Identification of atrial fibrillation associated genes and functional non-coding variants

Disease-associated genetic variants that lie in non-coding regions found by genome-wide association studies are thought to alter the functionality of transcription regulatory elements and target gene expression. To uncover causal genetic variants, variant regulatory elements and their target genes,...

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Bibliographic Details
Published in:Nature Communications Vol. 10; no. 1; pp. 4755 - 14
Main Authors: van Ouwerkerk, Antoinette F., Bosada, Fernanda M., van Duijvenboden, Karel, Hill, Matthew C., Montefiori, Lindsey E., Scholman, Koen T., Liu, Jia, de Vries, Antoine A. F., Boukens, Bastiaan J., Ellinor, Patrick T., Goumans, Marie José T. H., Efimov, Igor R., Nobrega, Marcelo A., Barnett, Phil, Martin, James F., Christoffels, Vincent M.
Format: Journal Article
Language:English
Published: London Springer Science and Business Media LLC 18.10.2019
Nature Publishing Group UK
Nature Publishing Group
Nature Portfolio
Subjects:
38
38/91
631/208/200
631/208/4041
631/337/100
631/337/572/2102
64
64/60
692/4019/592/75
Animals
Atrial Fibrillation
Atrial Fibrillation - genetics
Cardiac arrhythmia
Cardiomyocytes
Cell Line
Chromatin
Chromatin - genetics
Conformation
Connexin 43
Epigenomics
Epigenomics - methods
Fibrillation
Gap junctions
Gene expression
Gene Expression Profiling
Gene Expression Profiling - methods
Gene regulation
Genes
Genetic diversity
Genetic Predisposition to Disease
Genetic Predisposition to Disease - genetics
Genetic variance
Genetic Variation
Genome-wide association studies
Genome-Wide Association Study
Genome-Wide Association Study - methods
Genomes
Heart Atria
Heart Atria - cytology
Heart Atria - metabolism
Homology
Humanities and Social Sciences
Humans
Mice
multidisciplinary
Myocytes, Cardiac
Myocytes, Cardiac - cytology
Myocytes, Cardiac - metabolism
Polymorphism, Single Nucleotide
Q
Regulatory sequences
Regulatory Sequences, Nucleic Acid
Regulatory Sequences, Nucleic Acid - genetics
Science
Science (multidisciplinary)
Transcription
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:Disease-associated genetic variants that lie in non-coding regions found by genome-wide association studies are thought to alter the functionality of transcription regulatory elements and target gene expression. To uncover causal genetic variants, variant regulatory elements and their target genes, here we cross-reference human transcriptomic, epigenomic and chromatin conformation datasets. Of 104 genetic variant regions associated with atrial fibrillation candidate target genes are prioritized. We optimize EMERGE enhancer prediction and use accessible chromatin profiles of human atrial cardiomyocytes to more accurately predict cardiac regulatory elements and identify hundreds of sub-threshold variants that co-localize with regulatory elements. Removal of mouse homologues of atrial fibrillation-associated regions in vivo uncovers a distal regulatory region involved in Gja1 (Cx43) expression. Our analyses provide a shortlist of genes likely affected by atrial fibrillation-associated variants and provide variant regulatory elements in each region that link genetic variation and target gene regulation, helping to focus future investigations. The majority of disease-associated genetic variants lie in non-coding regions. Here the authors generated and compiled human transcriptomic, epigenomic and chromatin conformation datasets, to identify genes associated with atrial fibrillation and functional non-coding variants.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-019-12721-5