Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

IMPORTANCE: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. OBJECTIVE: To perform large-scale whole-genome sequencing to identify ge...

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Published in:JAMA : the journal of the American Medical Association 2018-12, Vol.320 (22), p.2354-2364
Main Authors: Choi, Seung Hoan, Weng, Lu-Chen, Roselli, Carolina, Lin, Honghuang, Haggerty, Christopher M, Shoemaker, M. Benjamin, Barnard, John, Arking, Dan E, Chasman, Daniel I, Albert, Christine M, Chaffin, Mark, Tucker, Nathan R, Smith, Jonathan D, Gupta, Namrata, Gabriel, Stacey, Margolin, Lauren, Shea, Marisa A, Shaffer, Christian M, Yoneda, Zachary T, Boerwinkle, Eric, Smith, Nicholas L, Silverman, Edwin K, Redline, Susan, Vasan, Ramachandran S, Burchard, Esteban G, Gogarten, Stephanie M, Laurie, Cecelia, Blackwell, Thomas W, Abecasis, Gonçalo, Carey, David J, Fornwalt, Brandon K, Smelser, Diane T, Baras, Aris, Dewey, Frederick E, Jaquish, Cashell E, Papanicolaou, George J, Sotoodehnia, Nona, Van Wagoner, David R, Psaty, Bruce M, Kathiresan, Sekar, Darbar, Dawood, Alonso, Alvaro, Heckbert, Susan R, Chung, Mina K, Roden, Dan M, Benjamin, Emelia J, Murray, Michael F, Lunetta, Kathryn L, Lubitz, Steven A, Ellinor, Patrick T
Format: Article
Language:English
Subjects:
Adult
Age
Age of Onset
Arrhythmia
Atrial Fibrillation - genetics
Cardiac arrhythmia
Case-Control Studies
Connectin
Connectin - genetics
Correlation analysis
Female
Fibrillation
Gene sequencing
Genetic diversity
Genetic Predisposition to Disease
Genetic variance
Genome-Wide Association Study
Genomes
Heart
Heterozygote
Humans
Loss of Function Mutation
Lungs
Male
Middle Aged
Patients
Precision medicine
Proteins
Quality Control
Statistical analysis
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Summary:IMPORTANCE: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. OBJECTIVE: To perform large-scale whole-genome sequencing to identify genetic variants related to AF. DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants). EXPOSURES: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. MAIN OUTCOMES AND MEASURES: Early-onset AF (defined as AF onset in persons
ISSN:0098-7484
1538-3598
1538-3598
DOI:10.1001/jama.2018.18179