Choi SH, et al. - In this case-control study involving 2781 participants, researchers conducted large-scale whole-genome sequencing to identify genetic variants in titin (TTN), the gene which encodes the sarcomeric protein titin, related to atrial fibrillation (AF), most common arrhythmia affecting 1% of the population. A statistically significant association was found between a loss-of-function (LOF) variant in the TTN gene and early-onset AF (defined as AF onset in persons <66 years of age), with the variant present in a small percentage of participants with early-onset AF.

Methods

• The National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that have undergone high-depth whole-genome sequencing in 18,526 people from the US, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa between 2014 and 2017.
• Study participants included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants.
• The UK Biobank (346,546 participants) and the MyCode Study (42,782 participants) replicated the results..
• Exposures included LOF variants in genes at AF loci and common genetic variation across the whole genome.
• Main outcome and measure included early-onset AF.
• The significance threshold for the rare variant analysis was P=4.55 × 10^-3 due to multiple testing.

Results

• Of the 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.
• The participants were sequenced in whole-genome at a mean depth of 37.8 fold and mean genome coverage of 99.1%.
• At least 1 LOF variant in TTN, the sarcomeric protein titin encoding gene, was present in 2.1% of case participants vs 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]).
• The proportion of people with early-onset AF who had 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 people 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 of TTN LOF variants with AF was replicated in an independent study involving 1582 patients with early-onset AF (cases) and 41,200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P=.01).