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

BioBank Japan Project; 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; Ole B Pedersen; Patrick T Ellinor

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

BioBank Japan Project
, 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, Ole B Pedersen, Patrick T Ellinor^*

^*Corresponding author af dette arbejde

Klinisk Immunologisk Afdeling

Publikation: Bidrag til tidsskrift › Letter › Forskning › 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.

Originalsprog	Engelsk
Sider (fra-til)	539-547
Antal sider	9
Tidsskrift	Nature Genetics
Vol/bind	57
Udgave nummer	3
DOI	https://doi.org/10.1038/s41588-024-02072-3
Status	Udgivet - mar. 2025

Finansiering

Bevillingsgivere	Bevillingsgivernummer
National Institutes of Health
National Cancer Institute
National Human Genome Research Institute
National Heart, Lung, and Blood Institute
National Institute on Drug Abuse
National Institute of Mental Health
National Institute of Neurological Disorders and Stroke
Department of Veterans Affairs	I01-BX004821

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10.1038/s41588-024-02072-3

Citationsformater

BioBank Japan Project, 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., ... Ellinor, P. T. (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. https://doi.org/10.1038/s41588-024-02072-3

@article{5be5cf84e3fc4c759ba4d6a48c9c4a27,

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, Genome-Wide Association Study, Humans, Multifactorial Inheritance/genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Myocytes, Cardiac/metabolism, Risk Factors, Male, Chromatin/genetics, Female, Loci, Common, Variants, Zfhx3, Cohort, Mutation",

author = "\{BioBank Japan Project\} and 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 Pedersen, \{Ole B\} and Ellinor, \{Patrick T\}",

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

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",

}

BioBank Japan Project, 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, Pedersen, OB & Ellinor, PT 2025, 'Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases', Nature Genetics, bind 57, nr. 3, s. 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 - BioBank Japan Project

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 - Pedersen, Ole B

AU - Ellinor, Patrick T

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 - Genome-Wide Association Study

KW - Humans

KW - Multifactorial Inheritance/genetics

KW - Genetic Predisposition to Disease

KW - Polymorphism, Single Nucleotide

KW - Myocytes, Cardiac/metabolism

KW - Risk Factors

KW - Male

KW - Chromatin/genetics

KW - Female

KW - Loci

KW - Common

KW - Variants

KW - Zfhx3

KW - Cohort

KW - Mutation

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

ER -

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

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