TY - JOUR
T1 - Association between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation
AU - Choi, Seung Hoan
AU - Weng, Lu Chen
AU - Roselli, Carolina
AU - Lin, Honghuang
AU - Haggerty, Christopher M.
AU - Shoemaker, M. Benjamin
AU - Barnard, John
AU - Arking, Dan E.
AU - Chasman, Daniel I.
AU - Albert, Christine M.
AU - Chaffin, Mark
AU - Tucker, Nathan R.
AU - Smith, Jonathan D.
AU - Gupta, Namrata
AU - Gabriel, Stacey
AU - Margolin, Lauren
AU - Shea, Marisa A.
AU - Shaffer, Christian M.
AU - Yoneda, Zachary T.
AU - Boerwinkle, Eric
AU - Smith, Nicholas L.
AU - Silverman, Edwin K.
AU - Redline, Susan
AU - Vasan, Ramachandran S.
AU - Burchard, Esteban G.
AU - Gogarten, Stephanie M.
AU - Laurie, Cecelia
AU - Blackwell, Thomas W.
AU - Abecasis, Gonçalo
AU - Carey, David J.
AU - Fornwalt, Brandon K.
AU - Smelser, Diane T.
AU - Baras, Aris
AU - Dewey, Frederick E.
AU - Jaquish, Cashell E.
AU - Papanicolaou, George J.
AU - Sotoodehnia, Nona
AU - Van Wagoner, David R.
AU - Psaty, Bruce M.
AU - Kathiresan, Sekar
AU - Darbar, Dawood
AU - Alonso, Alvaro
AU - Heckbert, Susan R.
AU - Chung, Mina K.
AU - Roden, Dan M.
AU - Benjamin, Emelia J.
AU - Murray, Michael F.
AU - Lunetta, Kathryn L.
AU - Lubitz, Steven A.
AU - Ellinor, Patrick T.
N1 - Publisher Copyright:
© 2018 American Medical Association. All rights reserved.
PY - 2018/12/11
Y1 - 2018/12/11
N2 - 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 18526 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 (346546 participants) and the MyCode Study (42782 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 <66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10 -3 . 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 41200 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.
AB - 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 18526 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 (346546 participants) and the MyCode Study (42782 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 <66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10 -3 . 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 41200 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.
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U2 - 10.1001/jama.2018.18179
DO - 10.1001/jama.2018.18179
M3 - Article
C2 - 30535219
AN - SCOPUS:85058607309
SN - 0098-7484
VL - 320
SP - 2354
EP - 2364
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 22
ER -