor (från-till)	53-64
Antal sidor	22
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-024-01978-2
Status	Publicerad - jan. 2025
MoE-publikationstyp	A1 Tidskriftsartikel-refererad

Bibliografisk information

Publisher Copyright:
© The Author(s) 2025.

Vetenskapsgrenar

1184 Genetik, utvecklingsbiologi, fysiologi

Åtkomst av dokument

10.1038/s41588-024-01978-2

s41588-024-01978-2Slutlig publicerad version, 4,37 MBLicens: CC BY-NC-ND

Citera det här

FinnGen, Million Veteran Program, Regeneron Genetics Center, Weng, L.-C., Rämö, J. T., Jurgens, S. J., Khurshid, S., Chaffin, M., Hall, A. W., Morrill, V. N., Wang, X., Nauffal, V., Sun, Y. V., Beer, D., Lee, S., Nadkarni, G. N., Duong, T. V., Wang, B., Czuba, T., ... Palotie, A. (2025). The impact of common and rare genetic variants on bradyarrhythmia development. Nature Genetics, 57(1), 53-64. https://doi.org/10.1038/s41588-024-01978-2

@article{71b941b0425245a48cd8c1228d2f6508,

title = "The impact of common and rare genetic variants on bradyarrhythmia development",

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.",

keywords = "1184 Genetics, developmental biology, physiology",

author = "FinnGen and \{Million Veteran Program\} and \{Regeneron Genetics Center\} and Lu-Chen Weng and R{\"a}m{\"o}, \{Joel T.\} and Jurgens, \{Sean J.\} and Shaan Khurshid and Mark Chaffin and Hall, \{Amelia Weber\} and Morrill, \{Valerie N.\} and Xin Wang and Victor Nauffal and Sun, \{Yan V.\} and Dominik Beer and Simon Lee and Nadkarni, \{Girish N.\} and Duong, \{Thuy Vy\} and Biqi Wang and Tomasz Czuba and Austin, \{Thomas R.\} and Yoneda, \{Zachary T.\} and Friedman, \{Daniel J.\} and Anne Clayton 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 Alvaro Alonso and Soliman, \{Elsayed Z.\} and Honghuang Lin and Lunetta, \{Kathryn L.\} and \{van der Pals\}, Jesper and Issa, \{Tariq Z.\} and Nafissi, \{Navid A.\} and May, \{Heidi T.\} and Peter Leong-Sit and Carolina Roselli and Choi, \{Seung Hoan\} and Mitnaul, \{Lyndon J.\} and Jones, \{Marcus B.\} and Staples, \{Jeffrey C.\} and William Salerno and Ayesha Rasool and Tommy Polanco and Razvan Panea and Max Orelus and Sean O{\textquoteright}Keeffe and Mrunali Nafde and Maxwell, \{Evan K.\} and Samuli Ripatti and Aarno Palotie",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = jan,

doi = "10.1038/s41588-024-01978-2",

language = "English",

volume = "57",

pages = "53--64",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research ",

number = "1",

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FinnGen, Million Veteran Program, Regeneron Genetics Center, Weng, L-C, Rämö, JT, Jurgens, SJ, Khurshid, S, Chaffin, M, Hall, AW, 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, SH, Mitnaul, LJ, Jones, MB, Staples, JC, Salerno, W, Rasool, A, Polanco, T, Panea, R, Orelus, M, O’Keeffe, S, Nafde, M, Maxwell, EK, Ripatti, S & Palotie, A 2025, 'The impact of common and rare genetic variants on bradyarrhythmia development', Nature Genetics, vol. 57, nr. 1, s. 53-64. https://doi.org/10.1038/s41588-024-01978-2

TY - JOUR

T1 - The impact of common and rare genetic variants on bradyarrhythmia development

AU - FinnGen

AU - Million Veteran Program

AU - Regeneron Genetics Center

AU - Weng, Lu-Chen

AU - Rämö, Joel T.

AU - Jurgens, Sean J.

AU - Khurshid, Shaan

AU - Chaffin, Mark

AU - Hall, Amelia Weber

AU - Morrill, Valerie N.

AU - Wang, Xin

AU - Nauffal, Victor

AU - Sun, Yan V.

AU - Beer, Dominik

AU - Lee, Simon

AU - Nadkarni, Girish N.

AU - Duong, Thuy Vy

AU - Wang, Biqi

AU - Czuba, Tomasz

AU - Austin, Thomas R.

AU - Yoneda, Zachary T.

AU - Friedman, Daniel J.

AU - Clayton, Anne

AU - Hyman, Matthew C.

AU - Judy, Renae L.

AU - Skanes, Allan C.

AU - Orland, Kate M.

AU - Treu, Timothy M.

AU - Oetjens, Matthew T.

AU - Alonso, Alvaro

AU - Soliman, Elsayed Z.

AU - Lin, Honghuang

AU - Lunetta, Kathryn L.

AU - van der Pals, Jesper

AU - Issa, Tariq Z.

AU - Nafissi, Navid A.

AU - May, Heidi T.

AU - Leong-Sit, Peter

AU - Roselli, Carolina

AU - Choi, Seung Hoan

AU - Mitnaul, Lyndon J.

AU - Jones, Marcus B.

AU - Staples, Jeffrey C.

AU - Salerno, William

AU - Rasool, Ayesha

AU - Polanco, Tommy

AU - Panea, Razvan

AU - Orelus, Max

AU - O’Keeffe, Sean

AU - Nafde, Mrunali

AU - Maxwell, Evan K.

AU - Ripatti, Samuli

AU - Palotie, Aarno

PY - 2025/1

Y1 - 2025/1

N2 - 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.

AB - 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.

KW - 1184 Genetics, developmental biology, physiology

U2 - 10.1038/s41588-024-01978-2

DO - 10.1038/s41588-024-01978-2

M3 - Article

AN - SCOPUS:85213950182

SN - 1061-4036

VL - 57

SP - 53

EP - 64

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -