Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk

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

doi:10.1038/s41588-025-02074-9

Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk

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 DarbarDoreen 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,

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	e020163
Pages (from-to)	548-562
Number of pages	15
Journal	Nature genetics
Volume	57
Issue number	3
DOIs	https://doi.org/10.1038/s41588-025-02074-9
Publication status	Published - Mar 2025

Keywords

Atrial Fibrillation/genetics
Case-Control Studies
Exome Sequencing
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Humans
Myocytes, Cardiac/metabolism
Risk Factors

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Choi, S. H., Jurgens, S. J., Xiao, L., Hill, M. C., Haggerty, C. M., Sveinbjörnsson, G., Morrill, V. N., Marston, N. A., Weng, L.-C., Pirruccello, J. P., Arnar, D. O., Gudbjartsson, D. F., Mantineo, H., von Falkenhausen, A. S., Natale, A., Tveit, A., Geelhoed, B., Roselli, C., Van Wagoner, D. R. (2025). Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk. Nature genetics, 57(3), 548-562. Article e020163. https://doi.org/10.1038/s41588-025-02074-9

@article{2979b8c3e06d43b4832ad251fb93f0f6,

title = "Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk",

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.",

keywords = "Atrial Fibrillation/genetics, Case-Control Studies, Exome Sequencing, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Myocytes, Cardiac/metabolism, Risk Factors",

author = "Choi, {Seung Hoan} and Jurgens, {Sean J} and Ling Xiao and Hill, {Matthew C} and Haggerty, {Christopher M} and Gar{\dh}ar Sveinbj{\"o}rnsson and Morrill, {Valerie N} and Marston, {Nicholas A} and Lu-Chen Weng and Pirruccello, {James P} and Arnar, {David O} and Gudbjartsson, {Daniel Fannar} and Helene Mantineo and {von Falkenhausen}, {Aenne S} and Andrea Natale and Arnljot Tveit and Bastiaan Geelhoed and Carolina Roselli and {Van Wagoner}, {David R} and Dawood Darbar and Doreen Haase and Soliman, {Elsayed Z} and Davogustto, {Giovanni E} and Goo Jun and Hugh Calkins and Anderson, {Jeffrey L} and Brody, {Jennifer A} and Halford, {Jennifer L} and John Barnard and Hokanson, {John E} and Smith, {Jonathan D} and Bis, {Joshua C} and Kendra Young and Johnson, {Linda S B} and Lorenz Risch and Gula, {Lorne J} and Kwee, {Lydia Coulter} and Chaffin, {Mark D} and Michael K{\"u}hne and Michael Preuss and Namrata Gupta and Nafissi, {Navid A} and Smith, {Nicholas L} and Nilsson, {Peter M} and {van der Harst}, Pim and Wells, {Quinn S} and Judy, {Renae L} and Schnabel, {Renate B} and Renee Johnson and Smit, {Roelof A J}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.",

year = "2025",

month = mar,

doi = "10.1038/s41588-025-02074-9",

language = "English",

volume = "57",

pages = "548--562",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "3",

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Choi, SH, Jurgens, SJ, Xiao, L, Hill, MC, Haggerty, CM, Sveinbjörnsson, G, Morrill, VN, Marston, NA, Weng, L-C, Pirruccello, JP, Arnar, DO, Gudbjartsson, DF, Mantineo, H, von Falkenhausen, AS, Natale, A, Tveit, A, Geelhoed, B, Roselli, C, Van Wagoner, DR, Darbar, D, Haase, D, Soliman, EZ, Davogustto, GE, Jun, G, Calkins, H, Anderson, JL, Brody, JA, Halford, JL, Barnard, J, Hokanson, JE, Smith, JD, Bis, JC, Young, K, Johnson, LSB, Risch, L, Gula, LJ, Kwee, LC, Chaffin, MD, Kühne, M, Preuss, M, Gupta, N, Nafissi, NA, Smith, NL, Nilsson, PM, van der Harst, P, Wells, QS, Judy, RL, Schnabel, RB, Johnson, R, Smit, RAJ 2025, 'Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk', Nature genetics, vol. 57, no. 3, e020163, pp. 548-562. https://doi.org/10.1038/s41588-025-02074-9

TY - JOUR

T1 - Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk

AU - Choi, Seung Hoan

AU - Jurgens, Sean J

AU - Xiao, Ling

AU - Hill, Matthew C

AU - Haggerty, Christopher M

AU - Sveinbjörnsson, Garðar

AU - Morrill, Valerie N

AU - Marston, Nicholas A

AU - Weng, Lu-Chen

AU - Pirruccello, James P

AU - Arnar, David O

AU - Gudbjartsson, Daniel Fannar

AU - Mantineo, Helene

AU - von Falkenhausen, Aenne S

AU - Natale, Andrea

AU - Tveit, Arnljot

AU - Geelhoed, Bastiaan

AU - Roselli, Carolina

AU - Van Wagoner, David R

AU - Darbar, Dawood

AU - Haase, Doreen

AU - Soliman, Elsayed Z

AU - Davogustto, Giovanni E

AU - Jun, Goo

AU - Calkins, Hugh

AU - Anderson, Jeffrey L

AU - Brody, Jennifer A

AU - Halford, Jennifer L

AU - Barnard, John

AU - Hokanson, John E

AU - Smith, Jonathan D

AU - Bis, Joshua C

AU - Young, Kendra

AU - Johnson, Linda S B

AU - Risch, Lorenz

AU - Gula, Lorne J

AU - Kwee, Lydia Coulter

AU - Chaffin, Mark D

AU - Kühne, Michael

AU - Preuss, Michael

AU - Gupta, Namrata

AU - Nafissi, Navid A

AU - Smith, Nicholas L

AU - Nilsson, Peter M

AU - van der Harst, Pim

AU - Wells, Quinn S

AU - Judy, Renae L

AU - Schnabel, Renate B

AU - Johnson, Renee

AU - Smit, Roelof A J

PY - 2025/3

Y1 - 2025/3

N2 - 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.

AB - 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.

KW - Atrial Fibrillation/genetics

KW - Case-Control Studies

KW - Exome Sequencing

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Humans

KW - Myocytes, Cardiac/metabolism

KW - Risk Factors

U2 - 10.1038/s41588-025-02074-9

DO - 10.1038/s41588-025-02074-9

M3 - Article

C2 - 40050430

SN - 1061-4036

VL - 57

SP - 548

EP - 562

JO - Nature genetics

JF - Nature genetics

IS - 3

M1 - e020163

ER -

Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk

Abstract

Keywords

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