Atrial fibrillation variant-to-gene prioritization through cross-ancestry eQTL and single-nucleus multiomic analyses

Atrial fibrillation (AF) is the most common arrhythmia in the world, and is linked to significant morbidity and mortality. Despite advances in the treatment and management of AF, important challenges remain for patients. Human genetics can provide strong therapeutic candidates, but the identification of the causal genes and their functions is difficult. Here, we apply an AF fine-mapping strategy that leverages results from a cross-ancestry genome-wide association study (GWAS), expression quantitative trait loci (eQTLs) from left atrial appendages (LAA) obtained from two cohorts with distinct ancestry (European and East Asian), and a paired RNAseq and ATACseq LAA single-nucleus assay (sn-multiome). We found that AF-associated LAA eQTLs are largely consistent across ancestries. At ten AF loci, our co-localization and fine-mapping analyses implicated 14 genes. Furthermore, by integrating our LAA sn-multiome data and other epigenomic datasets with our fine-mapping results, we identified four primary candidate causal AF variants, including rs7612445 at GNB4 and rs242557 at MAPT, for which we propose molecular mechanisms of AF-association at the cellular level. Finally, we showed that the repression of the strongest AF-associated eQTL gene, LINC01629, in human embryonic stem cell-derived cardiomyocytes using CRISPR inhibition results in the dysregulation of pathways linked to genes involved in the development of atrial tissue and the cardiac conduction system (e.g. HCN4, PITX2 and TBX5).