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Original Investigation
December 11, 2018

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

Seung Hoan Choi, PhD1; Lu-Chen Weng, PhD1,2; Carolina Roselli, MSc1; et al Honghuang Lin, PhD3,4; Christopher M. Haggerty, PhD5; M. Benjamin Shoemaker, MD, MSCI6; John Barnard, PhD7; Dan E. Arking, PhD8; Daniel I. Chasman, PhD1,9; Christine M. Albert, MD, MPH10; Mark Chaffin, MSc1; Nathan R. Tucker, PhD1,2; Jonathan D. Smith, PhD11; Namrata Gupta, PhD1; Stacey Gabriel, PhD1; Lauren Margolin, MS1; Marisa A. Shea, RN2; Christian M. Shaffer, BS6; Zachary T. Yoneda, MD6; Eric Boerwinkle, PhD12; Nicholas L. Smith, PhD13; Edwin K. Silverman, MD, PhD14; Susan Redline, MD, MPH15; Ramachandran S. Vasan, MD3; Esteban G. Burchard, MD, MPH16; Stephanie M. Gogarten, PhD17; Cecelia Laurie, PhD17; Thomas W. Blackwell, PhD18; Gonçalo Abecasis, PhD18; David J. Carey, PhD19; Brandon K. Fornwalt, MD, PhD5; Diane T. Smelser, PhD19; Aris Baras, MD20; Frederick E. Dewey, MD20; Cashell E. Jaquish, PhD21; George J. Papanicolaou, PhD21; Nona Sotoodehnia, MD, MPH22; David R. Van Wagoner, PhD23; Bruce M. Psaty, MD, PhD13,22,24,25; Sekar Kathiresan, MD1; Dawood Darbar, MD26; Alvaro Alonso, MD, PhD27; Susan R. Heckbert, MD, PhD13,24; Mina K. Chung, MD28; Dan M. Roden, MD6; Emelia J. Benjamin, MD, ScM3,29,30; Michael F. Murray, MD31; Kathryn L. Lunetta, PhD3,32; Steven A. Lubitz, MD, MPH1,2,33; Patrick T. Ellinor, MD, PhD1,2,33; For the DiscovEHR study and the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Author Affiliations
  • 1Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
  • 2Cardiovascular Research Center, Massachusetts General Hospital, Boston
  • 3National Heart, Lung, and Blood Institute and Boston University’s Framingham Heart Study, Framingham, Massachusetts
  • 4Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
  • 5Department of Imaging Science and Innovation, Geisinger, Danville, Pennsylvania
  • 6Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee
  • 7Departments of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio
  • 8McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 9Divisions of Preventive Medicine and Genetics, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 10Divisions of Preventive and Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 11Departments of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio
  • 12Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston
  • 13Department of Epidemiology and Cardiovascular Health Research Unit, University of Washington, Seattle
  • 14Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 15Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital, Boston, Massachusetts
  • 16Department of Bioengineering, School of Pharmacy, University of California, San Francisco
  • 17Department of Biostatistics, University of Washington, Seattle
  • 18Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor
  • 19Department of Molecular and Functional Genomics, Geisinger, Danville, Pennsylvania
  • 20Regeneron Genetics Center, Tarrytown, New York
  • 21Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
  • 22Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle
  • 23Departments of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio
  • 24Kaiser Permanente Washington Health Research Institute, Seattle, Washington
  • 25Department of Health Services, University of Washington, Seattle
  • 26Division of Cardiology, Department of Medicine, University of Illinois, Chicago
  • 27Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
  • 28Departments of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
  • 29Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
  • 30Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
  • 31Genomic Medicine Institute, Geisinger, Danville, Pennsylvania
  • 32Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
  • 33Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston
JAMA. 2018;320(22):2354-2364. doi:10.1001/jama.2018.18179
Key Points

Question  Are there associations between genetic variants in titin (TTN), the gene which encodes the sarcomeric protein titin, and early-onset atrial fibrillation?

Findings  In this case-control study that included 2781 participants with early-onset atrial fibrillation and 4959 controls, there was a statistically significant association between loss-of-function variants in TTN and atrial fibrillation (odds ratio, 1.76 [95% CI, 1.04-2.97]), with variants present in 2.1% of case participants and 1.1% of controls.

Meaning  Loss-of-function mutations in the TTN gene were associated with early-onset atrial fibrillation among some patients, but further research is needed to understand whether the relationship is causal.


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 <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 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.