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

TitleAssociation Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation.
Publication TypeJournal Article
Year of Publication2018
AuthorsChoi SHoan, Weng L-C, Roselli C, Lin H, Haggerty CM, M Shoemaker B, Barnard J, Arking DE, Chasman DI, Albert CM, Chaffin M, Tucker NR, Smith JD, Gupta N, Gabriel S, Margolin L, Shea MA, Shaffer CM, Yoneda ZT, Boerwinkle E, Smith NL, Silverman EK, Redline S, Vasan RS, Burchard EG, Gogarten SM, Laurie C, Blackwell TW, Abecasis G, Carey DJ, Fornwalt BK, Smelser DT, Baras A, Dewey FE, Jaquish CE, Papanicolaou GJ, Sotoodehnia N, Van Wagoner DR, Psaty BM, Kathiresan S, Darbar D, Alonso A, Heckbert SR, Chung MK, Roden DM, Benjamin EJ, Murray MF, Lunetta KL, Lubitz SA
Secondary AuthorsEllinor PT
Corporate AuthorsDiscovEHR study and the NHLBI Trans-Omics for Precision Medicine(TOPMed) Consortium
JournalJAMA
Volume320
Issue22
Pagination2354-2364
Date Published2018 12 11
ISSN1538-3598
KeywordsAdult, Age of Onset, Atrial Fibrillation, Case-Control Studies, Connectin, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Humans, Loss of Function Mutation, Male, Middle Aged, Quality Control
Abstract

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

Results: Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10-4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10-5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41 200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01).

Conclusions and Relevance: In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship.

DOI10.1001/jama.2018.18179
Alternate JournalJAMA
PubMed ID30535219
PubMed Central IDPMC6436530
Grant ListR01 HL095080 / HL / NHLBI NIH HHS / United States
R01 HL139731 / HL / NHLBI NIH HHS / United States
R01 HL138737 / HL / NHLBI NIH HHS / United States
R01 HL128914 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R35 HL135818 / HL / NHLBI NIH HHS / United States
R01 HL116690 / HL / NHLBI NIH HHS / United States
T32 HL139439 / HL / NHLBI NIH HHS / United States
UL1 RR024975 / RR / NCRR NIH HHS / United States
MC_PC_17228 / MRC_ / Medical Research Council / United Kingdom
R01 HL073410 / HL / NHLBI NIH HHS / United States
K23 HL114724 / HL / NHLBI NIH HHS / United States
R01 HL127659 / HL / NHLBI NIH HHS / United States
K24 HL105780 / HL / NHLBI NIH HHS / United States
R01 HL092217 / HL / NHLBI NIH HHS / United States
R01 HL092577 / HL / NHLBI NIH HHS / United States
MC_QA137853 / MRC_ / Medical Research Council / United Kingdom
R01 HL068986 / HL / NHLBI NIH HHS / United States
R01 HL085251 / HL / NHLBI NIH HHS / United States
U19 HL065962 / HL / NHLBI NIH HHS / United States
16EIA26410001 / AHA / American Heart Association-American Stroke Association / United States
R01 HL113338 / HL / NHLBI NIH HHS / United States
K01 HL140187 / HL / NHLBI NIH HHS / United States
R01 HL089856 / HL / NHLBI NIH HHS / United States
R21 HL093613 / HL / NHLBI NIH HHS / United States
R01 HL111314 / HL / NHLBI NIH HHS / United States