Biobank-driven genomic discovery yields new insight into atrial fibrillation biology
Open accessPublished version of a preprint
Abstract
To identify genetic variation underlying atrial fibrillation, the most common cardiac arrhythmia, we performed a genome-wide association study of >1,000,000 people, including 60,620 atrial fibrillation cases and 970,216 controls. We identified 142 independent risk variants at 111 loci and prioritized 151 functional candidate genes likely to be involved in atrial fibrillation. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans (GATA4, MYH6, NKX2-5, PITX2, TBX5)1, or near genes important for striated muscle function and integrity (for example, CFL2, MYH7, PKP2, RBM20, SGCG, SSPN). Pathway and functional enrichment analyses also suggested that many of the putative atrial fibrillation genes act via cardiac structural remodeling, potentially in the form of an 'atrial cardiomyopathy'2, either during fetal heart development or as a response to stress in the adult heart.
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The scale of genetic analysis based on sequence data still lags behind genome-wide genotyping data, with the largest sequence-based datasets one tenth the size of the largest GWAS.
“The scale of genetic analysis based on sequence data still lags behind that of genome-wide genotyping data (the largest sequence-based datasets are one tenth the size of the largest GWAS90–92), although reductions in sequencing costs are decreasing the differential.”
From A brief history of human disease genetics (2020) · cites this paper as [90]
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References 70 · Cited by 876
- Authors
- Nielsen, J. B., Thorolfsdottir, R. B., Fritsche, L. G., Zhou, W., Skov, M. W., Graham, S. E., Herron, T. J., McCarthy, S., Schmidt, E. M., Sveinbjornsson, G., Surakka, I., Mathis, M. R., Yamazaki, M., Crawford, R. D., Gabrielsen, M. E., Skogholt, A. H., Holmen, O. L., Lin, M., Wolford, B. N., Dey, R., Dalen, H., Sulem, P., Chung, J. H., Backman, J. D., Arnar, D. O., Thorsteinsdottir, U., Baras, A., O’Dushlaine, C., Holst, A. G., Wen, X., Hornsby, W., Dewey, F. E., Boehnke, M., Kheterpal, S., Mukherjee, B., Lee, S., Kang, H. M., Holm, H., Kitzman, J., Shavit, J. A., Jalife, J., Brummett, C. M., Teslovich, T. M., Carey, D. J., Gudbjartsson, D. F., Stefansson, K., Abecasis, G. R., Hveem, K., & Willer, C. J.
- Affiliations
- University of Michigan (US)
- Norwegian University of Science and Technology (NO)
- Copenhagen University Hospital (DK)
- Regeneron (United States) (US)
- Medical Device Development and Regulation Research Center (JP)
- deCODE Genetics (Iceland) (IS)
- Geisinger Health System (US)
- Corresponding author
- Abecasis, Gonçalo R.
- Hveem, Kristian
- Willer, Cristen J.
- ORCID
- Nielsen, Jonas B.
- Fritsche, Lars G.
- Zhou, Wei
- Graham, Sarah E.
- Herron, Todd J.
- Schmidt, Ellen M.
- Surakka, Ida
- Mathis, Michael R.
- Yamazaki, Masatoshi
- Crawford, Ryan D.
- Gabrielsen, Maiken E.
- Skogholt, Anne Heidi
- Lin, Maoxuan
- Wolford, Brooke N.
- Dey, Rounak
- Dalen, Håvard
- Sulem, Patrick
- Backman, Joshua D.
- Baras, Aris
- O’Dushlaine, Colm
- Holst, Anders G.
- Wen, Xiaoquan
- Hornsby, Whitney
- Boehnke, Michael
- Kheterpal, Sachin
- Mukherjee, Bhramar
- Lee, Seunggeun
- Kang, Hyun M.
- Kitzman, Jacob
- Shavit, Jordan A.
- Jalife, José
- Brummett, Chad M.
- Carey, David J.
- Gudbjartsson, Daniel F.
- Abecasis, Gonçalo R.
- Hveem, Kristian
- Willer, Cristen J.
- Venue
- Nature Genetics
- Published
- 2018-07-30
- Volume
- 50
- Issue
- 9
- Pages
- 1234-1239
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6530775
- OpenAlex
- W2884743521
- Cited by
- 876
- References
- 70
- Citations by year
- 2026: 64 · 2025: 130 · 2024: 181 · 2023: 129 · 2022: 108 · 2021: 115 · 2020: 84 · 2019: 53 · 2018: 11 · 2016: 1
- FWCI
- 51.83
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Funders
- American Heart Association
- Hjerteforeningen
- Norges Teknisk-Naturvitenskapelige Universitet
- Lundbeckfonden (R220-2016-1434)
- H. Lundbeck A/S
- National Institutes of Health (1r01hl130705-01a1)
- Japan Society for the Promotion of Science (15KK0341, 18H02802)
- Norwegian Institute of Public Health
- National Heart, Lung, and Blood Institute (R01HL127564, R01HL124232, R01-HL130705, R35HL135824, R01HL117626, R01HL109946)
- National Human Genome Research Institute (T32HG000040)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- atrial fibrillation, genetic risk variants, genome-wide association study, cardiac arrhythmias, atrial cardiomyopathy, cardiac structural remodeling, fetal heart development, cardiomyopathy genes, MYH6, GATA4, Nkx2.5, TBX5, biobanks
- MeSH terms
- Atrial Fibrillation, Heart Defects, Congenital, Humans, Mutation, Risk, Biological Specimen Banks, Genetic Predisposition to Disease, Genomics, Genome-Wide Association Study
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