Sequencing in over 120,000 cases unveils the rare coding variant architecture of atrial fibrillation

Abstract Background Atrial fibrillation (AF) is a common arrhythmia associated with heart failure, stroke and mortality. Large genomic studies have established an important heritable component to AF, providing an avenue for biological discovery and personalized medicine. We have previously shown that rare genetic variants in 7 genes confer a markedly elevated AF risk, with substantial impacts on disease course and prognosis. However, the number of AF-associated genes remain limited, and the contribution of rare coding variants to the heritability of AF remains unknown. Purpose We aimed to identify additional rare variants associated with AF, by extending sequencing-based association studies. We further aimed to estimate the contribution of known and unknown coding variation to AF heritability. Methods and results We performed a meta-analysis of exome and genome sequencing data from eight studies (UK Biobank, CCDG, MyCode, TOPMed, AllofUs, MGB, DECLARE and FOURIER), totaling 123,106 AF cases and 861,115 referents. We performed gene-based burden testing of rare (MAF0.1%) and low-frequency (MAF1%) variants, which were combined using 60 different masking strategies that include combinations of protein-truncating variants (PTV) and missense variants. In this approach, we identified 15 genes significantly associated with AF, including 8 genes previously identified through rare variant burden testing (TTN, LMNA, RPL3L, MYBPC3, KDM5B, PKP2, CTNNA3, ENTREP1) and 7 novel genes (ACTC1, PLEC, RBM20, SCN5A, ZFP36L2, FNIP1, FBN1) (Figure 1a). Most novel signals were driven by rare PTVs, except for SCN5A and ACTC1, which saw important contributions from missense variants (Figure 1b). In contrast to all other genes, SCN5A variants were associated with protection against AF, consistent with the efficacy of sodium channel blockers in treating the arrhythmia. Notably, ZFP36L2, FNIP1 and FBN1 represented genes not directly linked to AF biology in previous literature. We next estimated the contribution of rare coding variants to AF susceptibility, using burden-score-regression within two population-based cohorts (UK Biobank and AllofUs). The burden heritability from rare PTVs was approximately 2% among individuals of European genetic ancestry (UK Biobank: 1.7%±0.4%, P=2x10-5; AllofUs: 3.6%±1.6%, P=0.024), with concordant findings among individuals with African genetic ancestry (AllofUs: 5.0%±2.1%, P=0.017). Approximately 20% of burden heritability could be explained by the 15 significant genes, of which half (10%) was solely attributable to TTN. Conclusions In one of the largest sequencing studies of a common human disease to date, we identified rare coding variant associations for AF across 15 genes. Several of these genes represent promising novel targets for functional follow-up. Across the genome, rare PTVs confer a small but significant impact on population-wide AF susceptibility, driven largely by yet undiscovered genes.