Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation
Authors: Seung Hoan Choi, Lu-Chen Weng, Carolina Roselli, Honghuang Lin, Christopher M. Haggerty, M. Benjamin Shoemaker, John Barnard, Dan E. Arking, Daniel I. Chasman, Christine M. Albert, Mark Chaffin, Nathan R. Tucker, Jonathan D. Smith, Namrata Gupta, Stacey Gabriel, Lauren Margolin, Marisa A. Shea, Christian M. Shaffer, Zachary T. Yoneda, Eric Boerwinkle, Nicholas L. Smith, Edwin K. Silverman, Susan Redline, Ramachandran S. Vasan, Esteban G. Burchard, Stephanie M. Gogarten, Cecelia Laurie, Thomas W. Blackwell, Gonçalo Abecasis, David J. Carey, Brandon K. Fornwalt, Diane T. Smelser, Aris Baras, Frederick E. Dewey, Cashell E. Jaquish, George J. Papanicolaou, Nona Sotoodehnia, David R. Van Wagoner, Bruce M. Psaty, Sekar Kathiresan, Dawood Darbar, Alvaro Alonso, Susan R. Heckbert, Mina K. Chung, Dan M. Roden, Emelia J. Benjamin, Michael F. Murray, Kathryn L. Lunetta, Steven A. Lubitz, Patrick T. Ellinor
Journal: JAMA (2018)

<h3>Importance</h3> 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. <h3>Objective</h3> To perform large-scale whole-genome sequencing to identify genetic variants related to AF. <h3>Design, Setting, and Participants</h3> 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). <h3>Exposures</h3> Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. <h3>Main Outcomes and Measures</h3> Early-onset AF (defined as AF onset in persons &lt;66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was<i>P</i> = 4.55 × 10<sup>−3</sup>. <h3>Results</h3> 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<i>TTN</i>, 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<i>TTN</i>increased with an earlier age of AF onset (<i>P</i>value for trend, 4.92 × 10<sup>−4</sup>), and 6.5% of individuals with AF onset prior to age 30 carried a<i>TTN</i>LOF variant (OR, 5.94 [95% CI, 2.64-13.35];<i>P</i> = 1.65 × 10<sup>−5</sup>). The association between<i>TTN</i>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];<i>P</i> = .01). <h3>Conclusions and Relevance</h3> In a case-control study, there was a statistically significant association between an LOF variant in the<i>TTN</i>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.