Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases

Carolina Roselli; Ida Surakka; Morten S Olesen; Gardar Sveinbjornsson; Nicholas A Marston; Seung Hoan Choi; Hilma Holm; Mark Chaffin; Daniel Gudbjartsson; Matthew C Hill; Hildur Aegisdottir; Christine M Albert; Alvaro Alonso; Christopher D Anderson; Dan E Arking; David O Arnar; John Barnard; Emelia J Benjamin; Eugene Braunwald; Ben Brumpton; Archie Campbell; Nathalie Chami; Daniel I Chasman; Kelly Cho; Eue-Keun Choi; Ingrid E Christophersen; Mina K Chung; David Conen; Harry J Crijns; Michael J Cutler; Tomasz Czuba; Scott M Damrauer; Martin Dichgans; Marcus Dörr; Elton Dudink; ThuyVy Duong; Christian Erikstrup; Tõnu Esko; Diane Fatkin; Jessica D Faul; Manuel Ferreira; Daniel F Freitag; Santhi K Ganesh; J Michael Gaziano; Bastiaan Geelhoed; Jonas Ghouse; Christian Gieger; Franco Giulianini; Sarah E Graham; Pim van der Harst

doi:10.1038/s41588-024-02072-3

Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases

Carolina Roselli, Ida Surakka, Morten S Olesen, Gardar Sveinbjornsson, Nicholas A Marston, Seung Hoan Choi, Hilma Holm, Mark Chaffin, Daniel Gudbjartsson, Matthew C Hill, Hildur Aegisdottir, Christine M Albert, Alvaro Alonso, Christopher D Anderson, Dan E Arking, David O Arnar, John Barnard, Emelia J Benjamin, Eugene Braunwald, Ben BrumptonArchie Campbell, Nathalie Chami, Daniel I Chasman, Kelly Cho, Eue-Keun Choi, Ingrid E Christophersen, Mina K Chung, David Conen, Harry J Crijns, Michael J Cutler, Tomasz Czuba, Scott M Damrauer, Martin Dichgans, Marcus Dörr, Elton Dudink, ThuyVy Duong, Christian Erikstrup, Tõnu Esko, Diane Fatkin, Jessica D Faul, Manuel Ferreira, Daniel F Freitag, Santhi K Ganesh, J Michael Gaziano, Bastiaan Geelhoed, Jonas Ghouse, Christian Gieger, Franco Giulianini, Sarah E Graham, Pim van der Harst,

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

Abstract

Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.

Original language	English
Article number	11303
Pages (from-to)	539-547
Number of pages	9
Journal	Nature genetics
Volume	57
Issue number	3
DOIs	https://doi.org/10.1038/s41588-024-02072-3
Publication status	Published - Mar 2025

Keywords

Atrial Fibrillation/genetics
Chromatin/genetics
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Multifactorial Inheritance/genetics
Myocytes, Cardiac/metabolism
Polymorphism, Single Nucleotide
Risk Factors

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Roselli, C., Surakka, I., Olesen, M. S., Sveinbjornsson, G., Marston, N. A., Choi, S. H., Holm, H., Chaffin, M., Gudbjartsson, D., Hill, M. C., Aegisdottir, H., Albert, C. M., Alonso, A., Anderson, C. D., Arking, D. E., Arnar, D. O., Barnard, J., Benjamin, E. J., Braunwald, E. (2025). Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases. Nature genetics, 57(3), 539-547. Article 11303. https://doi.org/10.1038/s41588-024-02072-3

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title = "Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases",

abstract = "Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.",

keywords = "Atrial Fibrillation/genetics, Chromatin/genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance/genetics, Myocytes, Cardiac/metabolism, Polymorphism, Single Nucleotide, Risk Factors",

author = "Carolina Roselli and Ida Surakka and Olesen, {Morten S} and Gardar Sveinbjornsson and Marston, {Nicholas A} and Choi, {Seung Hoan} and Hilma Holm and Mark Chaffin and Daniel Gudbjartsson and Hill, {Matthew C} and Hildur Aegisdottir and Albert, {Christine M} and Alvaro Alonso and Anderson, {Christopher D} and Arking, {Dan E} and Arnar, {David O} and John Barnard and Benjamin, {Emelia J} and Eugene Braunwald and Ben Brumpton and Archie Campbell and Nathalie Chami and Chasman, {Daniel I} and Kelly Cho and Eue-Keun Choi and Christophersen, {Ingrid E} and Chung, {Mina K} and David Conen and Crijns, {Harry J} and Cutler, {Michael J} and Tomasz Czuba and Damrauer, {Scott M} and Martin Dichgans and Marcus D{\"o}rr and Elton Dudink and ThuyVy Duong and Christian Erikstrup and T{\~o}nu Esko and Diane Fatkin and Faul, {Jessica D} and Manuel Ferreira and Freitag, {Daniel F} and Ganesh, {Santhi K} and Gaziano, {J Michael} and Bastiaan Geelhoed and Jonas Ghouse and Christian Gieger and Franco Giulianini and Graham, {Sarah E} and {van der Harst}, Pim",

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

year = "2025",

month = mar,

doi = "10.1038/s41588-024-02072-3",

language = "English",

volume = "57",

pages = "539--547",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "3",

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Roselli, C, Surakka, I, Olesen, MS, Sveinbjornsson, G, Marston, NA, Choi, SH, Holm, H, Chaffin, M, Gudbjartsson, D, Hill, MC, Aegisdottir, H, Albert, CM, Alonso, A, Anderson, CD, Arking, DE, Arnar, DO, Barnard, J, Benjamin, EJ, Braunwald, E, Brumpton, B, Campbell, A, Chami, N, Chasman, DI, Cho, K, Choi, E-K, Christophersen, IE, Chung, MK, Conen, D, Crijns, HJ, Cutler, MJ, Czuba, T, Damrauer, SM, Dichgans, M, Dörr, M, Dudink, E, Duong, T, Erikstrup, C, Esko, T, Fatkin, D, Faul, JD, Ferreira, M, Freitag, DF, Ganesh, SK, Gaziano, JM, Geelhoed, B, Ghouse, J, Gieger, C, Giulianini, F, Graham, SE, van der Harst, P 2025, 'Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases', Nature genetics, vol. 57, no. 3, 11303, pp. 539-547. https://doi.org/10.1038/s41588-024-02072-3

TY - JOUR

T1 - Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases

AU - Roselli, Carolina

AU - Surakka, Ida

AU - Olesen, Morten S

AU - Sveinbjornsson, Gardar

AU - Marston, Nicholas A

AU - Choi, Seung Hoan

AU - Holm, Hilma

AU - Chaffin, Mark

AU - Gudbjartsson, Daniel

AU - Hill, Matthew C

AU - Aegisdottir, Hildur

AU - Albert, Christine M

AU - Alonso, Alvaro

AU - Anderson, Christopher D

AU - Arking, Dan E

AU - Arnar, David O

AU - Barnard, John

AU - Benjamin, Emelia J

AU - Braunwald, Eugene

AU - Brumpton, Ben

AU - Campbell, Archie

AU - Chami, Nathalie

AU - Chasman, Daniel I

AU - Cho, Kelly

AU - Choi, Eue-Keun

AU - Christophersen, Ingrid E

AU - Chung, Mina K

AU - Conen, David

AU - Crijns, Harry J

AU - Cutler, Michael J

AU - Czuba, Tomasz

AU - Damrauer, Scott M

AU - Dichgans, Martin

AU - Dörr, Marcus

AU - Dudink, Elton

AU - Duong, ThuyVy

AU - Erikstrup, Christian

AU - Esko, Tõnu

AU - Fatkin, Diane

AU - Faul, Jessica D

AU - Ferreira, Manuel

AU - Freitag, Daniel F

AU - Ganesh, Santhi K

AU - Gaziano, J Michael

AU - Geelhoed, Bastiaan

AU - Ghouse, Jonas

AU - Gieger, Christian

AU - Giulianini, Franco

AU - Graham, Sarah E

AU - van der Harst, Pim

PY - 2025/3

Y1 - 2025/3

N2 - Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.

AB - Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.

KW - Atrial Fibrillation/genetics

KW - Chromatin/genetics

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Multifactorial Inheritance/genetics

KW - Myocytes, Cardiac/metabolism

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

U2 - 10.1038/s41588-024-02072-3

DO - 10.1038/s41588-024-02072-3

M3 - Letter

C2 - 40050429

SN - 1061-4036

VL - 57

SP - 539

EP - 547

JO - Nature genetics

JF - Nature genetics

IS - 3

M1 - 11303

ER -

Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases

Abstract

Keywords

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