A Missense Variant in PLEC Increases Risk of Atrial Fibrillation

Genome-wide association studies (GWAS) have yielded variants at >30 loci that associate with atrial fibrillation (AF), including rare coding mutations in the sarcomere genes MYH6 and MYL4. The aim of this study was to search for novel AF associations and in doing so gain insights into the mechani...

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Bibliographic Details
Published in:Journal of the American College of Cardiology 2017-10, Vol.70 (17), p.2157-2168
Main Authors: Thorolfsdottir, Rosa B., Sveinbjornsson, Gardar, Sulem, Patrick, Helgadottir, Anna, Gretarsdottir, Solveig, Benonisdottir, Stefania, Magnusdottir, Audur, Davidsson, Olafur B., Rajamani, Sridharan, Roden, Dan M., Darbar, Dawood, Pedersen, Terje R., Sabatine, Marc S., Jonsdottir, Ingileif, Arnar, David O., Thorsteinsdottir, Unnur, Gudbjartsson, Daniel F., Holm, Hilma, Stefansson, Kari
Format: Article
Language:English
Subjects:
arrhythmia
atrial fibrillation
Atrial Fibrillation - genetics
Atrial Fibrillation - physiopathology
Audio frequencies
Cardiac arrhythmia
Cardiology
Cardiomyopathy
Chinchilla
Conduction
Crosslinking
Cytoskeleton
Disease
EKG
electrocardiogram
Electrocardiography
Fibrillation
Gene frequency
Genes
Genetics
Genome-Wide Association Study
Genomes
Genomic Structural Variation
Heart
Heart diseases
Hospitals
Humans
Measurement methods
Muscular dystrophy
Mutation
Mutation, Missense - genetics
Myosin Light Chains - genetics
Nucleotide sequence
Pathogenesis
plectin
Plectin - genetics
Risk
Sarcomeres
Sinuses
Stroke
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Summary:Genome-wide association studies (GWAS) have yielded variants at >30 loci that associate with atrial fibrillation (AF), including rare coding mutations in the sarcomere genes MYH6 and MYL4. The aim of this study was to search for novel AF associations and in doing so gain insights into the mechanisms whereby variants affect AF risk, using electrocardiogram (ECG) measurements. The authors performed a GWAS of 14,255 AF cases and 374,939 controls, using whole-genome sequence data from the Icelandic population, and tested novel signals in 2,002 non-Icelandic cases and 12,324 controls. They then tested the AF variants for effect on cardiac electrical function by using measurements in 289,297 ECGs from 62,974 individuals. The authors discovered 2 novel AF variants, the intergenic variant rs72700114, between the genes LINC01142 and METTL11B (risk allele frequency = 8.1%; odds ratio [OR]: 1.26; p = 3.1 × 10−18), and the missense variant p.Gly4098Ser in PLEC (frequency = 1.2%; OR: 1.55; p = 8.0 × 10−10), encoding plectin, a cytoskeletal cross-linking protein that contributes to integrity of cardiac tissue. The authors also confirmed 29 reported variants. p.Gly4098Ser in PLEC significantly affects various ECG measurements in the absence of AF. Other AF variants have diverse effects on the conduction system, ranging from none to extensive. The discovery of a missense variant in PLEC affecting AF combined with recent discoveries of variants in the sarcomere genes MYH6 and MYL4 points to an important role of myocardial structure in the pathogenesis of the disease. The diverse associations between AF variants and ECG measurements suggest fundamentally different categories of mechanisms contributing to the development of AF. [Display omitted]
ISSN:0735-1097
1558-3597
DOI:10.1016/j.jacc.2017.09.005