Atrial fibrillation: pathophysiology, genetic and epigenetic mechanisms

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis - and trans - expression quantitative trait locus (eQTL) analyses, using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis -eQTLs for 88% of genes, and these were replicable in numerous tissues. Distal trans -eQTLs (detected for 37% out of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell-type-composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans -eQTLs. Trans -eQTLs exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores (PGS) for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource and its results serve as a starting point for in-depth interpretation of complex phenotypes. Show more

Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF. Show more